leptin and Hypoxia

Chronic intermittent hypoxia (CIH) occurs frequently in premature infants who have apnea of prematurity. Immaturity of the respiratory network from low central respiratory drive and the greater contribution of the carotid body on baseline breathing leads to respiratory instability in premature infants presenting as apnea and periodic breathing. During the 2nd week after birth, the smallest and the youngest premature infants have increased frequency of apnea and periodic breathing and associated oxygen desaturations that can persist for weeks after birth. CIH increases the production of reactive oxygen species that causes tissue damage. Premature infants have decreased capacity to scavenge reactive oxygen species. Oxidative injury is the cause of many of the co-morbidities that are seen in premature infants. In this review we discuss who low fat mass and the resulting relative deficiencies in leptin and adiponectin could contribute to the increase frequency of oxygen desaturations that occurs days after birth in the smallest and youngest premature infants. Leptin is a central respiratory stimulant and adiponectin protects the lung from vascular leak, oxidative injury and vascular remodeling.

Topics: Adiponectin; Animals; Humans; Hypoxia; Infant; Infant, Premature; Leptin; Metabolism, Inborn Errors

Obesity-related sleep breathing disorders such as obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) cause intermittent hypoxia (IH) during sleep, a powerful trigger of oxidative stress. Obesity also leads to dramatic increases in circulating levels of leptin, a hormone produced in adipose tissue. Leptin acts in the hypothalamus to suppress food intake and increase metabolic rate. However, obese individuals are resistant to metabolic effects of leptin. Leptin also activates the sympathetic nervous system without any evidence of resistance, possibly because these effects occur peripherally without a need to penetrate the blood-brain barrier. IH is a potent stimulator of leptin expression and release from adipose tissue. Hyperleptinemia and leptin resistance may upregulate generation of reactive oxygen species, increasing oxidative stress and promoting inflammation. The current review summarizes recent data on a possible link between leptin and oxidative stress in the pathogenesis of sleep breathing disorders.

Topics: Humans; Hypoxia; Leptin; Obesity; Oxidative Stress; Sleep Apnea, Obstructive

Endometriosis is one of the most common gynecological diseases that significantly reduce the life quality of affected women. Research results from the past decade clearly demonstrated that aberrant production of estrogen and cyclooxygenase-2-derived prostaglandin E2 play indispensable roles in the pathogenesis of this disease. However, the etiology of endometriosis remains obscure. Recent evidence reveals a new facet of endometriotic pathogenesis by showing that hypoxia induces the expression of many important downstream genes to regulate the implantation, survival, and maintenance of ectopic endometriotic lesions. These new findings shed lights on future investigations of delineating the etiology of endometriosis and designing new therapeutic strategy for endometriosis.

Topics: Cyclooxygenase 2; Endometriosis; Estrogens; Female; Humans; Hypoxia; Leptin; Neovascularization, Pathologic; Prostaglandins

Preeclampsia is a syndrome occurring only in pregnancy characterized by systemic maternal inflammation and associated with the presence of the placenta. How these 2 aspects of the disease are linked has been the subject of numerous theories and ideas. Recently, there has been increasing interest in DNA shed from the placenta into the maternal circulation as a potential agent initiating the inflammatory response. This review will discuss the current evidence and future directions for placental DNA as the linking factor in preeclampsia in the context of other hypotheses.

Topics: Cell-Derived Microparticles; Cytokines; DNA; Female; Humans; Hypoxia; Leptin; Placenta; Pre-Eclampsia; Pregnancy; Systemic Inflammatory Response Syndrome; Trophoblasts; Vascular Endothelial Growth Factor Receptor-1

To summarize recent primary publications and discuss the impact these finding have on current understanding on the development of hypoventilation in obesity hypoventilation syndrome (OHS), also known as Pickwickian syndrome.. As a result of the significant morbidity and mortality associated with OHS, evidence is building for pre-OHS intermediate states that can be identified earlier and treated sooner, with the goal of modifying disease course. Findings of alterations in respiratory mechanics with obesity remain unchanged; however, elevated metabolism and CO2 production may be instrumental in OHS-related hypercapnia. Ongoing positive airway pressure trials continue to demonstrate that correction of nocturnal obstructive sleep apnea and hypoventilation improves diurnal respiratory physiology, metabolic profiles, quality of life, and morbidity/mortality. Finally, CNS effects of leptin on respiratory mechanics and chemoreceptor sensitivity are becoming better understood; however, characterization remains incomplete.. OHS is a complex multiorgan system disease process that appears to be driven by adaptive changes in respiratory physiology and compensatory changes in metabolic processes, both of which are ultimately counter-productive. The diurnal hypercapnia and hypoxia induce pathologic effects that further worsen sleep-related breathing, resulting in a slowly progressive worsening of disease. In addition, leptin resistance in obesity and OHS likely contributes to blunting of ventilatory drive and inadequate chemoreceptor response to hypercarbia and hypoxemia.

Topics: Animals; Humans; Hypoxia; Leptin; Metabolic Syndrome; Obesity Hypoventilation Syndrome; Quality of Life; Sleep Apnea, Obstructive

The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.

Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Cachexia; Cytokines; Ghrelin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Inflammation; Interleukin-6; Leptin; Myostatin; Neoplasm Metastasis; Neoplasms; Prognosis; Syndrome; Tumor Microenvironment; Tumor Necrosis Factor-alpha

In patients with chronic obstructive pulmonary disease (COPD), malnutrition and limited physical activity are very common and contribute to disease prognosis, whereas a balance between caloric intake and exercise allows body weight stability and muscle mass preservation. The goal of this review is to analyze the implications of chronic hypoxia on three key elements involved in energy homeostasis and its role in COPD cachexia. The first one is energy intake. Body weight loss, often observed in patients with COPD, is related to lack of appetite. Inflammatory cytokines are known to be involved in anorexia and to be correlated to arterial partial pressure of oxygen. Recent studies in animals have investigated the role of hypoxia in peptides involved in food consumption such as leptin, ghrelin, and adenosine monophosphate activated protein kinase. The second element is muscle function, which is strongly related to energy use. In COPD, muscle atrophy and muscle fiber shift to the glycolytic type might be an adaptation to chronic hypoxia to preserve the muscle from oxidative stress. Muscle atrophy could be the result of a marked activation of the ubiquitin-proteasome pathway as found in muscle of patients with COPD. Hypoxia, via hypoxia inducible factor-1, is implicated in mitochondrial biogenesis and autophagy. Third, hormonal control of energy balance seems to be affected in patients with COPD. Insulin resistance has been described in this group of patients as well as a sort of "growth hormone resistance." Hypoxia, by hypoxia inducible factor-1, accelerates the degradation of tri-iodothyronine and thyroxine, decreasing cellular oxygen consumption, suggesting an adaptive mechanism rather than a primary cause of COPD cachexia. COPD rehabilitation aimed at maintaining function and quality of life needs to address body weight stabilization and, in particular, muscle mass preservation.

Topics: Anorexia; Appetite; Cachexia; Cytokines; Energy Intake; Energy Metabolism; Exercise; Ghrelin; Human Growth Hormone; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin; Malnutrition; Muscular Atrophy; Nutritional Status; Oxygen; Pulmonary Disease, Chronic Obstructive

Obstructive sleep apnea syndrome (OSAS) is an often underestimated sleep disorder that has been associated with cardiovascular disease. OSAS is characterized by cycles of apnea and/or hypopnea during sleep caused by the collapse of the upper airways. Intermittent hypoxia deriving from the cycles of apnea/arousals (to retrieve the ventilation) plays a pivotal role in the pathogenesis of the disease. Obesity is the most frequent predisposing condition of OSAS. Recent evidence suggests that OSAS could be considered as a pro-atherosclerotic disease, independently of visceral fat amount. Oxidative stress, cardiovascular inflammation, endothelial dysfunction, and metabolic abnormalities in OSAS could accelerate atherogenesis. The present review is focused on the possible pathophysiological mediators which could favor atherosclerosis in OSAS.

Topics: Atherosclerosis; Cytokines; Disease Progression; Humans; Hypoxia; Inflammation; Leptin; Oxidative Stress; Platelet Aggregation; Risk Factors; Sleep Apnea, Obstructive

In several investigations on mountaineers under moderate hypoxia, at altitudes between 2,500 m and 4,500 m, weight loss occurs, fat levels in the serum and insulin resistance (in diabetic mountaineers) are reduced. Animal studies with different time dosage regimens of hypoxia in animal cages revealed different and partly confusing results regarding fat metabolism under hypoxia.. Hypothesis for the change in glucose and fat metabolism include a HIF promoted higher leptin rate under hypoxia and an increased glucose transport in peripheral organs.. This short review discusses some of the different investigations in this topic. In a second part it is shown how studies of metabolism in yeast cells with an upregulated glycolysis in the cell itself under hypoxic conditions could help to better understand metabolic changes under hypoxia.

Topics: Adaptation, Physiological; Blood Glucose; Energy Metabolism; Glycolysis; Humans; Hypoxia; Insulin Resistance; Leptin; Lipids; Models, Biological; Up-Regulation; Weight Loss; Yeasts

Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.

Topics: Adiponectin; Adipose Tissue; Animals; Humans; Hypoxia; Inflammation; Insulin Resistance; Leptin; Mice; Neovascularization, Physiologic; Obesity; Signal Transduction

Topics: Acclimatization; Altitude; Animals; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lagomorpha; Leptin; Myoglobin

Since first cloned and reported by Zhang et al in 1994 (Nature 372:425), the obese gene and its product-leptin has been studied profoundly. Our knowledge in body weight regulation and the role played by leptin has increased substantially. Leptin serves as an adiposity signal to inform the brain of the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Many articles have reported weight loss at high altitude, but the explanation has been limited to loss of appetite. New ideas were highlighted after studies by Grosfeld et al and Ambrosini et al on the obese gene under hypoxia condition. Cells with hypoxia treatment upregulated obese gene transcription and suggested that enhancement of leptin secretion in vivo under hypoxia environment may be one of the potential therapeutic methods for obesity treatment.

Topics: Body Weight; Humans; Hypoxia; Leptin

There is clear evidence of placental leptin production, as shown recently in trophoblast cultures and by dual in vitro placenta perfusion (median production of 225 pg/min per g of tissue; 98.4% released into the maternal and 1.6% into the fetal circulation). However, the physiological impact for the mother and the fetus is unclear. The classical role of leptin is to provide information about energy stores to the central nervous system, and to reduce appetite if the energy stores are full. In pregnancy, maternal plasma leptin concentrations are elevated, and lack the well established correlation with body fat energy stores that is observed in non-pregnant women, indicating an alternative function for leptin during pregnancy and fetal development. Maternal and fetal plasma leptin levels are dysregulated in pathological conditions such as gestational diabetes, pre-eclampsia and intra-uterine growth retardation, representing an effect or a cause of disturbances in the feto/placento/maternal unit.

Topics: Female; Fetal Blood; Fetal Growth Retardation; Fetus; Humans; Hypoxia; Leptin; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications

Severe hypoxia has been indicated to cause acute changes in appetite-related hormones, which attenuate perceived appetite. However, the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite have not been elucidated. Therefore, we examined the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite. Eight healthy males (21.0 ± 0.6 years; 173 ± 2.3 cm; 70.6 ± 5.0 kg; 23.4 ± 1.1 kg/m(2)) completed two experimental trials on separate days: a rest trial in normoxia (FiO2 = 20.9%) and a rest trial in hypoxia (FiO2 = 15.0%). The experimental trials were performed over 7 h in an environmental chamber. Blood samples and scores of subjective appetite were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after initiating exposure to hypoxia or normoxia within the chamber. Although each meal significantly reduced plasma active ghrelin concentrations (P < 0.05), the response did not differ significantly between the trials over 7 h. No significant differences in the area under the curves for plasma active ghrelin concentrations over 7 h were observed between the two trials. No significant differences were observed in glucagon-like peptide 1 or leptin concentrations over 7 h between the trials. The subjective feeling of hunger and fullness acutely changed in response to meal ingestions. However, these responses were not affected by exposure to moderate hypoxia. In conclusion, 7 h of exposure to moderate hypoxia did not change appetite-related hormonal responses or perceived appetite in healthy males.

Topics: Adult; Appetite; Appetite Regulation; Body Mass Index; Body Weight; Cross-Over Studies; Energy Intake; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypoxia; Leptin; Male; Postprandial Period; Young Adult

Environmental hypoxia and inactivity have both been shown to modulate appetite. To elucidate the independent and combined effects of hypoxia and bed rest-induced inactivity on appetite-related hormones and subjective appetite, eleven healthy, non-obese males underwent three experimental interventions in a cross-over and randomized fashion: 1) Hypoxic confinement combined with daily moderate-intensity exercise (HAMB, F. NCT02293772.

Topics: Adult; Appetite; Appetite Regulation; Bed Rest; Cross-Over Studies; Diet; Exercise; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypoxia; Leptin; Male; Peptide YY; Postprandial Period; Young Adult

Hypoxic and hypobaric conditions may augment the beneficial influence of training on cardiovascular risk factors. This pilot study aimed to explore for effects of a two-week hiking vacation at moderate versus low altitude on adipokines and parameters of carbohydrate and lipid metabolism in patients with metabolic syndrome.. Fourteen subjects (mean age: 55.8 years, range: 39 - 69) with metabolic syndrome participated in a 2-week structured training program (3 hours of guided daily hiking 4 times a week, training intensity at 55-65% of individual maximal heart rate; total training time, 24 hours). Participants were divided for residence and training into two groups, one at moderate altitude (1,900 m; n = 8), and the other at low altitude (300 m; n = 6). Anthropometric, cardiovascular and metabolic parameters were measured before and after the training period.. In study participants, training overall reduced circulating levels of total cholesterol (p = 0.024), low-density lipoprotein cholesterol (p = 0.025) and adiponectin (p < 0.001). In the group training at moderate altitude (n = 8), lowering effects on circulating levels were significant not only for total cholesterol, low-density-lipoprotein cholesterol and adiponectin (all, p < 0.05) but also for triglycerides (p = 0.025) and leptin (p = 0.015), whereas in the low altitude group (n = 6), none of the lipid parameters was significantly changed (each p > 0.05). Hiking-induced relative changes of triglyceride levels were positively associated with reductions in leptin levels (p = 0.006). As compared to 300 m altitude, training at 1,900 m showed borderline significant differences in the pre-post mean reduction rates of triglyceride (p = 0.050) and leptin levels (p = 0.093).. Preliminary data on patients with metabolic syndrome suggest that a 2-week hiking vacation at moderate altitude may be more beneficial for adipokines and parameters of lipid metabolism than training at low altitude. In order to draw firm conclusions regarding better corrections of dyslipidemia and metabolic syndrome by physical exercise under mild hypobaric and hypoxic conditions, a sufficiently powered randomized clinical trial appears warranted.. ClinicalTrials.gov ID NCT02013947 (first received November 6, 2013).

Topics: Adiponectin; Adult; Aged; Altitude; Blood Pressure; Cholesterol; Exercise Therapy; Female; Heart Rate; Humans; Hypoxia; Insulin; Leptin; Lipoproteins, LDL; Male; Metabolic Syndrome; Middle Aged; Pilot Projects; Triglycerides; Walking

Strategies designed to reduce adiposity and cardiovascular-accompanying manifestations have been based on nutritional interventions conjointly with physical activity programs. The aim of this 13-week study was to investigate the putative benefits associated to hypoxia plus exercise on weight loss and relevant metabolic and cardiorespiratory variables, when prescribed to obese subjects with sleep apnea syndrome following dietary advice. The participants were randomly distributed in the following three groups: control, normoxia, and hypoxia. All the subjects received dietary advice while, additionally, normoxia group was trained under normal oxygen concentration and Hypoxia group under hypoxic conditions. There was a statistically significant decrease in fat-free mass (Kg) and water (%) on the control compared to normoxia group (p < 0.05 and p < 0.01, respectively). Body weight, body mass index, and waist circumference decreased in all the groups after the study. Moreover, leukocyte count was increased after the intervention in hypoxia compared to control group (p < 0.05). There were no statistically significant variations within groups in other variables, although changes in appetite were found after the 13-week period. In addition, associations between the variations in the leukocyte count and fat mass have been found. The hypoxia group showed some specific benefits concerning appetite and cardiometabolic-related measurements as exertion time and diastolic blood pressure, with a therapeutical potential.

Topics: Adiponectin; Adult; Biomarkers; Blood Pressure; C-Reactive Protein; Exercise Therapy; Humans; Hypoxia; Leptin; Lipids; Male; Middle Aged; Sleep Apnea, Obstructive; Treatment Outcome

The present study was conducted to determine change in regional fat accumulation and appetite-related hormonal response following hypoxic training. Twenty sedentary subjects underwent hypoxic (n = 9, HYPO, FiO(2) = 15%) or normoxic training (n = 11, NOR, FiO(2) = 20·9%) during a 4-week period (3 days per week). They performed a 4-week training at 55% of maximal oxygen uptake (V·O(2max)) for each condition. Before and after the training period, V·O(2max), whole body fat mass, abdominal fat area, intramyocellular lipid content (IMCL), fasting and postprandial appetite-related hormonal responses were determined. Both groups showed a significant increase in V·O(2max) following training (P<0·05). Whole body and segmental fat mass, abdominal fat area, IMCL did not change in either group. Fasting glucose and insulin concentrations significantly reduced in both groups (P<0·05). Although area under the curve for the postprandial blood glucose concentrations significantly decreased in both groups (P<0·05), the change was significantly greater in the HYPO group than in the NOR group (P<0·05). Changes in postprandial plasma ghrelin were similar in both groups. A significant reduction of postprandial leptin response was observed in both groups (P<0·05), while postprandial glucagon-like peptide-1 (GLP-1) concentrations increased significantly in the NOR group only (P<0·05). In conclusion, hypoxic training for 4 weeks resulted in greater improvement in glucose tolerance without loss of whole body fat mass, abdominal fat area or IMCL. However, hypoxic training did not have synergistic effect on the regulation of appetite-related hormones.

Topics: Abdominal Fat; Adiposity; Adult; Appetite; Biomarkers; Blood Glucose; Exercise; Fasting; Ghrelin; Glucagon-Like Peptide 1; Heart Rate; Humans; Hypoxia; Insulin; Japan; Leptin; Male; Oxygen Consumption; Peptide Hormones; Postprandial Period; Sedentary Behavior; Time Factors

Both exposure to hypoxia and exercise training have the potential to modulate appetite and induce beneficial metabolic adaptations. The purpose of this study was to determine whether daily moderate exercise training performed during a 10-day exposure to normobaric hypoxia alters hormonal appetite regulation and augments metabolic health.. Fourteen healthy, male participants underwent a 10-day hypoxic confinement at ∼ 4000 m simulated altitude (FIO2 = 0.139 ± 0.003%) either combined with daily moderate intensity exercise (Exercise group; N = 8, Age = 25.8 ± 2.4 yrs, BMI = 22.9 ± 1.2 kg · m(-2)) or without any exercise (Sedentary group; N = 6 Age = 24.8 ± 3.1 yrs, BMI = 22.3 ± 2.5 kg · m(-2)). A meal tolerance test was performed before (Pre) and after the confinement (Post) to quantify fasting and postp randial concentrations of selected appetite-related hormones and metabolic risk markers. 13C-Glucose was dissolved in the test meal and 13CO2 determined in breath samples. Perceived appetite ratings were obtained throughout the meal tolerance tests.. While body mass decreased in both groups (-1.4 kg; p = 0.01) following the confinement, whole body fat mass was only reduced in the Exercise group (-1.5 kg; p = 0.01). At Post, postprandial serum insulin was reduced in the Sedentary group (-49%; p = 0.01) and postprandial plasma glucose in the Exercise group (-19%; p = 0.03). Fasting serum total cholesterol levels were reduced (-12%; p = 0.01) at Post in the Exercise group only, secondary to low-density lipoprotein cholesterol reduction (-16%; p = 0.01). No differences between groups or testing periods were noted in fasting and/or postprandial concentrations of total ghrelin, peptide YY, and glucagon-like peptide-1, leptin, adiponectin, expired 13CO2 as well as perceived appetite ratings (p>0.05).. These findings suggest that performing daily moderate intensity exercise training during continuous hypoxic exposure does not alter hormonal appetite regulation but can improve the lipid profile in healthy young males.

Topics: Adiponectin; Adult; Altitude; Appetite Regulation; Blood Glucose; Cholesterol; Exercise; Ghrelin; Glucagon-Like Peptide 1; Hormones; Humans; Hypoxia; Insulin; Leptin; Lipoproteins, LDL; Male; Peptide YY; Young Adult

High altitude (HA) is a model of severe hypoxia exposure in humans. We hypothesized that nocturnal hypoxemia or acute maximal exercise at HA might affect plasma leptin and VEGF levels.. Plasma leptin, VEGF and other metabolic variables were studied after nocturnal pulse oximetry and after maximal exercise in healthy lowlanders on the 3rd-4th day of stay in Lobuche (5050 m, HA) and after return to sea level (SL).. Leptin was similar at SL or HA in both pre- and post-exercise conditions. Pre-exercise VEGF at HA was lower, and cortisol was higher, than at SL, suggesting that nocturnal intermittent hypoxia associated with periodic breathing at HA might affect these variables.. Leptin levels appear unaffected at HA, whereas nocturnal hypoxic stress may affect plasma VEGF. Future HA studies should investigate the possible role of nocturnal intermittent hypoxemia on metabolism.

Topics: Adult; Altitude; Exercise; Female; Healthy Volunteers; Humans; Hypoxia; Leptin; Male; Oxyhemoglobins; Vascular Endothelial Growth Factor A

To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men and 3 women; age, 26 +/- 2 years; body mass index, 23.1 +/- 1.0 kg/m(2)) performed 2 randomized trials in a hypobaric chamber where a 75-g glucose solution was ingested under simulated altitude (ALT, 4300 m) or ambient (AMB, 362 m) conditions. Plasma glucose, insulin, C-peptide, epinephrine, leptin, and lactate concentrations were measured at baseline and 30, 60, 90, and 120 minutes after glucose ingestion during both trials. Compared with AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial (P = .04). There were no differences in the insulin and C-peptide responses between trials or in insulin sensitivity based on the homeostasis model assessment of insulin resistance. Epinephrine and lactate were both elevated during the ALT trial (P < .05), whereas the plasma leptin response was reduced compared with AMB (P < .05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se because insulin and C-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT are indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that, during acute altitude exposure, there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.

Topics: Adult; Altitude; Blood Glucose; C-Peptide; Epinephrine; Female; Glucose; Humans; Hypoxia; Insulin; Insulin Resistance; Lactic Acid; Leptin; Male; Solutions

The reason for weight loss at high altitudes is largely unknown. To date, studies have been unable to differentiate between weight loss due to hypobaric hypoxia and that related to increased physical exercise. The aim of our study was to examine the effect of hypobaric hypoxia on body weight at high altitude in obese subjects. We investigated 20 male obese subjects (age 55.7 +/- 4.1 years, BMI 33.7 +/- 1.0 kg/m(2)). Body weight, waist circumference, basal metabolic rate (BMR), nutrition protocols, and objective activity parameters as well as metabolic and cardiovascular parameters, blood gas analysis, leptin, and ghrelin were determined at low altitude (LA) (Munich 530 m, D1), at the beginning and at the end of a 1-week stay at high altitude (2,650 m, D7 and D14) and 4 weeks after returning to LA (D42). Although daily pace counting remained stable at high altitude, at D14 and D42, participants weighed significantly less and had higher BMRs than at D1. Food intake was decreased at D7. Basal leptin levels increased significantly at high altitude despite the reduction in body weight. Diastolic blood pressure was significantly lower at D7, D14, and D42 compared to D1. This study shows that obese subjects lose weight at high altitudes. This may be due to a higher metabolic rate and reduced food intake. Interestingly, leptin levels rise in high altitude despite reduced body weight. Hypobaric hypoxia seems to play a major role, although the physiological mechanisms remain unclear. Weight loss at high altitudes was associated with clinically relevant improvements in diastolic blood pressure.

Topics: Altitude; Atmospheric Pressure; Basal Metabolism; Blood Pressure; Body Mass Index; Body Weight; Energy Intake; Exercise; Humans; Hypoxia; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Weight Loss

Altitude exposure may suppress appetite and hence provide a viable weight-loss strategy. While changes in food intake and availability as well as physical activity may contribute to altered appetite at altitude, herein we aimed to investigate the isolated effects of hypobaric hypoxia on appetite regulation and sensation. Twelve healthy women (age: 24.0 ± 4.2 years, body mass: 60.6 ± 7.0 kg) completed two 4-day sojourns in a hypobaric chamber, one in normoxia [P

Topics: Adult; Altitude; Appetite; Energy Intake; Female; Ghrelin; Humans; Hypoxia; Leptin; Sensation; Weight Loss; Young Adult

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

Topics: Adipose Tissue, White; Animals; Cachexia; Hypoxia; Leptin; Mice; MicroRNAs; Neoplasms

Topics: Animals; Blood Glucose; Carotid Body; Glucose; Hypoxia; Leptin; Male; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Solitary Nucleus

It is increasingly recognized that hypoxia may develop in adipose tissue as its mass expands. Adipose tissue is also the main reservoir of lipophilic pollutants, including polychlorinated biphenyls (PCBs). Both hypoxia and PCBs have been shown to alter adipose tissue functions. The signaling pathways induced by hypoxia and pollutants may crosstalk, as they share a common transcription factor: aryl hydrocarbon receptor nuclear translocator (ARNT). Whether hypoxia and PCBs crosstalk and affect adipokine secretion in human adipocytes remains to be explored. Using primary human adipocytes acutely co-exposed to different levels of hypoxia (24 h) and PCB126 (48 h), we observed that hypoxia significantly inhibits the PCB126 induction of cytochrome P450 (CYP1A1) transcription in a dose-response manner, and that Acriflavine (ACF)-an HIF1α inhibitor-partially restores the PCB126 induction of CYP1A1 under hypoxia. On the other hand, exposure to PCB126 did not affect the transcription of the vascular endothelial growth factor-A (VEGFA) under hypoxia. Exposure to hypoxia increased leptin and interleukin-6 (IL-6), and decreased adiponectin levels dose-dependently, while PCB126 increased IL-6 and IL-8 secretion in a dose-dependent manner. Co-exposure to PCB126 and hypoxia did not alter the adipokine secretion pattern observed under hypoxia and PCB126 exposure alone. In conclusion, our results indicate that (1) hypoxia inhibits PCB126-induced CYP1A1 expression at least partly through ARNT-dependent means, suggesting that hypoxia could affect PCB metabolism and toxicity in adipose tissue, and (2) hypoxia and PCB126 affect leptin, adiponectin, IL-6 and IL-8 secretion differently, with no apparent crosstalk between the two factors.

Topics: Adipocytes; Adipokines; Adiponectin; Aryl Hydrocarbon Receptor Nuclear Translocator; Cytochrome P-450 CYP1A1; Environmental Pollutants; Humans; Hypoxia; Interleukin-6; Interleukin-8; Leptin; Polychlorinated Biphenyls; Vascular Endothelial Growth Factor A

Sleep-disordered breathing (SDB) affects over 50% of obese individuals. Exaggerated hypoxic chemoreflex is a cardinal trait of SDB in obesity. We have shown that leptin acts in the carotid bodies (CB) to augment chemoreflex and that leptin activates the transient receptor potential melastatin 7 (TRPM7) channel. However, the effect of leptin-TRPM7 signalling in CB on breathing and SDB has not been characterized in diet-induced obesity (DIO). We hypothesized that leptin acts via TRPM7 in the CB to increase chemoreflex leading to SDB in obesity. DIO mice were implanted with EEG/EMG electrodes and transfected with Lepr

Topics: Animals; Carotid Body; Hypoventilation; Hypoxia; Leptin; Mice; Mice, Obese; Obesity; RNA, Small Interfering; Sleep; Sleep Apnea Syndromes; Transient Receptor Potential Channels; TRPM Cation Channels

Hypoxia is caused by the excessive expansion of the white adipose tissue (AT) and is associated with obesity-related conditions such as insulin resistance, inflammation, and oxidative stress. Docosahexaenoic acid (DHA) is an omega-3 fatty acid reported to have beneficial health effects. However, the effects of DHA in AT against hypoxia-induced immune-metabolic perturbations in adipocytes exposed to low O. The apoptosis and reactive oxygen species (ROS) rates were evaluated. Metabolic parameters such as lactate, FFA, glycerol release, glucose uptake, and ATP content were assessed by a fluorometer. The expression of HIF-1, GLUT1 and the secretion of adipocytokines such as leptin, adiponectin, and pro-inflammatory markers was evaluated.. DHA-treated hypoxic cells showed significantly decreased basal free fatty acid release, lactate production, and enhanced glucose consumption. In addition, DHA-treatment of hypoxic cells caused a significant reduction in the apoptosis rate and ROS production with decreased lipid peroxidation. Moreover, DHA-treatment of hypoxic cells caused a decreased secretion of pro-inflammatory markers (IL-6, MCP-1) and leptin and increased adiponectin secretion compared with hypoxic cells. Furthermore, DHA-treatment of hypoxic cells caused significant reductions in the expression of genes related to hypoxia (HIF-1, HIF-2), anaerobic metabolism (GLUT1 and Ldha), ATP production (ANT2), and fat metabolism (FASN and PPARY).. This study suggests that DHA can exert potential anti-obesity effects by reducing the secretion of inflammatory adipokines, oxidative stress, lipolysis, and apoptosis.

Topics: 3T3-L1 Cells; Adenosine Triphosphate; Adipocytes; Adipokines; Adiponectin; Animals; Biomarkers; Docosahexaenoic Acids; Glucose Transporter Type 1; Hypoxia; Inflammation; Lactates; Leptin; Mice; Obesity; Reactive Oxygen Species

Hypoxia is associated with the pathogenesis of rheumatoid arthritis (RA). RA fibroblast-like synoviocytes (FLSs) are able to differentiate into osteoblasts and adipocytes. In this study, we aimed to investigate the role of hypoxia in the osteogenesis or adipogenesis of RA-FLSs. Bioinformatics analysis was performed to profile gene expression in the datasets of GSE21959, GSE32006, and GSE55875, and flow cytometry was performed for FLS characterization, while Alizarin Redand Oil Red O staining for osteogenic or adipogenic differentiation of FLSs, respectively. RNA interference leptin knockdown was used to determine the role of leptin in the osteogenesis and adipogenesis of RA-FLSs, and the expression of osteogenic and adipogenic markers was quantified by RT-qPCR and Western blotting. FLSs exhibited a mesenchymal stem cell (MSC)-like phenotype and we observed a limited self-renewal capacity in RA-FLSs compared to that in MSCs, but it was still greater than osteoarthritis (OA)-FLSs. Hypoxia did not change the RA-FLS MSC-like phenotype but inhibited the osteogenic differentiation and promoted the adipogenic differentiation of RA-FLSs. From the bioinformatics analysis ofGSE21959, GSE32006, and GSE55875 datasets, we found leptin, the only perturbed hypoxia-mediated upregulated gene across the three profiled datasets. Leptin knockdown in RA-FLSs reversed the hypoxia-mediated reduction of osteogenesis and hypoxia-mediated enhancement of adipogenesis by elevated expression of osteogenic markers and reduced expression of adipogenic markers, respectively. Therefore, hypoxia-leptin regulation of the osteogenic and adipogenic differentiation of RA-FLSs advances our understanding of RA pathogenesis, meanwhile also provides opportunities for future therapeutic intervention of RA.

Topics: Adipogenesis; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Fibroblasts; Humans; Hypoxia; Leptin; Osteogenesis; Synoviocytes; Up-Regulation

What is the central question of this study? Does leptin have an effect on hypoxia-induced apoptosis in human periodontal ligament cells (hPDLCs), and what is the potential underlying mechanism? What is the main finding and its importance? Hypoxia induces cell apoptosis and leptin expression in hPDLCs through the induction of hypoxia-inducible factor-1α and accumulation of reactive oxygen species (ROS). Leptin shows feedback inhibition on hypoxia-induced ROS-mediated apoptosis in hPDLCs, suggesting a new application of leptin for hypoxic damage in periodontal diseases.. Hypoxia-induced apoptosis of human periodontal ligament cells (hPDLCs) is an important contributor to the progression of various periodontal diseases. Although leptin has been shown to protect connective tissue cells against hypoxia-induced injury, whether it might do so by attenuating hypoxia-induced apoptosis in hPDLCs remains unclear. Here, using CoCl

Topics: Apoptosis; Cell Hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Periodontal Ligament; Reactive Oxygen Species

Hypoxia and hyperoxia are disparate stressors which can have destructive influences on fish growth and physiology. It is yet to be determined if hypoxia and hyperoxia have a cumulative effect in aquatic ecosystems that affect biological parameters in fish, and to understand if this is associated with gene expression. Here we address whether growth performance and expressions of growth, immune system and stress related genes were affected by hypoxia and hyperoxia in fish. Rainbow trout was chosen as the study organism due to its excellent service as biomonitor. After an acclimatization period, fish were exposed to hypoxia (4.0 ± 0.5 ppm O

Topics: Animals; Fish Proteins; Gene Expression Regulation; Growth Hormone; HSP70 Heat-Shock Proteins; Hyperoxia; Hypoxia; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Liver; Oncorhynchus mykiss; Oxygen; Stress, Physiological; Weight Gain

EGFR-TKIs such as erlotinib and gefitinib have been introduced into the first-line treatment for patients having a mutation of deletion in exon 19 or L858R missense mutations in exon 21. Almost all patients who respond to EGFR-TKIs at first place eventually develop acquired resistance after several months of therapy. The secondary mutations and bypass signaling activation are involved in the generation of the resistance. Hypoxia in non-small cell lung cancer (NSCLC) is an important factor in treatment resistance including radiotherapy, chemotherapy and EGFR-TKI therapy. In this study, the effect of hypoxic cancer microenvironment in the bypass signaling activation was investigated. We found that bone marrow-derived mesenchymal stem cells (BMSCs) residing in the hypoxic solid cancer microenvironment highly produced molecules associated with adipocytes including adipokine leptin and IGFBPs. Leptin could induce the resistance of lung cancer cells to erlotinib through activating IGF-1R signaling. IGFBP2 counteracted the activation role of IGF-1 and induced erlotinib resistance by activating IGF-1R signaling in an IGF-1 independent manner. IGFBP2 had synergistic effect with leptin to induce erlotinib resistance. Leptin and IGFBP2 may be predictive factors for acquired resistance for EGFR-TKIs.

Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Bone Marrow; Cell Proliferation; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Insulin-Like Growth Factor Binding Protein 2; Leptin; Lung Neoplasms; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Receptor, IGF Type 1; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

High altitude hypobaric hypoxia environment impairs male's reproductive function. Leptin is an adipose tissue-derived hormone which regulates body weight homeostasis. Its receptor (LepR) has been found in all levels of male reproductive axis, indicating that it can affect male reproductive system in a direct or (and) indirect way. However, the role of leptin signaling in hypobaric hypoxia induced male reproductive dysfunction remains to be elucidated. In this study, we investigated the changes of leptin levels in male SD rats in stimulated altitude of 5500 m hypobaric hypoxia environment and their effects on the hypothalamus-pituitary-gonad axis (HPG axis). A hypoxia animal model was established using a hypobaric hypoxia chamber. Rats were divided randomly into 1, 7, 14, 28-day hypoxia group, recovery group (14 days hypoxia+14 days normoxia) and their control groups. Hypoxia groups displayed obvious changes of testicular and epididymis index compared to control groups. The total number of sperm and sperm motility rate decreased dramatically, while sperm deformity rate increased in hypoxia groups. The flow cytometry analysis showed that the percentage of haploid in 1-day, 7-day and 28-day hypoxia groups increased while the proportion of diploid decreased in 14-day and 28-day hypoxia group. TUNEL staining showed that the testis cells apoptosis index (AI) of hypoxia groups increased significantly, and the apoptosis of cells mainly focus on spermatogonia and spermatocytes. The expression of GnRH in hypothalamus decreased dramatically under hypoxia condition, accompanied with the reduction of serum testosterone (T) level in 1-day and 28-day hypoxia groups and free-testosterone level (FT) in 1-day and 14-day hypoxia groups. Importantly, ELISA analysis showed that serum leptin level decreased in 7-day hypoxia groups and acylated-ghrelin, gastrin also changed, accompanying with reduction of LepR in hypothalamus in hypoxia groups. Immunohistochemical staining exhibited increased leptin and LepR in testis under hypobaric hypoxia conditions. Our results suggested that simulated high altitude hypobaric hypoxia environment decreased male reproductive function, depressed HPG axis activity and altered the serum concentration of hormones related to food intake in adult male rats. Additionally, hypobaric hypoxia induced the leptin-LepR expression in adult male rats' testis, suggesting leptin-LepR signaling may mediate hypoxia-induced impairment in male rats' reproductive

Topics: Altitude; Altitude Sickness; Animals; Apoptosis; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Hypoxia; Leptin; Male; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Reproduction; Sperm Count; Sperm Motility; Spermatogenesis; Testis

Topics: Animals; Behavior, Animal; Brain Ischemia; Carotid Artery, Common; Cerebrovascular Circulation; Cognition Disorders; Corpus Callosum; Cytokines; Hypoxia; Inflammation; Leptin; Male; Memory, Short-Term; Mice; Mice, Inbred C57BL; Microglia; Neuroglia; Perfusion; Phenotype; Receptors, Leptin; White Matter

This study was to investigate the degree of susceptibility to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), between the two mice inbred lines C57BL/6N (6N) and C57BL/6J (6J).. Four-week old male mice of 6N and 6J substrains (n = 8) were randomized to standard diet (SD) group or high fat (HF) diet group. At the age of 13-week, all two groups of mice were subjected to either air or IH (IH30; thirty hypoxic events per hour) for one week.. All mice fed with HF diet exhibited obesity with more body weight and fat mass (percentage to body weight) gain. IH reduced serum LDL, HDL and total cholesterol levels in lean 6J mice. In obese mice, IH lowered obesity-induced serum total cholesterol level in 6J substrain but raised further in 6N substrain. Furthermore, IH caused elevation of serum FFA and MDA levels, and pro-inflammatory cytokines MCP-1 and IL-6 levels in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of lean 6J but not lean 6N mice. There was reduced number of adipocytes and elevation of macrophages in SAT and VAT of HF-induced obese mice of both substrains. IH led to increased number of adipocytes and macrophages in SAT of lean 6J mice.. The genetic difference between 6N and 6J mice may have direct impact on metabolic and inflammatory responses after IH. Therefore, attention must be given for the selection of C57BL mice substrains in the experimental IH-exposed mouse model.

Topics: Adiponectin; Animals; Biomarkers; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Hypoxia; Inflammation; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Thinness; Weight Gain

Neonatal anoxia may cause neurological injuries, behavioral alterations and changes in somatic growth. Somatic developmental changes suggest a possible effect of anoxia on energy metabolism and/or feeding behavior. Short-term effects of oxygen deficit on energy homeostasis have been described. In contrast, just a few studies report long-term effects. This study investigated the effects of neonatal anoxia on energy metabolism and somatic development at adulthood of males and females Wistar rats.. Male (m) and female (f) rats were exposed, on postnatal day 2 (P2), to either 25-min of Anoxia or Control treatment. At P34 part of the subjects of each group was fasted for 18 h, refeed for 1 h and then perfused 30 min later, at P35; the remaining subjects were submitted to these treatments at P94 and perfused at P95. Therefore, there were 8 groups: AmP35, AmP95, AfP35, AfP95, CmP35, CmP95, CfP35 and CfP95. For subjects perfused at P95, body weight and food intake were recorded up to P90. For subjects perfused at P35 and P95, glycemia, leptin and insulin were assessed after fasting and refeed. After perfusion the encephalon and pancreas were collected for Fos immunohistochemistry and Hematoxylin-Eosin stain analyses.. Even though neonatal anoxia did not interfere with regular food intake, it reduced body weight gain along growing in both male and female subjects as compared to the corresponding controls. At P35 neonatal anoxia decreased post-prandial glycemia and increased insulin. While at P95 neonatal anoxia altered the pancreatic histomorphology and increased post-fasting weight loss, decreasing leptin, insulin and glycemia secretion, as well Fos immunoreactivity (IR) in ARC.. Neonatal anoxia impairs long-term energy metabolism and somatic development in Wistar rats, with differences related to sex and age.

Topics: Animals; Animals, Newborn; Blood Glucose; Energy Metabolism; Fasting; Female; Hypoxia; Insulin; Leptin; Male; Rats; Rats, Wistar; Weight Gain

We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study, we examined whether activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia.. Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU-9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119-treated rats as well as obese and lean MC4R-deficient rats were exposed to CIH for 7-18 consecutive days.. Chronic intermittent hypoxia reduced cumulative food intake by 18 ± 5 g while MAP and HR increased by 10 ± 3 mm Hg and 9 ± 5 bpm in untreated rats. SHU-9119 increased food intake (from 15 ± 1 to 46 ± 3 g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10 ± 1 vs 9 ± 1 mm Hg for untreated and SHU-9119 treated rats). In obese MC4R-deficient rats, CIH for 7 days raised BP by 11 ± 4 mm Hg. However, when MC4R-deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity.. These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia.

Topics: Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Eating; Heart Rate; Hematocrit; Hypercapnia; Hypoxia; Insulin; Leptin; Male; Obesity; Pulmonary Ventilation; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sympathetic Nervous System

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

Topics: Adiponectin; Animals; Animals, Newborn; Anxiety, Separation; Biomarkers; Blood Glucose; Female; Hypothermia; Hypoxia; Insulin; Insulin Resistance; Leptin; Male; Maternal Deprivation; Rats, Sprague-Dawley; Resistin; Sex Factors; Testosterone

Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models.. Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca

Topics: Adenosine; Animals; Carotid Body; Carotid Sinus; Diet, High-Fat; Hypoxia; Insulin Resistance; Leptin; Male; Pulmonary Ventilation; Rats, Wistar; Receptors, Leptin; Respiration

Hypoxia-induced adipokine release has been attributed mainly to HIF-1α. Here we investigate the role of intracellular calcium and NF-kB in the hypoxia-dependent release of leptin, VEGF, IL-6 and the hypoxia-induced inhibition of adiponectin release in human adipocytes.. We used intracellular calcium imaging to compare calcium status in preadipocytes and in adipocytes. We subjected both cell types to hypoxic conditions and measured the release of adipokines induced by hypoxia in the presence and absence of HIF-1α inhibitor YC-1, NF-. We demonstrate reduced intracellular calcium oscillations and increased oxidative stress as the cells transitioned from preadipocytes to adipocytes. We show that differentiation of preadipocytes to adipocytes is associated with distinct morphological changes in the mitochondria. We also show that hypoxia-induced secretion of leptin, VEGF, IL-6 and hypoxia-induced inhibition of adiponectin secretion are independent of HIF-1α expression. The hypoxia-induced leptin, VEGF and IL-6 release are [Ca. Our work suggests a major role for [Ca

Topics: Adipocytes; Adiponectin; Calcium; Cell Differentiation; Gene Expression Regulation; Humans; Hypoxia; Interleukin-6; Leptin; NF-kappa B; Signal Transduction; Vascular Endothelial Growth Factor A

The effect of gestational hypoxia on the neonatal leptin surge, development of hypothalamic arcuate nuclei (ARH) projections and appetite that could contribute to the programming of offspring obesity is lacking. We examined the effect of 12% O2 from gestational days 15-19 in the Sprague-Dawley rat on post-weaning appetite, fat deposition by MRI, adipose tissue cytokine expression, the neonatal leptin surge, ARH response to exogenous leptin, and αMSH projections to the paraventricular nucleus (PVN) in response to a high fat (HFD) or control diet (CD) in male offspring. Normoxia (NMX) and Hypoxia (HPX) offspring exhibited increased food intake when fed a HFD from 5-8 weeks post-birth; HPX offspring on the CD had increased food intake from weeks 5-7 vs. NMX offspring on a CD. HPX offspring on a HFD remained hyperphagic through 23 weeks. Body weight were the same between offspring from HPX vs. NMX dams from 4-12 weeks of age fed a CD or HFD. By 14-23 weeks of age, HPX offspring fed the CD or HFD as well as male NMX offspring fed the HFD were heavier vs. NMX offspring fed the CD. HPX offspring fed a CD exhibited increased abdominal adiposity (MRI) that was amplified by a HFD. HPX offspring fed a HFD exhibited the highest abdominal fat cytokine expression. HPX male offspring had higher plasma leptin from postnatal day (PN) 6 through 14 vs. NMX pups. HPX offspring exhibited increased basal c-Fos labeled cells in the ARH vs. NMX pups on PN16. Leptin increased c-Fos staining in the ARH in NMX but not HPX offspring at PN16. HPX offspring had fewer αMSH fibers in the PVN vs. NMX offspring on PN16. In conclusion, gestational hypoxia impacts the developing ARH resulting in hyperphagia contributing to adult obesity on a control diet and exacerbated by a HFD.

Topics: Adipose Tissue; alpha-MSH; Animals; Animals, Newborn; Anxiety; Arcuate Nucleus of Hypothalamus; Behavior, Animal; Diet; Fear; Feeding Behavior; Female; Fetal Weight; Hyperphagia; Hypoxia; Interleukin-1beta; Interleukin-6; Leptin; Magnetic Resonance Imaging; Male; Maternal Nutritional Physiological Phenomena; Maze Learning; Motor Activity; Obesity; Pregnancy; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Water; Weaning

The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

Topics: Animals; Blood Glucose; Cholesterol; Diet, High-Fat; Female; Glucose Tolerance Test; Hyperinsulinism; Hypoxia; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Obesity; Physical Conditioning, Animal; Placenta; Pregnancy; Triglycerides

Topics: Acne Vulgaris; Animals; Cell Proliferation; Dermatitis, Seborrheic; Humans; Hypoxia; Inflammation; Keratinocytes; Leptin; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Sebaceous Glands; TOR Serine-Threonine Kinases

Increased peripheral chemosensitivity (PChS) has been proposed as mechanism underlying obesity-related sympathoactivation, with insulin and/or leptin as possible mediators. However, human data on PChS in obesity are scarce. Therefore, we explored this issue in a sample of 41 healthy men aged 30-59 years, divided according to body fat percentage (fat %) into two groups: <25 and ≥25 %.. PChS was assessed using transient hypoxia method [respiratory (PChS-MV), heart rate (PChS-HR), and blood pressure (PChS-SBP) responses were calculated]. Baroreflex sensitivity (BRS-Seq) was assessed using sequence method. Fasting plasma insulin and leptin levels were measured. Homeostatic model assessment (HOMA) was used to assess insulin sensitivity/resistance.. Individuals with ≥25 % body fat demonstrated increased PChS-SBP (p < 0.01), but unchanged PChS-MV and PChS-HR (both p > 0.4). PChS-SBP was related positively with anthropometric characteristics (e.g. waist circumference, fat %), plasma insulin and HOMA (all p < 0.05), and negatively with BRS-Seq (p = 0.001), but not with plasma leptin (p = 0.27).. In healthy men, overweight/obesity is accompanied by augmented blood pressure response from peripheral chemoreceptors, while respiratory and heart rate responses remain unaltered. Hyperinsulinaemia and insulin resistance (but not hyperleptinaemia) are associated with augmented pressure response from chemoreceptors.

Topics: Adiposity; Adult; Baroreflex; Blood Pressure; Humans; Hypoxia; Insulin; Leptin; Male; Middle Aged; Obesity; Overweight

Pulmonary arterial hypertension (PAH) encompasses a group of conditions with distinct causes. Immunologic disorders are common features of all forms of PAH and contributes to both disease susceptibility and progression. Regulatory T lymphocytes (Treg) are dysfunctional in patients with idiopathic PAH (iPAH) in a leptin-dependent manner. However, it is not known whether these abnormalities are specific to iPAH. Hence, we hypothesized that (1) Treg dysfunction is also present in heritable (hPAH) and connective tissue disease-associated PAH (CTD-PAH); (2) defective leptin-dependent signaling is present in hPAH and CTD-PAH and could contribute to Treg dysfunction; (3) modulating the leptin axis in vivo could protect against Treg dysfunction; and (4) restoration of Treg activity could limit or reverse experimental chronic hypoxia-induced pulmonary hypertension in vivo.. We analyzed 62 patients with PAH (30 with iPAH, 18 with hPAH, and 14 with CTD-PAH), 7 patients with CTD without PAH, and 20 healthy control subjects.. Our results indicate that Treg are dysfunctional in all PAH forms tested, as well as in patients with CTD without PAH. Importantly, the leptin axis is crucial in Treg dysfunction in patients with iPAH and those with CTD (with or without PAH), whereas in patients with hPAH, Treg are altered in a leptin-independent manner. We found that leptin receptor-deficient rats, which develop less severe hypoxia-induced pulmonary hypertension, are protected against decreased Treg function after hypoxic exposure.. Taken together, our results suggest that Treg dysfunction is common to all forms of PAH and may contribute to the development and the progression of the disease.

Topics: Animals; Connective Tissue Diseases; Disease Progression; Familial Primary Pulmonary Hypertension; Female; Humans; Hypoxia; Leptin; Male; Middle Aged; Rats; Rats, Sprague-Dawley; Respiratory Function Tests; T-Lymphocytes, Regulatory

Intermittent hypoxia (IH) is a major pathophysiological consequence of obstructive sleep apnea. Recently, it has been shown that IH results in changes in body energy balance, leptin secretion and concomitant alterations in arcuate nucleus (ARC). In this study, the role of leptin on these changes was investigated in leptin-deficient rats exposed to IH or normoxic control conditions. Body weights, consumatory and locomotor behaviours, and protein signaling in ARC were assessed immediately after IH exposure. Compared to normoxia, IH altered body weight, food intake, locomotor pattern, and the plasma concentration of leptin and angiotensin II in the wild-type rat. However, these changes were not observed in the leptin-deficient rat. Within ARC of wild-type animals, IH increased phosphorylated signal transducer and activator of transcription 3 and pro-opiomelanocortin protein expression, but not in the leptin-deficient rat. The long-form leptin receptor protein expression was not altered following IH in either rat strain. These data suggest that leptin is involved in mediating the alterations to body energy balance and ARC activity following IH.

Topics: Angiotensin II; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Drinking; Eating; Hypoxia; Leptin; Locomotion; Male; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor

What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidaemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partly protect against IH-induced inflammation.

Topics: Adiponectin; Animals; Blood Glucose; Cardiovascular Diseases; Cytokines; Disease Models, Animal; Endothelin-1; Hypoxia; Inflammation; Insulin; Interleukin-6; Leptin; Lipids; Liver; Male; Myocardium; NF-kappa B; Obesity; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha

Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

Topics: Animals; Anti-Obesity Agents; Drug Evaluation, Preclinical; Eating; Hypoxia; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Macrophages; Male; Mice, Inbred C57BL; Random Allocation; Resveratrol; Stilbenes; Weight Gain

Leptin, produced mainly by white adipose tissue, is a hormone that promotes vascular smooth muscle cell (VSMC) migration and proliferation, a process involved in the pathophysiology of atherosclerosis. Leptin expression in human coronary artery smooth cell (HCASMC) is induced by hypoxia. However, our understanding of the process of atherosclerosis in HCASMC is only emerging. Since the mechanisms by which hypoxia regulates leptin in HCASMC are as yet unknown, this study aims to investigate the mechanics of molecular regulation of leptin expression in HCASMC under hypoxia. We subjected cultured HCASMCs to hypoxia for varying periods of time. Through use of different signal pathway inhibitors, we were able to sort out and identify the pathway through which hypoxia-induced leptin expression occurs.. Leptin mRNA and protein levels increased after 2.5% hypoxia for 2-to-4 hours, with earlier expression of angiotensin II (AngII) and reactive oxygen species (ROS). The addition before hypoxia of the c-Jun N-terminal kinase (JNK) pathway inhibitor (SP600125), JNK small interfering RNA (siRNA), AngII receptor blockers (ARBs; losartan), or N-acetyl-L-cysteine (NAC, an ROS scavenger), had the effect of inhibiting JNK phosphorylation and leptin expression. Gel shift assay and luciferase promoter study showed that leptin/activator protein 1 (AP-1) binding and transcriptional activity to the leptin promoter increased after hypoxia, and SP600125, JNK siRNA, losartan, and NAC abolished the binding and transcriptional activity induced by hypoxia. The use of SP600125, JNK siRNA, losartan, and NAC effectively inhibited the binding and transcriptional activity induced by hypoxia. Migration and proliferation, ROS generation, and the presence of leptin in the nuclei of HCASMCs also increased under hypoxia.. Hypoxia in HCASMCs increases leptin expression through the induction of AngII, ROS, and the JNK pathway to enhance atherosclerosis in HCASMCs.

Topics: Angiotensin II; Coronary Vessels; Gene Expression Regulation; Humans; Hypoxia; Leptin; Myocytes, Smooth Muscle; Reactive Oxygen Species; Signal Transduction

To investigate the effect of leptin on the proliferation of airway smooth muscle cells (ASMCs) and the expressions of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) of hypoxic rats.. The rat ASMCs were cultured under normoxic and hypoxic states. The hypoxic cells were divided into hypoxia group, leptin 50 μg/L hypoxia group (L50 group), leptin 100 μg/L hypoxia group (L100 group), leptin 200 μg/L hypoxia group (L200 group), leptin 200 μg/L and leptin receptor antibody hypoxia group (ob-R antibody group) by random number table. All the groups are cultured for 24 hours. Then the CCK-8 method was used to assay cell proliferation rate, and Western blotting and real-time RT-PCR to measure the expressions of HIF-1α and NF-κB at protein and mRNA levels.. Compared with the normoxic group, each hypoxia group had significantly increased cell proliferation . Compared with the hypoxia group, cell proliferation rate was significantly raised in L50, L100 and L200 groups, and it was positively correlated with the concentration (r=0.992). Compared with L50, L100 and L200 groups, the ob-R antibody group showed significantly decreased cell proliferation rate. Compared with the normoxic group, each hypoxic group has increased expressions of HIF-1α and NF-κB mRNA and proteins; compared with the hypoxia group, the expressions were significantly elevated in the L50, L100 and L200 groups and showed a positive correlation with the concentration; but the expressions were reduced in the ob-R antibody group as compared with L50, L100 and L200 groups.. Leptin can promote rat ASMCs proliferation and the expressions of HIF-1α and NF-κB under hypoxic condition.

Topics: Animals; Cell Proliferation; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Male; Myocytes, Smooth Muscle; NF-kappa B; Rats; Rats, Sprague-Dawley; Respiratory System

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH. In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH. We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

Topics: Adult; Animals; Blotting, Western; Case-Control Studies; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Signal Transduction; Up-Regulation; Vascular Remodeling

Experimental models of intermittent hypoxia (IH) have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS).. Mice were fed either a standard diet or a high fat diet (HFD) for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day) or intermittent air (FiO2 21%). Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO) release.. Mice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH) activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.. In a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Glycolysis; Hypoxia; Insulin; Leptin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Nitric Oxide; Sleep Apnea, Obstructive

To investigate the possibility that leptin exerts an effect in NTS by inducing changes in the expression of pre- and/or post-synaptic proteins, experiments were done in Sprague-Dawley wild-type rats (WT) rats and leptin-deficient rats (Lep(Δ151/Δ151); KILO rat) exposed to 8h of continuous intermittent hypoxia (IH) or normoxia. Protein was extracted from the caudal medial NTS and analyzed by western blot for the expression of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), synaptophysin, synaptopodin and growth-associated protein-43 (GAP-43). In WT rats, BDNF and GAP 43 protein expression levels were not altered after IH or normoxia, although there was a trend towards an increase in BDNF expression. On the other hand, after IH, protein expression of both isoforms of the BDNF receptor TrkB (gp95 and gp145) was higher. Furthermore, synaptophysin protein expression was lower compared to normoxic WT rats. In the KILO rat, no changes were observed in the protein expression of BDNF, TrkB, or GAP 43 after IH when compared to KILO normoxic controls. However, synaptophysin was lower in the IH exposed KILO rat compared to normoxic controls, as found in the WT rat. Expression of synaptopodin was not detected in NTS in either IH or normoxic animals of all groups. These results suggest that leptin released during IH may contribute to neurotrophic changes occurring within NTS and that these changes may be associated with altered chemoreceptor reflex function.

Topics: Animals; Brain-Derived Neurotrophic Factor; GAP-43 Protein; Hypoxia; Leptin; Male; Microfilament Proteins; Protein Isoforms; Rats, Sprague-Dawley; Receptor, trkB; Solitary Nucleus; Synaptophysin

Leptin is a hormone produced mostly in adipose tissue and playing a key role in the control of feeding and energy expenditure aiming to maintain a balance between food intake and metabolic activity. In recent years, it has been described that leptin might also contributes to control ventilation as the administration of the hormone reverses the hypoxia and hypercapnia commonly encountered in ob/ob mice which show absence of the functional hormone. In addition, it has been shown that the carotid body (CB) of the rat expresses leptin as well as the functional leptin-B receptor. Therefore, the possibility exists that the ventilatory effects of leptin are mediated by the CB chemoreceptors. In the experiments described below we confirm the stimulatory effect of leptin on ventilation, finding additionally that the CB does not mediate the instant to instant control of ventilation.

Topics: Animals; Blood Glucose; Carotid Body; Catecholamines; Hypoxia; Leptin; Rats; Rats, Wistar; Respiration

In this study, we aimed to establish a chronic intermittent hypoxia model in rats and explore the possible role of vaspin in insulin sensitivity.. Healthy male Wistar rats were randomly divided into two groups: normal control group (NC) and chronic intermittent hypoxia group (CIH). The NC group was raised under physiological conditions and the CIH group was kept in the plexiglass chamber between 9 am and 5 pm undergoing intermittent hypoxic challenge for 8 hours/day for 8 weeks. Arterial blood pressure of rats (tail cannulation) was measured before and after the study. Fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), fasting insulin (FINS), vaspin, and leptin levels were measured. Vaspin mRNA expression in visceral adipose tissues was measured with Real Time-PCR. The protein levels of vaspin, Akt and phospho-Akt in visceral tissues were determined by Western-blot.. At baseline, all the measurements in the CIH and NC groups were comparable. By the end of the experiment, the blood pressure of the CIH group was significantly higher than the NC group. The levels of FPG, FINS, TG, TC, leptin, and vaspin in the CIH group were significantly higher than in NC group. Plasma vaspin levels were correlated with FINS, HOMA-IR, and TG levels. Vaspin expression in both mRNA and protein levels in visceral adipose tissues of the CIH group were clearly higher than the NC group. Phospho-Akt protein level was decreased in visceral adipose tissues of the CIH group compared to the NC group.. In the chronic intermittent hypoxia rat model, the expression of vaspin in visceral adipose tissues and plasma were increased, which were correlated with insulin resistance.

Topics: Animals; Arterial Pressure; Biomarkers; Blood Glucose; Cholesterol; Disease Models, Animal; Hypoxia; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger; Serpins; Sleep Apnea, Obstructive; Time Factors; Triglycerides; Up-Regulation

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive vascular smooth muscle cells proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance with consequent right ventricular (RV) failure and death. Recently, emerging evidence has shown that leptin signaling is involved in different cardiac pathologies; however, the role of leptin remains limited in the setting of PAH. Thus, in this study, we tested the hypothesis of direct involvement of leptin in the development of PAH. Our data show that leptin activity in plasma and protein level in the lung were higher in hypoxia- and monocrotaline-induced PAH models compared with control animals. Wild-type (WT) and C57BL/6J-Lep(ob) (ob/ob) male mice were exposed to normobaric hypoxia (10% O(2)) or normoxia (21% O(2)). After 2 and 4 weeks of chronic hypoxia exposure, WT mice developed PAH as reflected by the increased values of RV systolic pressure, RV hypertrophy index, the medial wall thickness of pulmonary arterioles, and muscularization of pulmonary arterioles. And, all these alterations were attenuated in ob/ob mice treated with hypoxia. Leptin could stimulate the proliferation of pulmonary arterial smooth muscle cells (PASMCs) by activating extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and Akt pathways. These data suggest that the leptin signaling pathway is crucial for the development of PAH. Leptin activates ERK, STAT, and Akt pathways and subsequently PASMCs proliferation, providing new mechanistic information about hypoxia-induced PAH.

Topics: Animals; Arteries; Cell Proliferation; Hypertension, Pulmonary; Hypoxia; Leptin; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley

Autophagy is the basic catabolic progress involved in cell degradation of unnecessary or dysfunctional cellular components. It has been proven that autophagy could be utilized for cell survival under stresses. Hypoxic-preconditioning (HPC) could reduce apoptosis induced by ischemia and hypoxia/serum deprivation (H/SD) in bone marrow-derived mesenchymal stem cells (BMSCs). Previous studies have shown that both leptin signaling and autophagy activation were involved in the protection against apoptosis induced by various stress, including ischemia-reperfusion. However, it has never been fully understood how leptin was involved in the protective effects conferred by autophagy. In the present study, we demonstrated that HPC can induce autophagy in BMSCs by increased LC3-II/LC3-I ratio and autophagosome formation. Interestingly, similar effects were also observed when BMSCs were pretreated with rapamycin. The beneficial effects offered by HPC were absent when BMSCs were incubated with autophagy inhibitor, 3-methyladenine (3-MA). In addition, down-regulated leptin expression by leptin-shRNA also attenuated HPC-induced autophagy in BMSCs, which in turn was associated with increased apoptosis after exposed to sustained H/SD. Furthermore, increased AMP-activated protein kinase phosphorylation and decreased mammalian target of rapamycin phosphorylation that were observed in HPC-treated BMSCs can also be attenuated by down-regulation of leptin expression. Our data suggests that leptin has impact on HPC-induced autophagy in BMSCs which confers protection against apoptosis under H/SD, possibly through modulating both AMPK and mTOR pathway.

Topics: Adenylate Kinase; Animals; Apoptosis; Autophagy; Base Sequence; Blotting, Western; DNA Primers; Gene Knockdown Techniques; Hypoxia; Ischemic Preconditioning; Leptin; Male; Mice; Mice, Inbred C57BL; TOR Serine-Threonine Kinases

Intermittent hypoxia (IH), resulted from recurring episodes of upper airway obstruction, is the hallmark feature and the most important pathophysiologic pathway of obstructive sleep apnea (OSA). IH is believed to be the most important factor causing systemic inflammation. Studies suggest that insulin resistance (IR) is positively associated with OSA. In this study, we hypothesized that the recurrence of IH might result in cellular and systemic inflammation, which was manifested through the levels of proinflammatory cytokines and adipokines after IH exposure, and because IR is linked with inflammation tightly, this inflammatory situation may implicate an IR status.. We developed an IH 3T3-L1 adipocyte and rat model respectively, recapitulating the nocturnal oxygen profile in OSA. In IH cells, nuclear factor kappa B (NF-κB) DNA binding reactions, hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (Glut-1), necrosis factor alpha (TNF-α), interleukin (IL) -6, leptin, adiponectin mRNA transcriptional activities and protein expressions were measured. In IH rats, blood glucose, insulin, TNF-α, IL-6, leptin and adiponectin levels were analyzed.. The insulin and blood glucose levels in rats and NF-κB DNA binding activities in cells had significantly statistical results described as severe IH>moderate IH>mild IH>sustained hypoxia>control. The mRNA and protein levels of HIF-1α and Glut-1 in severe IH group were the highest. In cellular and animal models, both the mRNA and protein levels of TNF-α, IL-6 and leptin were the highest in severe IH group, when the lowest in severe IH group for adiponectin.. Oxidative stress and the release of pro-inflammatory cytokines/adipokines, which are the systemic inflammatory markers, are associated with IH closely and are proportional to the severity of IH. Because IR and glucose intolerance are linked with inflammation tightly, our results may implicate the clinical relationships between OSA and IR.

Topics: Adipocytes; Adipokines; Adiponectin; Animals; Blood Glucose; Cytokines; Glucose Transporter Type 1; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Models, Animal; NF-kappa B; Oxidative Stress; Oxygen; Rats; Sleep Apnea, Obstructive; Tumor Necrosis Factor-alpha

Leptin is a potent anorexigen, but little is known about the physiological conditions under which this cytokine regulates food intake in fish. In this study, we characterized the relationships between food intake, O2-carrying capacity, liver leptin-A1 (lep-a1) gene expression, and plasma leptin-A1 in rainbow trout infected with a pathogenic hemoflagellate, Cryptobia salmositica. As lep gene expression is hypoxia-sensitive and Cryptobia-infected fish are anemic, we hypothesized that Cryptobia-induced anorexia is mediated by leptin. A 14-week time course experiment revealed that Cryptobia-infected fish experience a transient 75% reduction in food intake, a sharp initial drop in hematocrit and hemoglobin levels followed by a partial recovery, a transient 17-fold increase in lep-a1 gene expression, and a sustained increase in plasma leptin-A1 levels. In the hypothalamus, peak anorexia was associated with decreases in mRNA levels of neuropeptide Y (npy) and cocaine- and amphetamine-regulated transcript (cart), and increases in agouti-related protein (agrp) and pro-opiomelanocortin A2 (pomc). In contrast, in non-infected fish pair-fed to infected animals, lep-a1 gene expression and plasma levels did not differ from those of non-infected satiated fish. Pair-fed fish were also characterized by increases in hypothalamic npy and agrp, no changes in pomc-a2, and a reduction in cart mRNA expression. Finally, peak infection was characterized by a significant positive correlation between O2-carrying capacity and food intake. These findings show that hypoxemia, and not feed restriction, stimulates leptin-A1 secretion in Cryptobia-infected rainbow trout and suggest that leptin contributes to anorexia by inhibiting hypothalamic npy and stimulating pomc-a2.

Topics: Agouti-Related Protein; Animals; Eating; Female; Fish Diseases; Fish Proteins; Gene Expression; Hematocrit; Hemoglobins; Host-Parasite Interactions; Hypothalamus; Hypoxia; Kinetoplastida; Leptin; Liver; Male; Nerve Tissue Proteins; Neuropeptide Y; Oncorhynchus mykiss; Pro-Opiomelanocortin; Radioimmunoassay; RNA, Messenger

Hypoxia preconditioning enhances the therapeutic effect of mesenchymal stem cells (MSCs). However, the mechanism underlying hypoxia-induced augmentation of the protective effect of MSCs on myocardial infarction (MI) is poorly understood. We show that hypoxia-enhanced survival, mobility, and protection of cocultured cardiomyocytes were paralleled by increased expression of leptin and cell surface receptor CXCR4. The enhanced activities were abolished by either knockdown of leptin with a selective shRNA or by genetic deficiency of leptin or its receptor in MSCs derived, respectively, from ob/ob or db/db mice. To characterize the role of leptin in the regulation of MSC functions by hypoxia and its possible contribution to enhanced therapeutic efficacy, cell therapy using MSCs derived from wild-type, ob/ob, or db/db mice was implemented in mouse models of acute MI. Augmented protection by hypoxia pretreatment was only seen with MSCs from wild-type mice. Parameters that were differentially affected by hypoxia pretreatment included MSC engraftment, c-Kit(+) cell recruitment to the infarct, vascular density, infarct size, and long-term contractile function. These data show that leptin signaling is an early and essential step for the enhanced survival, chemotaxis, and therapeutic properties of MSCs conferred by preculture under hypoxia. Leptin may play a physiological role in priming MSCs resident in the bone marrow endosteum for optimal response to systemic signaling molecules and subsequent tissue repair.

Topics: Animals; Apoptosis; Cell Survival; Cytoprotection; Heart Function Tests; Humans; Hypoxia; Ischemic Preconditioning, Myocardial; Leptin; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice, Inbred C57BL; Neovascularization, Physiologic; Paracrine Communication; Receptors, CXCR4; Reproducibility of Results; Signal Transduction

Obstructive sleep apnea (OSA) consists of sleep-related repetitive obstructions of upper airways that generate episodes of recurrent or intermittent hypoxia (IH). OSA commonly generates cardiovascular and metabolic pathologies defining the obstructive sleep apnea syndrome (OSAS). Literature usually links OSA-associated pathologies to IH episodes that would cause an oxidative status and a carotid body-mediated sympathetic hyperactivity. Because cardiovascular and metabolic pathologies in obese patients and those with OSAS are analogous, we used models (24-wk-old Wistar rats) of IH (applied from weeks 22 to 24) and diet-induced obesity (O; animals fed a high-fat diet from weeks 12 to 24) to define the effect of each individual maneuver and their combination on the oxidative status and sympathetic tone of animals, and to quantify cardiovascular and metabolic parameters and their deviation from normality. We found that IH and O cause an oxidative status (increased lipid peroxides and diminished activities of superoxide dismutases), an inflammatory status (augmented C-reactive protein and nuclear factor kappa-B activation), and sympathetic hyperactivity (augmented plasma and renal artery catecholamine levels and synthesis rate); combined treatments worsened those alterations. IH and O augmented liver lipid content and plasma cholesterol, triglycerides, leptin, glycemia, insulin levels, and HOMA index, and caused hypertension; most of these parameters were aggravated when IH and O were combined. IH diminished ventilatory response to hypoxia, and hypercapnia and O created a restrictive ventilatory pattern; a combination of treatments led to restrictive hypoventilation. Data demonstrate that IH and O cause comparable metabolic and cardiovascular pathologies via misregulation of the redox status and sympathetic hyperactivity.

Topics: Animals; Arterial Pressure; Blood Glucose; Diet, High-Fat; Hypoxia; Insulin; Leptin; Lipids; Liver; Male; Muscle, Skeletal; Obesity; Oxidative Stress; Rats; Rats, Wistar; Sympathetic Nervous System

Activation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI), due to interstitial fibrosis. Mesenchymal stem cells (MSCs) have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC). Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis.. Cardiac fibroblast (CF) activation was induced by hypoxia (0.5% O2). The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery.. Co-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs.. Our data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.

Topics: Animals; Cell Differentiation; Collagen; Gene Expression; Hypoxia; Ischemic Preconditioning, Myocardial; Leptin; Mesenchymal Stem Cells; Mice; Myocardial Infarction; Myofibroblasts; Signal Transduction; Smad2 Protein; Trans-Activators; Transforming Growth Factor beta; Ventricular Remodeling

Hypoxia modulates the production of proteins involved in e.g. inflammation, angiogenesis and glucose utilization and hypoxia may therefore be an important factor underlying adipose tissue dysfunction in obesity. Resveratrol (RSV) is a natural polyphenolic compound and has been shown to have powerful anti-inflammatory effects and beneficial effects on several obesity-related complications. Thus, in the present study we investigated whether RSV has effects on hypoxic markers (GLUT-1, VEGF), hypoxia-induced key markers of inflammation (IL8, IL6), and leptin in human adipose tissue in vitro. Hypoxia was induced by incubating human adipose tissue fragments with 1% O2 for 24h as compared to 21% O2 The gene expressions were investigated by RT-PCR and protein release by Elisa. Hypoxia increases the expression of glucose transporter-1 (GLUT-1) (19-fold, p<0.001), vascular endothelial growth factor (VEGF) (10-fold, p<0.05), interleukin-8 (IL8) (8-fold, p<0.05), interleukin-6 (IL6) (5-fold, p<0.05) and leptin (9-fold). The protein levels of VEGF released to the medium was increased (8-fold, p<0.01) by hypoxia. RSV dose-dependently inhibited several of these hypoxia-induced expressions and at a concentration of 50 μM RSV almost completely inhibited the hypoxic responses at the above mentioned gene expression levels (p<0.05-p<0.001) and significantly attenuated the hypoxia-induced protein releases by 50-60%. These results demonstrate that hypoxia induces extensive changes in human adipose tissue in the expression and release of inflammation and angiogenesis-related adipokines. In addition the inhibition of hypoxia-mediated inflammation and angiogenesis might represent a novel mechanism of RSV in preventing obesity-related pathologies.

Topics: Adipose Tissue; Adult; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Female; Glucose Transporter Type 1; Humans; Hypoxia; In Vitro Techniques; Inflammation; Interleukin-6; Interleukin-8; Leptin; Neovascularization, Physiologic; Resveratrol; RNA, Messenger; Stilbenes; Vascular Endothelial Growth Factor A

This study was done to investigate whether chronic intermittent hypoxia (CIH) induced changes in leptin and leptin receptor protein levels, and known downstream mediators of leptin receptor signaling in the carotid body. Rats were subjected to CIH (120s normoxia, 80s hypoxia) or normoxia for 8h/day to either short term (7 days) or long term CIH exposure (95 days). After both 7 and 95 days of CIH, carotid body leptin protein expression was decreased, while protein levels of the long form leptin receptor (OB-Rb) were elevated. On the other hand, protein expression levels of the short form leptin receptor (OB-R100) were unchanged. Furthermore, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) protein levels were found to be significantly decreased at only the 7 day period. On the other hand, suppressor of cytokine signaling 3 (SOCS3) protein levels were elevated at only the 7 day period, while phosphorylated extracellular-signal-regulated kinase 1/2 (pERK1/2) was elevated only at the 95 day period. In both the normoxia and the CIH groups, carotid body leptin was decreased at the 95 day period compared to 7 days. However, OB-Rb or Ob-R100 protein levels were not changed in the normoxic or CIH group at either time point. Furthermore, pSTAT3 protein levels were found to be significantly higher, while SOCS3 levels were significantly lower in the 95 day CIH group compared to the 7 day CIH group. Taken together, these data indicate that CIH induces changes in leptin and leptin downstream signaling proteins within the carotid bodies which may contribute to alterations in carotid chemoreceptor sensitivity.

Topics: Animals; Carotid Body; Disease Models, Animal; Gene Expression Regulation; Hypoxia; Leptin; Male; MAP Kinase Signaling System; Rats; Rats, Sprague-Dawley; Receptors, Leptin; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors

This study was done to investigate the effects of acute intermittent hypoxia (IH) on metabolic factors associated with energy balance and body weight, and on hypothalamic satiety-inducing pathways. Adult male Sprague-Dawley rats were exposed to either 8h IH or normoxic control conditions. Food intake, locomotion and body weights were examined after IH. Additionally, plasma levels of leptin, adiponectin corticosterone, insulin and blood glucose were measured following exposure to IH. Furthermore, adipose tissue was removed and analyzed for leptin and adiponectin content. Finally, the hypothalamic arcuate nucleus (ARC) was assessed for alterations in protein signaling associated with satiety. IH reduced body weight, food intake and active cycle locomotion without altering adipose tissue mass. Leptin protein content was reduced while adiponectin content was elevated in adipose tissue after IH. Plasma concentration of leptin was significantly increased while adiponectin decreased after IH. No changes were found in plasma corticosterone, insulin and blood glucose. In ARC, phosphorylation of signal transducer and activator of transcription-3 and pro-opiomelanocortin (POMC) expression were elevated. In addition, POMC-expressing neurons were activated as determined by immediate early gene FRA-1/2 expression. Finally, ERK1/2 and its phosphorylation were reduced in response to IH. These data suggest that IH induces significant alterations to body energy balance through changes in the secretion of leptin which exert effects on satiety-inducing pathways within the hypothalamus.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Energy Metabolism; Feeding Behavior; Hypothalamus; Hypoxia; Leptin; Locomotion; Male; Nerve Tissue Proteins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; Transcription Factors

Glomus cells in the carotid body are responsible for detecting changes in the partial pressure of blood oxygen (PO₂). These glomus cells have recently been found to express leptin receptors and are activated by intermittent hypoxia (IH) and systemic leptin injections, although the function of leptin within the carotid body remains unknown. The present study was done to investigate whether IH activates leptin signalling pathways within leptin-expressing carotid body glomus cells. Rats were subjected to IH (120-s normoxia, 80-s hypoxia for 8 h) or normoxia (8 h). Exposure to IH increased plasma leptin levels almost sixfold compared to normoxic controls. Additionally, IH was found to increase leptin, ERK1/2 and Fra-1/2 immunoreactivity within glomus cells. Systemic leptin injections evoked similar effects on leptin, ERK1/2 and Fra-1/2 immunoreactivity within the glomus cells. Furthermore, using Western blot analysis, IH was found to increase protein expression of leptin, the short form of the leptin receptor (Ob-R₁₀₀ kDa) and suppressor of cytokine signalling 3. On the other hand, IH induced a decrease in long form of leptin receptors (Ob-Rb) protein expression. Taken together, these data suggest that the increased levels of leptin within the circulation and those within the glomus cells induced by IH may alter carotid bodies chemosensitivity to hypoxic stimuli.

Topics: Animals; Blotting, Western; Carotid Body; Fluorescent Antibody Technique; Fos-Related Antigen-2; Hypoxia; Leptin; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Preterm infants are exposed to numerous stressors during hospitalization and by term corrected gestational age they have lower body weight but a greater proportion of total body as well as abdominal visceral adipose tissue (VAT) accumulation. Greater abdominal VAT stores have a known association with metabolic syndrome. Mechanical-tactile stimulation (MTS) improves modulation of stress response in both humans and rodents. We hypothesize that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in adult rats. Neonatal stress, administered to rat pups from postnatal days 5 to P9, consisted of needle puncture and hypoxic/hyperoxic challenge during 60 min of maternal separation (STRESS; n=20). Mechanical-tactile stimulation (MTS; n=20) was administered to rat pups for 10 min during maternal separation in the stress protocol. Control animals received standard care (CTL; n=20). MRI measured adult (P120) abdominal total fat mass, subcutaneous (SAT) and visceral adipose tissue (VAT). Body weight and fasting serum adiponectin, leptin, glucose, insulin, and corticosterone were also measured. STRESS results in elevated VAT/SAT ratio compared to CTL but lower abdominal total fat mass and abdominal SAT. STRESS males experience hyperinsulinemia. Both STRESS and MTS had elevated leptin with lower adiponectin and corticosterone compared to CTL. In summary, neonatal stress promotes greater abdominal VAT accumulation and, in males, caused hyperinsulinemia and hypoadiponectinemia. Importantly, MTS normalized the VAT/SAT ratio and prevented hyperinsulinemia. We speculate that MTS ameliorates some of the negative metabolic consequences of early life perturbations due to neonatal stress exposure.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Animals, Newborn; Blood Glucose; Corticosterone; Female; Hyperinsulinism; Hyperoxia; Hypoxia; Insulin; Leptin; Male; Physical Stimulation; Rats; Rats, Sprague-Dawley; Sex Factors; Stress, Physiological; Stress, Psychological; Touch

We previously reported elevated adipose leptin expression, plasma leptin concentrations, and adrenocortical leptin receptor expression in the long-term hypoxic (LTH) ovine fetus. This study addressed whether leptin antagonist (LA) administration to LTH fetal sheep altered expression of key genes governing cortisol synthesis. Ewes were maintained at high altitude (3,820 meters) from 40 to 130 days gestation (dG), returned to Loma Linda University, and implanted with a maternal tracheal catheter. Reduced Po2 was maintained by nitrogen infusion. On 132 dG, LTH (n = 11) and age-matched, normoxic control (n = 11) fetuses underwent vascular catheter implantation. At 138 dG, fetuses were continuously infused with either saline or the LA (1.5 mg·kg(-1)·day(-1)) for 4 days and samples collected for blood gases, ACTH, and cortisol. Fetal adrenal cortex was collected for determination of steriodogenic acute regulatory protein (StAR), ACTH, and leptin receptor, cholesterol side-chain cleavage (CYP11A1), cytochrome P-450 11β-hydroxylase (CYP11B1), 17α-hydroxylase (CYP17), 21-hydroxylase (CYP21), signal transducer and activator of transcription 3 (STAT3), pSTAT3, and 17β-hydroxysteroid dehydrogenase (HSD3B) expression. In the saline-infused LTH fetuses, StAR, ACTH receptor, CYP11A1, and CYP17 expression was significantly lower compared with control (P < 0.05), whereas levels of CYP11B1, CYP21, and HSD3B mRNA were similar between groups. LA infusion restored expression of StAR, pSTAT3, CYP11A1, and CYP17, but not ACTH receptor, to normal ontogenic levels in the LTH group while having no effect on control fetuses. Neither fetal plasma ACTH nor cortisol concentrations were altered by LA infusion. We speculate that while leptin plays a role in governing expression of key enzymes and StAR in response to LTH, other factors play a role in modulating cortisol synthesis in these fetuses.

Topics: 17-Hydroxysteroid Dehydrogenases; Adrenal Cortex; Animals; Female; Fetus; Gene Expression Regulation; Gestational Age; Hydrocortisone; Hypoxia; Leptin; Receptors, Corticotropin; Receptors, Leptin; Sheep; Steroid 21-Hydroxylase; Time Factors

Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently.. Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF- 1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified.. Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only.. WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

Topics: Adipocytes, White; Adipokines; Adipose Tissue, Brown; Animals; Antimutagenic Agents; Cells, Cultured; Cobalt; Deferoxamine; Hypoxia; Immunoblotting; Leptin; Mice; Siderophores

Glomus cells within the carotid body are known to respond to hypoxic stimuli. Recently, these cells have been shown to express the long form of the leptin receptor (Ob-Rb). However, whether these glomus cells expressing the Ob-Rb are activated by hypoxic stimuli is not known. Therefore, in this study we investigated whether intermittent hypoxia (IH) or changes in circulating levels of leptin induced phosphorylated signal transducer and activator of transcription 3 (pSTAT3), the immediate early gene c-fos protein, or fos-related antigen-1 protein (Fra-1) within carotid body glomus cells that expressed the Ob-Rb, and within neurons of the petrosal (PG) and nodose (NG) ganglia. Rats were subjected to IH (120 s normoxia, 80s hypoxia for 8h) or normoxia (8h), or intravenous injections of leptin (50 or 200 ng/0.1 mL) or the vehicle saline. Plasma leptin levels were measured in animals exposed to IH and normoxia. Exposure to 8h of IH increased plasma leptin levels greater than 2-fold compared to normoxic controls. Animals were then perfused with Zamboni's fixative, and the region of the carotid bifurcation containing the carotid body and PG/NG complex was removed, paraffin embedded and sectioned at 6 μm for immunohistochemical processing. Carotid body glomus cells were identified by their expression of tyrosine hydroxylase immunoreactivity. These glomus cells also expressed the OB-Rb and were found to express pSTAT3-, fos-, and Fra-1-like immunoreactivity in response to both IH and systemic leptin injections. IH and leptin injections also increased fos and Fra-1 like expression in the PG, NG and jugular ganglion. Taken together, these data suggest IH alters circulating leptin which in turn activates directly carotid body glomus cells to exert a modulatory effect on the peripheral chemoreceptor reflex.

Topics: Animals; Carotid Body; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hypoxia; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Leptin; STAT3 Transcription Factor

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON--16% of calories from fat) or high fat diet (HF--45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival.

Topics: Adipose Tissue; Animals; Dietary Fats; Disease Models, Animal; Female; Fetal Death; Fetus; Humans; Hypoxia; Leptin; Obesity; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Triglycerides

Metabolic syndrome (MBS), a cluster of metabolic abnormalities and visceral fat accumulation, increases cardiovascular risks in postmenopausal women. In addition to visceral fat, perivascular adipose tissue has been recently found to play an important role in vascular pathophysiology. Hence, the present study investigates the effects of estrogen on both intra-abdominal fat (visceral fat) and periaortic fat (perivascular fat) accumulation as well as hypoxia in ovariectomized female rats. Female rats were divided into sham operation, ovariectomy and ovariectomy with 17β-estradiol supplementation groups. Twelve weeks later, we found that estrogen improved MBS via reducing body weight gain, the weight of periaortic and intra-abdominal fat, hepatic triglyceride, and total serum cholesterol levels. Estrogen also increased insulin sensitivity through restoring glucose and serum leptin levels. For periaortic fat, western blot showed estrogen inhibited hypoxia by reducing the levels of VEGF and HIF-1α, which is consistent with the results from immunohistochemical staining. The correlation analysis indicated that perivascular fat had a positive correlation with body weight, intra-abdominal fat or serum total cholesterol, but a negative correlation with insulin sensitivity index. For intra-abdominal fat, real-time fluorescent RT-PCR showed estrogen improved fat dysfunction via reducing the levels of relative leptin, MCP-1 but increasing adiponectin mRNA. Estrogen reduced the levels of VEGF and HIF-1α to inhibit hypoxia but restored the levels of PPARγ and Srebp-1c, which are important for lipid capacity function of intra-abdominal fat. These results demonstrated estrogen improved MBS through down-regulating VEGF and HIF-1α to inhibit hypoxia of periaortic and intra-abdominal fat in ovariectomized female rats.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Chemokine CCL2; Cholesterol; Down-Regulation; Estrogens; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Metabolic Syndrome; Organ Size; Ovariectomy; PPAR gamma; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Triglycerides; Uterus; Vascular Endothelial Growth Factor A

Appetite suppression is a common response to hypoxia in fish that confers significant energy savings. Yet little is known about the endocrine signals involved in the regulation of food intake during chronic hypoxia. Thus, we assessed the impact of chronic hypoxia on food intake, the expression of the potent anorexigenic signal leptin and its receptor (lepr), the mRNA levels of key hypothalamic appetite-regulating genes, and the activity of the hypothalamic-pituitary-interrenal (HPI) axis in common carp, Cyprinus carpio. Fish exposed to 10% O(2) saturation for 8 days were chronically anorexic and consumed on average 79% less food than normoxic controls. Hypoxia also elicited gradual and parallel increases in the expression of liver leptin-a-I, leptin-a-II, lepr and erythropoietin, a known hypoxia-responsive gene. In contrast, the liver mRNA levels of all four genes remained unchanged in normoxic fish pair-fed to the hypoxia treatment. In the hypothalamus, expression of the appetite-regulating genes were consistent with an inhibition and stimulation of hunger in the hypoxic and pair-fed fish, respectively, and reduced feed intake led to a decrease in lepr. Although both treatments elicited similar delayed increases in plasma cortisol, they were characterized by distinct HPI axis effector transcript levels and a marked differential increase in pituitary lepr expression. Together, these results show that a reduction in O(2) availability, and not feed intake, stimulates liver leptin-a expression in common carp and suggest that this pleiotropic cytokine is involved in the regulation of appetite and the endocrine stress response during chronic hypoxia.

Topics: Animals; Appetite Regulation; Carps; Eating; Fish Proteins; Gene Expression Regulation; Hypothalamus; Hypoxia; Leptin; Oxygen; Pituitary Gland; Receptors, Leptin; RNA, Messenger

Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IH(L)) have not been extensively examined, it would appear that IH(L) and high-frequency intermittent hypoxia (IH(H)) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IH(H) (cycles of 90 s 6.4% O(2) and 90 s 21% O(2) during daylight), IH(L) (8% O(2) during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IH(H) and IH(L) displayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IH(L) and IH(H), with IH(L) manifesting the lowest insulin sensitivity compared with either IH(H) or CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IH(L), IH(H), and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IH(L)-exposed mice. Thus IH(H) and IH(L) elicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles.

Topics: Adaptation, Physiological; Animals; Body Weight; Circadian Rhythm; Glucose Transporter Type 4; Hypoxia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Models, Animal; Muscle, Skeletal; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rest; Time Factors; Trans-Activators; Transcription Factors

Obstructive sleep apnoea syndrome (OSAS) causes nocturnal chronic intermittent hypoxia (IH) that contributes to excess cardiovascular morbidity. To explore the consequences of IH, we used our recently developed model of nocturnal IH in healthy humans to characterise the profile of this blood pressure increase, to determine if it is sustained and to explore potential physiological mechanisms. We performed 24-h ambulatory monitoring of blood pressure in 12 healthy subjects before and after 2 weeks of IH exposure. We also assessed systemic haemodynamics, muscle sympathetic nerve activity (MSNA), ischaemic calf blood flow responses and baroreflex gain. We obtained blood samples for inflammatory markers before, during and after exposure. IH significantly increased daytime ambulatory blood pressure after a single night of exposure (3 mmHg for mean and diastolic) and further increased daytime pressures after 2 weeks of exposure (8 mmHg systolic and 5 mmHg diastolic). Mean ± sd MSNA increased across the exposure (17.2 ± 5.1 versus 21.7 ± 7.3 bursts·min⁻¹; p < 0.01) and baroreflex control of sympathetic outflow declined from -965.3 ± 375.1 to -598.4 ± 162.6 AIU·min⁻¹ ·mmHg⁻¹ (p < 0.01). There were no evident changes in either vascular reactivity or systemic inflammatory markers. These data are the first to show that the arterial pressure rise is sustained throughout the waking hours beyond the acute phase immediately after exposure. Moreover, they may suggest that sympathoactivation induced by IH likely contributes to blood pressure elevation and may derive from reduced baroreflex inhibition. These mechanisms may reflect those underlying the blood pressure elevation associated with OSAS.

Topics: Adiponectin; Adult; Blood Pressure; Body Mass Index; C-Reactive Protein; Chemokine CCL5; Female; Humans; Hypertension; Hypoxia; Intercellular Adhesion Molecule-1; Interleukin-8; Leptin; Male; Receptors, Interleukin-1; Sleep Apnea Syndromes; Sympathetic Nervous System; Tumor Necrosis Factor-alpha

Leptin and its receptor (Ob-R) are co-expressed in human placenta suggesting auto- and paracrine mechanisms of the hormone. So far it is unclear, how changes in the placental environment affect Ob-R expression. Hence, the main purpose of the study was to investigate leptin receptor expression and regulation under hypoxic conditions. The influences of hypoxia and leptin on signal transduction and cell proliferation in chorioncarcinoma cell lines as well as primary villous trophoblasts were determined.. We found a time-dependent induction of leptin receptor mRNA and protein in placental cells under hypoxic conditions. In contrast, soluble leptin receptor expression did not change under oxygen deprivation. Leptin treatment neither activated the p42/p44 nor the STAT3 pathway in placental cells, being independent of hypoxic or normoxic conditions. Furthermore, leptin added to the culture medium in high concentrations was unable to interfere with the rate of proliferation.. Our data demonstrate that hypoxia leads to an increase of Ob-R expression in placental cells. Interestingly, leptin-dependent signal transduction and proliferation remained unaffected. A possible role of the soluble leptin receptor in modulating free leptin levels will be discussed.

Topics: Cell Line, Tumor; Cell Proliferation; Choriocarcinoma; Chorionic Villi; Female; Gene Expression; Humans; Hypoxia; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oxygen; Placenta; Pregnancy; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trophoblasts; Up-Regulation; Uterine Neoplasms

Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

Topics: Acetylcholine; Animals; Chronic Disease; Hyperlipidemias; Hypoxia; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myocytes, Cardiac; Signal Transduction; Stearoyl-CoA Desaturase; Vascular Resistance

Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) during sleep. Both obesity and OSA are associated with insulin resistance and systemic inflammation, which may be attributable to tissue hypoxia. We hypothesized that a pattern of hypoxic exposure determines both oxygen profiles in peripheral tissues and systemic metabolic outcomes, and that obesity has a modifying effect. Lean and obese C57BL6 mice were exposed to 12 h of intermittent hypoxia 60 times/h (IH60) [inspired O₂ fraction (Fi(O₂)) 21-5%, 60/h], IH 12 times/h (Fi(O₂) 5% for 15 s, 12/h), sustained hypoxia (SH; Fi(O₂) 10%), or normoxia while fasting. Tissue oxygen partial pressure (Pti(O₂)) in liver, skeletal muscle and epididymal fat, plasma leptin, adiponectin, insulin, blood glucose, and adipose tumor necrosis factor-α (TNF-α) were measured. In lean mice, IH60 caused oxygen swings in the liver, whereas fluctuations of Pti(O₂) were attenuated in muscle and abolished in fat. In obese mice, baseline liver Pti(O₂) was lower than in lean mice, whereas muscle and fat Pti(O₂) did not differ. During IH, Pti(O₂) was similar in obese and lean mice. All hypoxic regimens caused insulin resistance. In lean mice, hypoxia significantly increased leptin, especially during SH (44-fold); IH60, but not SH, induced a 2.5- to 3-fold increase in TNF-α secretion by fat. Obesity was associated with striking increases in leptin and TNF-α, which overwhelmed effects of hypoxia. In conclusion, IH60 led to oxygen fluctuations in liver and muscle and steady hypoxia in fat. IH and SH induced insulin resistance, but inflammation was increased only by IH60 in lean mice. Obesity caused severe inflammation, which was not augmented by acute hypoxic regimens.

Topics: Acute Disease; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Disease Models, Animal; Hypoxia; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Oxygen; Time Factors; Tumor Necrosis Factor-alpha

Hypoxia is the most widespread deleterious consequence of eutrophication and has become a major cause of fishery decline. One feature of chronic exposure to hypoxia in fish is inhibition of feeding. In this study, we investigated if the gene that encodes the appetite-suppressing hormone leptin is regulated by hypoxia in zebrafish (Danio rerio). Exposure of adult zebrafish to hypoxic conditions (1+/-0.2 mg O(2) L(-1)) for 4 and 10 days significantly increased leptin-a (zlep-a) mRNA levels in the liver. To evaluate the role of hypoxia-inducible factor 1 (HIF-1) in regulating zlep-a expression, zebrafish embryos were exposed to cobalt chloride (CoCl(2), a HIF-1 inducer) and overexpressed with HIF-1alpha mRNA. Both CoCl(2) treatment and HIF-1alpha overexpression markedly increased zlep-a expression in developing embryos, indicating the possible involvement of HIF-1 in zlep-a regulation. In vivo promoter analysis indicated that zlep-a promoter activity is found in the muscle fibers of zebrafish embryos and enhanced by CoCl(2). This is the first report to show that leptin gene expression in fish is regulated by hypoxia possibly via the involvement of HIF-1.

Topics: Animals; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Liver; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Zebrafish; Zebrafish Proteins

Hypoxia is a strong modulator of angiogenesis, accelerating adipose tissue expansion, suggesting that hypoxia inducible factor 1alpha (HIF1alpha) can be a novel target for anti-obesity. We conjugated antisense-HIF1alpha-oligonucleotide (ASO) with low molecular weight protamine (LMWP), a cell-penetrating peptide, to enhance its ability to block hypoxic-angiogenesis, thereby eliciting an anti-obesity effect. Nano-sized ASO-LMWP (AS-L) conjugates enhanced cellular uptake of ASO without yielding a cytotoxic effect and protected the ASO against enzymatic attack and chemical reduction. AS-L showed enhanced intra-cellular localization compared to naked ASO and the complex of ASO with lipofectamine during hypoxic-differentiation. Consequently AS-L induced significant down-regulation of leptin and VEGF gene expressions, thereby reducing fat accumulation in the cell. This proof-of-concept study shows that AS-L produces an inhibitory effect on adipogenesis and angiogenesis during differentiation, indicating LMWP mediated ASO delivery can potentially be a safe and promising treatment for obesity.

Topics: Adipocytes; Adipogenesis; Animals; Cell Differentiation; Cell Hypoxia; Down-Regulation; Gene Expression; Hypoxia; Leptin; Mice; Molecular Weight; Obesity; Oligonucleotides; Oligonucleotides, Antisense; Peptides; Protamines

Normal gestation implants on a relatively hypoxic deciduas so that trophoblast deeply invades endometrium and angiogenesis seeks for oxygen supply. If implantation occurs before those hypoxic conditions occur, trophoblast invasion is defective, due to the relatively high oxygen tension in the decidual environment, laying the foundations for subsequent pre-eclampsia.

Topics: Carbon Monoxide; Female; Humans; Hyperoxia; Hypoxia; Leptin; Oxidative Stress; Pre-Eclampsia; Pregnancy; Smoking

Molecular mechanism underlying leptin-mediated neuronal protection against glucose-oxygen-serum deprivation (GOSD) insult was investigated by focusing on the interactions among leptin, Interleukin-1beta (IL-1beta) and glutamate and their impacts on the growth of neurons under GOSD. The trypan blue dye exclusion assay, 4', 6-diamidino-2-phenylindole (DAPI) assay, cytokine antibody array assay, immunocytochemical staining assay, glutamate determination kit, immunoblocking and chemical blocking strategies were applied to serve the study goal. Results showed that in response to 6 h of GOSD, cortical neurons can secrete significant amounts of leptin and IL-1beta to protect neurons from GOSD-induced cell damage. Serine/threonine kinase Akt (Akt) and extracellular signal-related kinase (ERK) inhibitors significantly reversed leptin-mediated neuroprotection. GOSD-induced IL-1beta was further enhanced by leptin in Akt/ERK-dependent manner. Blockade of endogenous leptin with specific antibodies significantly inhibited GOSD-induced IL-1beta expression and increased glutamate release from GOSD neurons. IL-1 blockade with IL-1 receptor antagonist (IL-1ra) on the other hand, inhibited leptin-mediated neuroprotection and suppression of glutamate release from GOSD neurons. Pre-treating GOSD neurons with leptin and IL-1beta in combined significantly increased their survival but decreased their releases of glutamate. The results indicate that leptin may act through Akt and ERK signaling pathways to protect neurons from GOSD insult; the protection was in part IL-1beta dependent and through which the glutamate release from GOSD neurons was inhibited. Therapeutic values of leptin and IL-1beta were suggested in the treatment of cerebral ischemia at early stage.

Topics: Analysis of Variance; Animals; Cells, Cultured; Cerebral Cortex; Glucose; Glutamic Acid; Hypoxia; Immunohistochemistry; Interleukin-1beta; Leptin; Neurons; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors

The aim of this study was to determine the effects of intermittent hypoxia training (IHT), with and without fatty-diet, on bodyweight, serum glucose, leptin, insulin, and their receptors, and to test whether erythropoietin (EPO) mediates these effects.. Kunming mice were divided into four groups. 1: untreated control; 2: IHT; 3: fatty-diet; 4: fatty-diet and IHT. After 40 days exposure to IHT, the bodyweight, serum glucose, serum leptin, insulin and EPO were measured by ELISA. Liver leptin and insulin receptors were quantified. A separate set of mice were treated with several doses of EPO (0-320 U/kg i.p.) for 5 days. In addition, human hepatic cell lines were treated with EPO for 24h and the expression of genes OB-Ra, OB-Rb and IR were measured using RT-PCR.. IHT reduced bodyweight and serum glucose, with corresponding increases in the serum levels of leptin, insulin, EPO and expression of leptin and insulin receptors in liver. Repeated EPO treatment increased serum leptin concentration, but had no effects on insulin levels. The expression of the genes OB-Ra, OB-Rb and IR were increased after EPO treatment.. We postulate that, in mice, IHT reduces bodyweight and serum glucose by increasing EPO synthesis which secondarily increases leptin and insulin production in liver.

Topics: Animals; Blood Glucose; Body Weight; Cell Line; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hypoxia; Leptin; Liver; Mice; Receptor, Insulin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction

Individuals affected by hypoxia experience a variety of immune-associated sickness symptoms including malaise, fatigue, lethargy and loss of interest in the physical and social environment. Recently, we demonstrated that the interleukin (IL)-1beta arm of the neuroimmune system was critical to the sickness symptoms caused by hypoxia, and that IL-1 receptor antagonist (IL-1RA), IL-1beta's endogenous inhibitor, was critical to promoting sickness recovery. Here, we report that leptin is key to recovery from hypoxia because it dramatically augmented IL-1RA production in mice. We found that hypoxia increased leptin in white adipose tissue (WAT) which in turn, caused a marked rise in serum IL-1RA. Interestingly, in-vitro, leptin was a more potent inducer of IL-RA, in macrophages, than hypoxia. In leptin receptor defective (db/db) and leptin deficient (ob/ob) mice, sickness recovery from hypoxia was delayed 3-fold. Importantly, in ob/ob mice, leptin administration completely reversed this delayed recovery and induced a marked increase in serum IL-1RA. Finally, leptin administration to normal mice reduced hypoxia recovery time by 1/3 and dramatically increased WAT and serum IL-1RA. Leptin did not alter recovery from hypoxia in IL-1RA knock out mice. These results show that by enhancing IL-1RA production leptin promoted sickness recovery from hypoxia.

Topics: Adipose Tissue, White; Animals; Behavior, Animal; Enzyme-Linked Immunosorbent Assay; Hypoxia; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Leptin; Macrophages; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Movement; Receptors, Leptin; Time Factors

Leptin is an adipose hormone endowed with angiopoietic, neurotrophic, and neuroprotective properties. We tested the hypothesis that leptin might act as an endogenous mediator of recovery after ischemic stroke and investigated whether nuclear transcription factors kappaB activation is involved in leptin-mediated neuroprotection.. The antiapoptotic effects of leptin were evaluated in cultured mouse cortical neurons from wild-type or NF-kappaB/c-Rel(-/-) mice exposed to oxygen-glucose deprivation. Wild-type, c-Rel(-/-) and leptin-deficient ob/ob mice were subjected to permanent middle cerebral artery occlusion. Leptin production was measured in brains from wild-type mice with quantitative reverse transcriptase-polymerase chain reaction and immunostaining. Mice received a leptin bolus (20 microg/g) intraperitoneally at the onset of ischemia.. Leptin treatment activated the nuclear translocation of nuclear transcription factors kappaB dimers containing the c-Rel subunit, induced the expression of the antiapoptotic c-Rel target gene Bcl-xL in both control and oxygen-glucose deprivation conditions, and counteracted the oxygen-glucose deprivation-mediated apoptotic death of cultured cortical neurons. Leptin-mediated Bcl-xL induction and neuroprotection against oxygen-glucose deprivation were hampered in cortical neurons from c-Rel(-/-) mice. Leptin mRNA was induced and the protein was detectable in microglia/macrophage cells from the ischemic penumbra of wild-type mice subjected to permanent middle cerebral artery occlusion. Ob/ob mice were more susceptible than wild-type mice to the permanent middle cerebral artery occlusion injury. Leptin injection significantly reduced the permanent middle cerebral artery occlusion-mediated cortical damage in wild-type and ob/ob mice, but not in c-Rel(-/-) mice.. Leptin acts as an endogenous mediator of neuroprotection during cerebral ischemia. Exogenous leptin administration protects against ischemic neuronal injury in vitro and in vivo in a c-Rel-dependent manner.

Topics: Animals; bcl-X Protein; Blotting, Western; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Cerebral Infarction; DNA; Female; Fluorescent Antibody Technique; Glucose; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hypoxia; Immunohistochemistry; Immunoprecipitation; Leptin; Mice; Mice, Inbred C57BL; NF-kappa B; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Up-Regulation

Topics: Animals; Cytokines; Humans; Hypoxia; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Leptin; Social Behavior

Hypoxia and insulin are known key players in the activation leptin transcription and translation in vivo and in vitro. These insulin- and hypoxia-dependent effects are leptin transcription are mediated via independent elements on the leptin-promotor, even more coincubation of the two stimuli in vitro results in a supraadditive effect on leptin transcription. The aim of this study was to examine whether hyperinsulinemia is able to interfere with the hypoxia-driven expression of leptin in adipose and extra-adipose tissue in vivo.. We used the KK/HlJ mouse strain as a model for hyperinsulinemia and C57BL/6J mice as control. These two groups were exposed to hypoxia for 12 h. Serum levels of insulin and leptin were analyzed by ELISA, mRNA expression of leptin was measured via real-time PCR.. In the hyperinsulinemic KK/HlJ mice, hypoxia was not able to further increase the amount of leptin in serum. Instead, a significant decrease of insulin levels was detected, while serum leptin and insulin levels increased in C57BL/6J. Analysis of leptin mRNA expression in subcutaneous fat, mesenteric fat and kidney revealed that hypoxia induces leptin transcription in kidneys of C57/BL6 but not in hyperinsulinemic animals. In contrast, leptin expression in adipose tissue was not increased during hypoxia.. We conclude that leptin regulation during hypoxia in vivo depends at least in part on the modulating role of insulin. The hypoxia driven induction of insulin expression in C57/BL6 animals may be responsible for the stimulation of leptin transcription. In contrast, already hyperinsulinemic animals showed no induction - neither of insulin nor leptin after short-term hypoxia.

Topics: Animals; Blood Glucose; Body Weight; Hyperinsulinism; Hypoxia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Transcription, Genetic

To develop an intermittent hypoxia/reoxygenation (IH/ROX) rabbit carotid artery model and then investigate the inflammation status of rabbit carotid artery endothelium after IH exposure and its relationship with leptin.. After anesthetization, rabbit's right common carotid artery was cleared of surrounding tissue with anatomic microscope, cannulated to its distal part and the proximal part was ligated. Preparations were challenged by changing the PO(2) of the gas mixture equilibrating the perfusate. Alternate perfusing (2 mL/min) of equilibrated perfusate bubbled with normoxia or hypoxia gas mixtures formed IH/ROX cycles in the right carotid common artery, simulating the pattern of hypoxic episodes seen in obstructive sleep apnea (OSA), or continuous perfusing of hypoxia perfusate to form continuous hypoxia (CH) modes. Sixty adult male New Zealand White rabbits (2.5-3.0 kg) were separated into six groups, ten per group. Groups were: A, intermittent normoxia (IN) group, perfused with perfusion equilibrated with 21% O(2) [PO(2) about 141 +/- 2.87 mmHg] for 15 s and 21% O(2) for 1 min 45 s, 60 cycles; B, severe IH group, 5% O(2) [PO(2) about 35.2 +/- 1.27 mmHg] 15 s and 21% O(2) 1 min 45 s, 60 cycles; C, mild IH group, 10% O(2) [PO(2) about 54.3 +/- 3.31 mmHg] 15 s and 21% O(2) 1 min 45 s, 60 cycles; D, severe IH+Lep group, protocol was the same with severe IH group; E, CH group, IN for 1 h 45 min and then 5% O(2) for 15 min; and F, Lep group, the same with IN group. Right common carotid artery parts distal to the cannula were harvested after exposure, and endothelial cell layers were gotten from longitudinal outspread vessels. Nuclear factor kappaB (NFkappaB) DNA binding activities of partial cell layers were measured with electrophoretic mobility shift assay in the IN group, severe IH group, mild IH group, and CH group nuclear extracts. The other part of the cell layers in the IN group, severe IH group, severe IH+Lep group, and Lep group were cultured for 2 h, and during the culture procedure, recombinated human leptin solutions were added to culture dishes of severe IH+Lep group and Lep group (resulted concentration, 10 ng/mL). Enzyme-linked immunosorbent assay was used to analyze medium interleukin-6 (IL-6) concentrations, reverse transcription polymerase chain reaction was used to analyze endothelial cell Ras homology A (RhoA) mRNA expression levels. Statistical analysis was done with SPSS 11.5 software package.. NFkappaB DNA binding activities were significantly different between groups (F = 112.428, P < 0.001). This activity in the severe IH group (4.27 +/- 0.64) was higher than that in the mild IH group (2.33 +/- 0.45, P < 0.001), IN group (1.00 +/- 0.26, P < 0.001), and CH group (1.15 +/- 0.36, P < 0.001). RhoA mRNA expression levels were different in groups (F = 26.634, P < 0.001).This level in the severe IH+Lep group (2.54 +/- 0.53) was higher than that in the severe IH group (1.57 +/- 0.44, P = 0.002), IN group (1.00 +/- 0.31, P < 0.001), and Lep group (1.31 +/- 0.30, P < 0.001). IL-6 concentrations were different in groups (F = 79.922, P < 0.001). IL-6 concentration in the severe IH+Lep group (1591.50 +/- 179.57 pg/mL) was higher than that in the severe IH group (1217.20 +/- 320.62 pg/mL, P = 0.036), IN group (325.40 +/- 85.26 pg/mL, P < 0.001), and Lep group (517.40 +/- 183.09 pg/mL, P < 0.001).. IH/ROX activated the inflammation pathway significantly in the endothelium, which was more intensive than CH and intensity-dependent. When exposed to both IH/ROX and leptin, inflammation occurs more dramatically. It means that synergic activating roles were performed by IH/ROX and leptin. This study may have a clinical implication that IH can cause endothelial damage through activated inflammation in OSA patients, and if the OSA patients have obesity at the same time, the endothelial damage or the inflammation would be more significant because of elevated leptin level as a synergic factor.

Topics: Animals; Carotid Artery, Common; DNA Primers; DNA, Complementary; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Hypoxia; Interleukin-6; Leptin; Male; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; rhoA GTP-Binding Protein; RNA, Messenger; Sleep Apnea, Obstructive

Mitochondrial beta-oxidation of fatty acid provides a major source of energy in mammals. High altitude (HA), characterized by hypobaric hypoxia and low ambient temperatures, causes alteration in metabolic homeostasis. Several studies have depicted that hypoxic exposure in small mammals causes hypothermia due to hypometabolic state. Moreover, cold exposure along with hypoxia reduces hypoxia tolerance in animals. The present study investigated the rate of beta-oxidation and key enzymes, carnitine palmitoyl transferase-I (CPT-I) and hydroxyacyl CoA dehydrogenase (HAD), in rats exposed to cold-hypobaric hypoxic environment. Male Sprague Dawley rats (190-220 g) were randomly divided into eight groups (n = 6 rats in each group): 1 day hypoxia (H1); 7 days hypoxia (H7); 1 day cold (C1); 7 days cold (C7); 1 day cold-hypoxia (CH1); 7 days cold-hypoxia (CH7) exposed; and unexposed control for 1 and 7 days (UC1 and UC7). After exposure, animals were anaesthetized with ketamine (50 mg/kg body weight) and xylazine (10 mg/kg body weight) intraperitonialy and sacrificed. Mitochondrial CPT-I, HAD, (14)C-palmitate oxidation in gastrocnemius muscle and liver, and plasma leptin were measured. Mitochondrial CPT-I was significantly reduced in muscle and liver in CH1 and CH7 as compared to respective controls. HAD activity was significantly reduced in H1 and CH7, and in H1, H7, CH1, and CH7 as compared to unexposed controls in muscle and liver, respectively. A concomitant decrease in (14)C-palmitate oxidation was found. Significant reduction in plasma leptin in hypoxia and cold-hypoxia suggested hypometabolic state. It can be concluded that ss-oxidation of fatty acids is reduced in rats exposed to cold-hypoxic environment due to the persisting hypometabolic state in cold-hypoxia exposure.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Animals; Body Weight; Carbon Isotopes; Carnitine O-Palmitoyltransferase; Cold Temperature; Hypoxia; Leptin; Male; Mitochondria; Muscle, Skeletal; Oxidation-Reduction; Palmitates; Rats; Rats, Sprague-Dawley; Time Factors

Cardiomyocyte apoptosis is a component of cardiac remodeling that can contribute to heart failure in obesity. A role for leptin in mediating this process has been suggested and the objective of this work was to investigate the effect of leptin on apoptosis and associated mechanisms in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic myocardial ischemia/reperfusion. Qualitative immunofluorescent and quantitative laser scanning cytometry approaches demonstrated that exposure of cells to HR increased DNA fragmentation (TUNEL staining) which was attenuated by leptin (6 nM, 1 h) pretreatment. We also found increased annexin-V binding and caspase-3 activity in cells exposed to HR, both of which were attenuated by leptin pretreatment. Leptin reduced HR-induced translocation of the pro-apoptotic protein Bax to the mitochondrial membrane, which provides a mechanism to explain its protective effect. Consequently, leptin attenuated the HR-induced decrease in mitochondrial membrane potential and increase in cytochrome c release from mitochondria. Leptin treatment increased the phosphorylation of p38 MAPK and AMPK and respective inhibitors of these kinases, SB203580 and Compound C, prevented the ability of leptin to decrease HR-induced caspase-3 activity. In conclusion, we establish mechanisms via which leptin exerts anti-apoptotic effects that may be of significance in understanding the development of heart failure in obesity.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Annexin A5; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Line; Cytochromes c; Cytoprotection; DNA Fragmentation; Hypoxia; In Situ Nick-End Labeling; Leptin; Membrane Potential, Mitochondrial; Mitochondria; Oxygen; p38 Mitogen-Activated Protein Kinases; Phosphatidylserines; Protein Binding; Protein Kinases; Protein Transport; Rats; Signal Transduction

The endocrine system plays an important role in the adaptation to hypoxia. The aim of this study was to assess the effect of chronic hypoxia on insulin, adiponectin, leptin, and ghrelin levels in a neonatal animal model. Sprague-Dawley rats were placed in a normobaric hypoxic environment at birth. Controls remained in room air. Rats were killed at 2 and 8 weeks of life. Insulin, adiponectin, leptin, and ghrelin were measured. At 2 weeks of life, there was no significant difference in insulin, adiponectin, and leptin levels between the hypoxic and control rats. The only statistically significant difference was found in ghrelin levels, which were lower in the hypoxic group (3.19 +/- 3.35 vs 24.52 +/- 5.09 pg/mL; P < .05). At 8 weeks of life, insulin was significantly higher in the hypoxic group (0.72 +/- 0.14 vs 0.44 +/- 0.26 ng/mL; P < .05) and adiponectin was significantly lower (1257.5 +/- 789.5 vs 7817.3 +/- 8453.7 ng/mL; P < .05). Leptin and ghrelin did not show significant difference in this age group, but leptin level per body weight was higher in the hypoxic group. Finally, we conclude that 2 weeks of continuous neonatal hypoxic exposure leads to a decrease in plasma ghrelin only with no significant change in insulin, adiponectin, and leptin and that 8 weeks of hypoxia leads to a decrease in adiponectin with an increase in insulin despite a significant decrease in weight.

Topics: Adiponectin; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Female; Ghrelin; Hematocrit; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric

We investigated whether the increase of leptin expression in preeclamptic placentas is additionally influenced by soluble maternal factors under hypoxic and nonhypoxic conditions.. Term trophoblast cells were isolated and stimulated with sera from preeclamptic women under normoxic or hypoxic conditions. Levels of leptin mRNA and protein were evaluated by real-time RT-PCR or ELISA and Western blot analysis.. Leptin concentrations were increased in the serum of patients with preeclampsia and gestational diabetes. Hypoxia, insulin, and dexamethasone induced leptin expression in trophoblast cells. The incubation with sera from preeclamptic women led to a small, though, significant, increase of leptin gene expression. The effect of preeclamptic serum on leptin gene expression in trophoblast cells was lost under hypoxia. The serum of women with gestational diabetes did not increase leptin expression neither in normoxic nor hypoxic primary trophoblast cells.. Our results can not exclude a soluble maternal factor in the serum of women with preeclampsia accounting for increased leptin expression in placental tissue in addition to hypoxia. However, an important biological role of this small increase in nonhypoxic conditions does not seem very likely.

Topics: Adult; Case-Control Studies; Cells, Cultured; Diabetes, Gestational; Female; Humans; Hypoxia; Leptin; Pre-Eclampsia; Pregnancy; Trophoblasts

This article tests mice's indicators of body nutritional metabolism under tolerable hypoxic conditions, in order to explore the effects of moderate intermittent hypoxia on the bodyweight, blood sugar and blood cholesterol of obese mice and to identify the role of leptin in these effects; this study applies high-fat diet to establish Mice Obesity Models and observes the intervention effects of intermittent hypoxic training in this Model. Small healthy mice are classified in 4 groups at random, that is, Group A (Normal), Group B (Normal Hypoxia) fed with normal foods and undergoing Intermittent Hypoxic Training (IHT), Group C (Fatty-diet) fed with High-Fat and High-Sugar (HFHS) foods without IHT and Group D (Fatty-diet and Hypoxia) fed with HFHS foods with IHT. After 40 days of feeding and hypoxic training, weigh the mice, measure the levels of blood sugar and blood cholesterol with a full automatic biochemical analyzer, measure serum leptin concentration by enzyme-linked immunosorbent assay (ELISA) technique, inspect liver leptin receptor expression and liver fat slice by immunohistochemistry. It is found that compared to control group, after experiment, the average bodyweight, blood sugar, blood cholesterol and serum leptin concentration in Group C is increased significantly and numerous fat cells are distributed in the liver, which indicates that hyperlipemia model has been successfully established; after intermittent hypoxic training, the average bodyweight, blood sugar, blood cholesterol and liver fat cells distribution density and scope in Group B and D are lower than those in Group A and C, while serum leptin concentration is increased significantly; liver leptin receptor expression in Group D is higher than that in Group C. And hypoxia groups have no trauma conclusion. Moderate intermittent hypoxia can reduce bodyweight by increasing leptin concentration and enhancing liver leptin expression and it can also reduce the level of blood sugar and blood cholesterol and meanwhile prevent steatosis in liver cells effectively.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Female; Hypoxia; Leptin; Liver; Mice; Models, Biological; Obesity; Oxygen; Pressure; Receptors, Leptin; Tissue Distribution

Altitude exposure has been associated with loss of appetite and weight loss in healthy humans; however, the endocrine factors that contribute to these changes remain unclear. Leptin and glucagon-like peptide-1 (GLP-1) are peptide hormones that contribute to the regulation of appetite. Leptin increases with hypoxia; however, the influence of hypoxia on GLP-1 has not been studied in animals or humans to date. We sought to determine the influence of normobaric hypoxia on plasma leptin and GLP-1 levels in 25 healthy humans. Subjects ingested a control meal during normoxia and after 17 h of exposure to normobaric hypoxia (fraction of inspired oxygen of 12.5%, simulating approximately 4100 m). Plasma leptin was assessed before the meal, and GLP-1 was assessed premeal, at 20 min postmeal, and at 40 min postmeal. We found that hypoxia caused a significant elevation in plasma leptin levels (normoxia, 4.9 +/- 0.8 pg.mL-1; hypoxia, 7.7 +/- 1.5 pg.mL-1; p < 0.05; range, -16% to 190%), no change in the average GLP-1 response to hypoxia, and only a small trend toward an increase in GLP-1 levels 40 min postmeal (fasting, 15.7 +/- 0.9 vs 15.9 +/- 0.7 pmol.L-1; 20 min postmeal, 21.7 +/- 0.9 vs 21.8 +/- 1.2 pmol.L-1; 40 min postmeal, 19.5 +/- 1.2 vs. 21.0 +/- 1.2 pmol.L-1 for normoxia and hypoxia, respectively; p > 0.05 normoxia vs hypoxia). There was a correlation between SaO2 and leptin after the 17 h exposure (r = 0.45; p < 0.05), but no relation between SaO2 and GLP-1. These data confirm that leptin increases with hypoxic exposure in humans. Further study is needed to determine the influence of hypoxia and altitude on GLP-1 levels.

Topics: Adult; Anaerobic Threshold; Blood Cell Count; Female; Glucagon-Like Peptide 1; Hemodynamics; Humans; Hypoxia; Leptin; Male; Oxygen; Young Adult

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin; Species Specificity

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Humans; Hypoxia; Leptin

Topics: Acclimatization; Altitude; Animals; Confounding Factors, Epidemiologic; Feedback, Physiological; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin

Topics: Acclimatization; Altitude; Animals; Blood-Brain Barrier; Feedback, Physiological; Humans; Hypoxia; Leptin

Topics: Acclimatization; Altitude; Animals; Blood-Brain Barrier; Feedback, Physiological; Humans; Hypoxia; Leptin

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Humans; Hypoxia; Leptin; Sympathetic Nervous System

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Gene Expression Regulation; Humans; Hypoxia; Leptin

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin; Sleep Apnea, Obstructive

Topics: Acclimatization; Altitude; Animals; Feedback, Physiological; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin

Topics: Acclimatization; Altitude; Animals; Eating; Feedback, Physiological; Humans; Hypoxia; Leptin; Rats; Rats, Transgenic; Receptors, Leptin

Topics: Acclimatization; Altitude; Animals; Eating; Feedback, Physiological; Humans; Hypoxia; Leptin

Topics: Acclimatization; Altitude; Animals; Confounding Factors, Epidemiologic; Feedback, Physiological; Gene Expression Regulation; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin

The physiological adaptations of the neonatal rat to hypoxia from birth include changes in gastrointestinal function and intermediary metabolism. We hypothesized that the hypoxic lactating dam would exhibit alterations in mammary gland function leading to changes in the concentration of milk peptides that are important in neonatal gastrointestinal development. The present study assessed the effects of chronic hypoxia on peptides produced by the mammary glands and present in milk. Chronic hypoxia decreased the concentration of epidermal growth factor (EGF) in expressed milk and pup stomach contents and decreased maternal mammary gland EGF mRNA. The concentration of parathyroid hormone-related protein (PTHrp) was unchanged in milk and decreased in pup stomach contents; however, mammary PTHLH mRNA was increased by hypoxia. There was a significant increase in adiponectin concentrations in milk from hypoxic dams. Chronic hypoxia decreased maternal body weight, and pair feeding normoxic dams an amount of food equivalent to hypoxic dam food intake decreased body weight to an equivalent degree. Decreased food intake did not affect the expression of EGF, PTHLH, or LEP mRNA in mammary tissue. The results indicated that chronic hypoxia modulated mammary function independently of hypoxia-induced decreases in maternal food intake. Decreased EGF and increased adiponectin concentrations in milk from hypoxic dams likely affect the development of neonatal intestinal function.

Topics: Adiponectin; Animals; Animals, Suckling; Eating; Epidermal Growth Factor; Female; Hypoxia; Lactation; Leptin; Male; Mammary Glands, Animal; Milk; Parathyroid Hormone-Related Protein; Postpartum Period; Rats; Rats, Sprague-Dawley; RNA, Messenger

To determine the influence of continuous hypoxia on body weight, food intake, hepatic glycogen, circulatory glucose, insulin, glucagon, leptin, and corticosterone, and the involvement of the corticotropin-releasing factor receptor type 1 (CRFR1) in modulation of these hormones, rats were exposed to a simulated altitude of 5 km (approximately 10.8% O2) in a hypobaric chamber for 1, 2, 5, 10, and 15 d. Potential involvement of CRFR1 was assessed through five daily sc injections of a CRFR1 antagonist (CP-154,526) prior to hypoxia. Results showed that the levels of body weight, food intake, blood glucose, and plasma insulin were significantly reduced; the content of hepatic glycogen initially and transiently declined, whereas the early plasma glucagon and leptin remarkably increased; plasma corticosterone was markedly increased throughout the hypoxic exposure of 1-15 d. Compared with hypoxia alone, CRFR1 antagonist pretreatment in the hypoxic groups prevented the rise in corticosterone, whereas the levels of body weight and food intake were unchanged. At the same time, the reduction in blood glucose was greater and the pancreatic glucose was increased, plasma insulin reverted toward control, and plasma glucagon decreased. In summary, prolonged hypoxia reduced body weight, food intake, blood glucose, and plasma insulin but transiently enhanced plasma glucagon and leptin. In conclusion, CRFR1 is potentially involved in the plasma insulin reduction and transient glucagon increase in hypoxic rats.

Topics: Altitude; Animals; Blood Glucose; Body Weight; Corticosterone; Eating; Glucagon; Hypoxia; Insulin; Leptin; Liver Glycogen; Male; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone

In order to explore the effect and underlying mechanism of hypoxia on body weight, the effect of intermittent moderate hypoxia on high-fat diet-induced obesity was observed in mice, and the role of leptin in hypoxic effect was identified. Healthy Kunming mice were divided randomly into 4 groups (n=20 in each group). The control group: the mice were fed normally under the normal oxygen pressure. Hypoxia group: the mice were fed normally, and given intermittent moderate hypoxia training. Obesity group: the mice were fed diet rich in fat and sugar under the normal oxygen pressure. Hypoxia + obesity group: the mice were fed diet rich in fat and sugar, and given intermittent moderate hypoxia training. After 40 d of feeding and training, the body weight of mice was determined, and the average increasing rate of body weight in each group was calculated and normalized with food intake. Meanwhile, plasma leptin level was measured with ELISA method, and fatty degeneration and leptin receptor expression in liver were observed by Sudan III staining and immunohistochemistry, respectively. The obesity mouse model was successfully established with increases in body weight, plasma leptin level and distribution of adipocytes in the liver. The average body weight and density of adipocytes in the liver in hypoxia and hypoxia + obesity groups decreased obviously, while plasma leptin level and leptin receptor expression in the liver were increased. It is suggested that intermittent moderate hypoxia reduces body weight through elevating plasma leptin level and/or enhancing leptin receptor expression in the liver.

Topics: Adipocytes; Animals; Body Weight; Female; Hypoxia; Immunohistochemistry; Leptin; Liver; Mice; Mice, Obese; Obesity; Receptors, Leptin

Chronic hypoxia induces complex metabolic and endocrine adaptations. High-altitude (HA) exposure is a physiological model of hypoxia.. To further investigate the endocrine and metabolic responses to extreme HA.. We studied nine male elite climbers at sea level and at 5200 m after climbing Mt. Everest.. After 7 weeks at HA, body weight was reduced (P<0.05); regarding endocrine variables we observed: a) an increase of 2-h mean GH concentration (P<0.05) as well as of total IGF-I and IGF binding protein-3 levels (P<0.05 for both); b) a prolactin increase (P<0.05) coupled with testosterone decrease (P<0.01) and progesterone increase (P<0.05) without any change in estradiol levels: c) no change in cortisol, ACTH, and dehydroepiandrosterone sulfate (DHEAS) levels; d) an increase in free thyroxine (P<0.05) and free tri-iodothyronine (T(3)) decrease (P<0.05) but no change in TSH levels; e) a plasma glucose decrease (P<0.05) without any change in insulin levels; f) an increase in mean free fatty acid levels (P<0.05); g) despite body weight loss, leptin levels showed non-significant trend toward decrease, while ghrelin levels did not change at all.. The results of the present study in a unique experimental human model of maximal exposure to altitude and physical exercise demonstrate that extreme HA and strenuous physical exercise are coupled with specific endocrine adaptations. These include increased activity of the GH/IGF-I axis and a low T(3) syndrome but no change in ghrelin and leptin that was expected taking into account body weight decrease. These findings would contribute to better understanding human endocrine and metabolic physiology in hypoxic conditions.

Topics: Adult; Altitude; Body Weight; Estradiol; Exercise; Human Growth Hormone; Humans; Hypoxia; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Pituitary Hormones; Progesterone; Prolactin; Testosterone; Thyroxine; Triiodothyronine

Hypoxia-inducible transcription factors (HIFs) have been characterized as the most important regulators of O(2)-dependent gene transcription. We investigated expression of HIF-dependent growth factors and HIF-independent somatotrophic factors in term placenta in response to hypoxic ischemia.. Our cross-sectional in vivo analysis included term placentas of gestations complicated by the following: (1) birth asphyxia (n = 22); (2) chronic hypoxic ischemia (n = 22); and (3) controls (n = 28). Gene expression of leptin, insulin-like growth factor (IGF)-1, IGF-2, ghrelin, and human placental growth hormone (hPGH) were measured by TaqMan reverse transcriptase-polymerase chain reaction.. Acute and chronic hypoxia significantly increased leptin messenger ribonucleic acid (mRNA) levels, compared with controls (P < .001). Augmented IGF-2 mRNA levels were present in chronic hypoxia (P < .001) but not in birth asphyxia. IGF-1, ghrelin, and hPGH mRNA levels did not change in relation to hypoxia.. IGF-2 and leptin are suggested to be involved in adaptive response to hypoxic ischemia in term placenta with differential transcriptional regulation related to the duration of hypoxia.

Topics: Cross-Sectional Studies; Gene Expression; Humans; Hypoxia; Infant, Newborn; Insulin-Like Growth Factor II; Intercellular Signaling Peptides and Proteins; Ischemia; Leptin; Placenta

Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels.. The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations.. We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study.. The average age of the subjects was (mean +/- SE) 62 +/- 13 years, BMI 40.9 +/- 2.2 kg/m(2), PaCO(2) 6.7 +/- 0.2 kPa, PaO(2 )8.9 +/- 0.4 kPa and total respiratory disturbance index 44 +/- 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6-3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred.. Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.

Topics: Body Mass Index; Carbon Dioxide; Continuous Positive Airway Pressure; Female; Humans; Hypercapnia; Hypoventilation; Hypoxia; Leptin; Male; Middle Aged; Obesity; Oxygen; Polysomnography; Positive-Pressure Respiration; Prospective Studies; Sleep Apnea, Obstructive; Syndrome

Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains under discussion and that of orexigenic and anorexigenic hypothalamic neuropeptides remains unknown. The present study was designed to address this issue by using obese (Lepr(fa)/Lepr(fa)) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygous lean (Lepr(FA)/Lepr(FA)) and obese (Lepr(fa)/Lepr(fa)) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2, or 4 days (barometric pressure, 505 hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue with real-time quantitative PCR and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38 and 67% of initial values at day 1, respectively, P < 0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic neuropeptide Y levels in lean rats 2 days after hypoxia exposure contributed to accounting for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorectic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Gene Expression; Hematocrit; Hypoxia; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

This study was designed to test the hypothesis that long-term hypoxia (LTH) increases fetal plasma leptin and fetal adipose or placental leptin expression and alters hypothalamic and adrenocortical leptin receptor (OB-R) expression. Pregnant ewes were maintained at high altitude (3,820 m) from day 30 to approximately 130 days of gestation. Reduced Po2 was maintained in the laboratory by nitrogen infusion through a maternal tracheal catheter. On day 132, normoxic control and LTH fetuses underwent surgical implantation of vascular catheters (n=6 for each group). Five days after surgery, maternal and fetal arterial blood samples were collected for leptin, insulin, and glucose analysis. Placental tissue, periadrenal fat, and fetal hypothalami and adrenal glands were collected from additional control (n=7) and LTH (n=8) fetuses for analysis of leptin mRNA by quantitative, real-time, RT-PCR (qRT-PCR). There was a significant (P<0.03) elevation in fetal plasma leptin in the LTH fetuses (3.5+/-0.7 ng/ml) vs. control (1.1+/-0.1 ng/ml). There were no differences in either glucose or insulin concentrations between the two groups. Periadrenal adipose leptin mRNA was significantly higher in the LTH group compared with control, as was placental leptin expression. The levels of leptin mRNA in adipose were approximately 70 times higher vs. placenta. LTH significantly reduced expression of OB-Ra (short-isoform) in the hypothalamus (P=0.0156), while resulting in a significant increase in adrenal OB-Rb (long-form) expression (P<0.03). Our data suggest that leptin is a hypoxia-inducible gene in the ovine fetus and OB-R expression is altered by LTH. These changes may be responsible in part, for our previously observed alterations in fetal hypothalamic-pituitary-adrenal function following LTH.

Topics: Adipose Tissue; Adrenal Glands; Animals; Female; Fetus; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Hypothalamus; Hypoxia; Leptin; Pituitary-Adrenal System; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Sheep

Hypertension frequently occurs in obese subjects. It has been reported that leptin and resistin induce endothelin-1 expression in vascular endothelial cells. Altered function of brain microvascular endothelial cells may be related to increased occurrences of stroke in hypertensive patients. In the present study, we therefore studied the effects of leptin and resistin on the expression of endothelin-1 and adrenomedullin in bovine brain microvascular endothelial cells. Northern blot analysis showed that leptin (10(-10)-10(-8) mol/l), resistin (10(-10)-10(-8) mol/l) or a combination of leptin and resistin (10(-8) mol/l for each) had no significant effects on the expression of endothelin-1 mRNA or adrenomedullin mRNA in cultured bovine brain microvascular endothelial cells. On the other hand, hypoxia induced, and tumor necrosis factor-alpha (10 ng/ml) decreased, the expression levels of endothelin-1 and adrenomedullin mRNAs, indicating that the bovine brain microvascular endothelial cells were able to respond to hypoxia and tumor necrosis factor-alpha. Consistent with the results of Northern blot analysis, immunoreactive endothelin and immunoreactive adrenomedullin concentrations in the medium were not significantly changed by the treatment with leptin, resistin, or a combination of leptin and resistin. The present study thus showed that neither leptin nor resistin affects the expression of endothelin-1 or adrenomedullin in bovine brain microvascular endothelial cells.

Topics: Adrenomedullin; Animals; Brain; Cattle; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Hypertension; Hypoxia; Leptin; Microcirculation; Peptides; Resistin; RNA, Messenger; Stroke; Tumor Necrosis Factor-alpha

The lipodystrophic syndrome (LD) is a disorder resulting from selective damage of adipose tissue by antiretroviral drugs included in therapy controlling human-immunodeficiency-virus-1. In the therapy cocktail the nucleoside reverse transcriptase inhibitors (NRTI) contribute to the development of this syndrome. Cellular target of NRTI was identified as the mitochondrial polymerase-gamma and their toxicity described as a mitochondrial DNA (mtDNA) depletion resulting in a mitochondrial cytopathy and involved in fat redistribution. No mechanisms offer explanation whatsoever for the lipo-atrophic and lipo-hypertrophic phenotype of LD. To understand the occurrence we proposed that the pO2 (oxygen partial pressure) could be a key factor in the development of the LD. For the first time, we report here differential effects of NRTIs on human adipose cells depending on pO2 conditions.. We showed that the hypoxia conditions could alter adipogenesis process by modifying expression of adipocyte makers as leptin and the peroxisome proliferator-activated receptor PPARgamma and inhibiting triglyceride (TG) accumulation in adipocytes. Toxicity of NRTI followed on adipose cells in culture under normoxia versus hypoxia conditions showed, differential effects of drugs on mtDNA of these cells depending on pO2 conditions. Moreover, NRTI-treated adipocytes were refractory to the inhibition of adipogenesis under hypoxia. Finally, our hypothesis that variations of pO2 could exist between adipose tissue from anatomical origins was supported by staining of the hypoxic-induced angiopoietin ANGPTL4 depended on the location of fat.. Toxicity of NRTIs have been shown to be opposite on human adipose cells depending on the oxygen availability. These data suggest that the LD phenotype may be a differential consequence of NRTI effects, depending on the metabolic status of the targeted adipose tissues and provide new insights into the opposite effects of antiretroviral treatment, as observed for the lipo-atrophic and lipo-hypertrophic phenotype characteristic of LD.

Topics: Adipogenesis; Adipose Tissue; Cells, Cultured; DNA, Mitochondrial; Gene Expression Regulation; HIV-Associated Lipodystrophy Syndrome; Humans; Hypoxia; Leptin; Oligopeptides; Oxygen; Peptides, Cyclic; Phenotype; PPAR gamma; Reverse Transcriptase Inhibitors; Somatostatin; Triglycerides

Leptin is a circulating hormone that is secreted primarily by adipose tissue. However, recent studies have demonstrated leptin production by other tissues, including placenta, stomach, kidney, liver, and lung, a process not only activated by stimuli such as insulin or corticosteroids, but also by hypoxia, which is mediated by the hypoxia inducible factor-1. In contrast to this fact, smokers have lower plasma leptin levels. The purpose of this study was to determine whether tissue hypoxygenation [induced by lack of oxygen] or inhalation of carbon monoxide (CO) are sufficient to up-regulate leptin in fat cells as well as in peripheral organs such as lung, liver, and kidney of rats. In hypoxic rats, leptin expression was unchanged or even reduced in adipose tissue. In contrast, in liver, kidney, and lung we observed an increase in leptin expression compared with normoxic controls, whereas plasma levels were unchanged. When animals were exposed to CO, generating a functional anemia known to activate the HIF-1-dependent transcription, a significant decrease in leptin gene expression in adipose tissue and in all organs tested was observed. Plasma leptin concentrations after CO exposure were significantly diminished compared with those in control animals. These findings suggest that tissue hypoxygenation up-regulates leptin expression in nonadipose tissue. However, this is not sufficient to raise plasma leptin levels in rats. Inhalation of CO leads to a significant decrease in leptin mRNA and protein concentration in the plasma of the animals, suggesting a negative effect of CO on leptin transcription.

Topics: Acute Disease; Adipose Tissue; Administration, Inhalation; Animals; Carbon Monoxide; Drug Administration Schedule; Gene Expression; Hypoxia; Kidney; Leptin; Liver; Lung; Rats; Rats, Sprague-Dawley; RNA, Messenger

To investigate the influence of hypoxia on leptin and leptin receptor gene expression of C57BL/6J mice.. C57BL/6J mice, exposed to hypoxia in the man-made auto pressure and hypoxia control cabin (XQ-I), were divided into 3 groups: the normal control group, 24 h hypoxia group and 48 h hypoxia group. Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA levels of leptin and leptin receptor.. (1) Compared with the normal control group (0.508 +/- 0.207), the leptin mRNA level of 24 h hypoxia group (0.903 +/- 0.190) and 48 h hypoxia group (0.856 +/- 0.336) were up-regulated markedly (all < 0.05); (2) Compared with the normal control group (Ra 0.630, Rb 0.258 +/- 0.049, Rc 0.133), the Ra, Rb, Rc mRNA levels of 24 h hypoxia group (Ra 0.724, Rb 0.381 +/- 0.038, Rc 0.299) and 48 h hypoxia group (Ra 0.700, Rb 0.345 +/- 0.042, Rc 0.292) were up-regulated to different degrees.. As an independent factor, hypoxia can stimulate increased expression of leptin, leptin receptor Ra, Rb, Rc mRNA. It is suggested that leptin play an important role in positive regulation of respiratory function.

Topics: Adipose Tissue; Animals; Hypoxia; Leptin; Male; Mice; Mice, Inbred C57BL; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Time Factors

Ghrelin, leptin, and endogenous glucocorticoids play a role in appetite regulation, energy balance, and growth. The present study assessed the effects of dexamethasone (DEX) on these hormones, and on ACTH and pituitary proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor-1 (CRHR1) mRNA expression, during a common metabolic stress - neonatal hypoxia. Newborn rats were raised in room air (21% O2) or under normobaric hypoxia (12% O2) from birth to postnatal day (PD) 7. DEX was administered on PD3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). Pups were studied on PD7 (24 h after the last dose of DEX). DEX significantly increased plasma leptin and ghrelin in normoxic pups, but only increased ghrelin in hypoxic pups. Hypoxia alone resulted in a small increase in plasma leptin. Plasma corticosterone and pituitary POMC mRNA expression were decreased 24 h following the last dose of DEX, whereas plasma ACTH and pituitary CRHR1 mRNA expression had already increased (normoxia and hypoxia). Hypoxia alone increased corticosterone, but had no effect on ACTH or pituitary POMC and CRHR1 mRNA expression. Neonatal DEX treatment, hypoxia, and the combination of both affect hormones involved in energy homeostasis. Pituitary function in the neonate was quickly restored following DEX-induced suppression of the hypothalamic-pituitary-adrenal axis. The changes in ghrelin, leptin, and corticosterone may be beneficial to the hypoxic neonate through the maintenance of appetite and shifts in intermediary metabolism.

Topics: Adrenocorticotropic Hormone; Animals; Animals, Newborn; Blotting, Northern; Corticosterone; Dexamethasone; Enzyme-Linked Immunosorbent Assay; Female; Ghrelin; Glucocorticoids; Hypoxia; Leptin; Male; Peptide Hormones; Pituitary Gland; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger

The aim of this study was to find out whether high altitude (HA)-induced hypophagia was macronutrient-specific using a self-selection procedure. Body composition was assessed by dual X-ray absorptiometry before and after exposure and by dissection at the end of the experiment. Energy intake, macronutrient selection, body composition, plasma insulin and leptin concentrations were measured in rats (FHx) exposed 16 h daily for 10 days to hypobaric hypoxia (HH) simulating an altitude of 5500 m. Rats were fasted during the exposure to HH and had access to food only during the 8 h of normoxia in their active period. This group was compared to control group (C) with ad libitum access to food and a group of rats submitted only to the 16-h fast (FNx). Results showed that sustained hypophagia was specific to protein (55 +/- 5% of C, P < .05), whereas after a decline, carbohydrate intake reached its basal level on the 5th day. HH dramatically reduced fat-free mass gain (P < .05 and P < .0001 compared to C and FNx, respectively). Plasma leptin concentrations at the onset of the period of access to food were not significantly different from those of controls. Across groups, leptin was positively correlated with fat mass (r = .71, P < .001) and negatively with energy intake (r = -.52, P < .05), more specifically with protein intake (r = -.57, P < .05). These results suggest that HA leads to a reduced preference for protein impairing fat-free mass gain and that leptin may contribute to this hypophagia.

Topics: Altitude; Animals; Body Composition; Body Constitution; Body Mass Index; Dietary Proteins; Drinking; Eating; Energy Intake; Food Deprivation; Food Preferences; Hypoxia; Insulin; Leptin; Male; Rats; Rats, Wistar; Statistics as Topic; Time Factors

Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1) leptin deficiency affects the hypoxic ventilatory response and 2) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 +/- 0.7 vs. 8.9 +/- 0.7 ml x min(-1) x %CO(2)(-1), P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep.

Topics: Animals; Hypoxia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Pulmonary Ventilation; Signal Transduction; Sleep; Species Specificity; Wakefulness

Obesity adversely affects lung function in humans often reducing arterial blood oxygenation. To determine if obesity adversely affects lung function in cynomolgus monkeys, which is a species that is often used for pulmonary research, pulmonary mechanics, ventilation, functional residual capacity (FRC), and arterial blood gases were measured using spontaneous respiration and on mechanical ventilation with room air or 100% O(2). Body fat percentage was measured by dual energy X-ray absorption. Blood leptin levels were measured by radioimmune assay. Obese monkeys breathed faster with lower tidal volume, but pulmonary resistance and dynamic lung compliance did not change with body fat. FRC and blood leptin were, respectively, negatively and positively correlated with percent body fat. FRC correlated moderately with ventilatory parameters and strongly with arterial oxygen tension, alveolar-arterial oxygen difference and venous admixture. Therefore, obesity in cynomolgus monkeys had marked, deleterious effects on FRC, ventilation and arterial oxygenation. Obesity may be an important confounding variable in lung function studies in primates.

Topics: Animals; Antigens; Blood Gas Analysis; Body Composition; Functional Residual Capacity; Hypoxia; Leptin; Macaca fascicularis; Male; Obesity; Pulmonary Gas Exchange; Respiratory Function Tests; Respiratory Mechanics; Respiratory Physiological Phenomena

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Fasting; Gene Expression; Glucose Intolerance; Hypoxia; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

Topics: Animals; Gene Expression; Hypoxia; Leptin

The anorexic effect of exposure to high altitude may be related to the reduction in the arterial oxygen content (Ca(O2)) induced by hypoxemia and possibly the associated decreased convective oxygen transport (COT). This study was then performed to evaluate the effects of either transfusion-induced polycythemia or previous acclimation to hypobaria with endogenously induced polycythemia on the anorexic effect of simulated high altitude (SHA) in adult female rats. Food consumption, expressed in g/d/100 g body weight, was reduced by 40% in rats exposed to 506 mbar for 4 d, as compared to control rats maintained in room air. Transfusion polycythemia, which significantly increased hematocrit, hemoglobin concentration, Ca(O2), and COT, did not change the anorexic response to the exposure to hypobaric air. Depression of food intake during exposure to SHA also occurred in rats fasted during 31 h before exposure and allowed to eat ad libitum for 2 h during exposure. Body mass loss was similar in 48-h fasted rats that were either hypoxic or normoxic. Body mass loss was similar in normoxic and hypoxic rats, the former eating the amount of food freely eaten by the latter. Hypoxia-acclimated rats with endogenously induced polycythemia taken to SHA again had diminished food intake and lost body mass at rates that were very close to those found in nonacclimated ones. Exposure to SHA also led to a decrease in food consumption, body weight, and plasma leptin in adult female mice. Analysis of data suggest that body mass loss that accompanies SHA-induced hypoxia is due to hypophagia and that experimental manipulation of the blood oxygen transport capacity cannot ameliorate it. Leptin does not appear to be an inducer of the anorexic response to hypoxia, at least in mice and rats.

Topics: Acclimatization; Altitude Sickness; Animals; Anorexia; Appetite; Blood Gas Analysis; Body Weight; Fasting; Female; Hypoxia; Leptin; Mice; Oxygen; Polycythemia; Rats; Rats, Wistar; Reference Values

In addition to having a major role in energy homeostasis, leptin is emerging as a pleiotropic cytokine with multiple physiological effector functions. The recently discovered proangiogenic activity of leptin suggested the hypothesis that its production might be regulated by hypoxia, as are other angiogenic factors. To examine this proposal, the expression of leptin protein and mRNA was measured and found to be markedly up-regulated in response to ambient or chemical hypoxia (upon exposure to desferrioxamine or cobalt chloride), an effect that requires intact RNA synthesis, suggesting a transcriptional mechanism. Transient transfection of cultured cells with deletion constructs of the leptin gene promoter linked to a reporter gene revealed a functional hypoxia response element (HRE) located at position -116 within the proximal upstream region. This putative HRE harbors a characteristic 5'-RCGTG-3' core motif, a hallmark of hypoxia-sensitive genes and recognized by the hypoxia-inducible factor 1 (HIF1), which consists of a HIF1alpha/HIFbeta heterodimer. Constructs harboring this -116/HRE supported reporter gene expression in response to hypoxia but not when mutated. Expression of HIF1alpha cDNA in normoxic cells mimicked hypoxia-induced reporter gene expression in cells cotransfected with the wild type leptin -116/HRE construct but not with the mutant. Gel shift assays with a (32)P-labeled leptin promoter -116/HRE probe and nuclear extracts from hypoxia-treated cells indicated binding of the HIF1alpha/beta heterodimer, which was blocked with an excess of unlabeled -116/HRE probe or a HIF1-binding probe from the erythropoietin gene enhancer. Taken together, these observations demonstrate that the leptin gene is actively engaged by hypoxia through a transcriptional pathway commonly utilized by hypoxia-sensitive genes.

Topics: Base Sequence; Binding Sites; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; Fibroblasts; Gene Expression Regulation; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Molecular Sequence Data; Promoter Regions, Genetic; Response Elements; Transcription Factors; Transcriptional Activation

The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone).

Topics: Animals; Animals, Newborn; Body Composition; Body Weight; Bone Density; Female; Human Growth Hormone; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley

We observed recentlyl that placental leptin is markedly increased in preeclampsia. Since this disorder is associated with vascular disorders, we have tested the hypothesis that hypoxia regulates leptin expression. We show that hypoxia increased leptin mRNA and secretion in trophoblast-derived BeWo cells. This effect was mediated through leptin promoter activation. 5' deletion analysis allowed us to delineate two regions containing 1.87 kb and 1.20 kb of the promoter which conferred respectively high and low responsiveness to hypoxia. These data indicate that leptin is up-regulated by hypoxia through a transcriptional mechanism likely to involve distinct hypoxia-responsive cis-acting sequences on the promoter.

Topics: Adipose Tissue; Animals; Blotting, Northern; Blotting, Western; Cell Line; DNA Primers; Gene Expression; Glucose Transporter Type 3; Humans; Hypoxia; Immunoenzyme Techniques; Leptin; Luciferases; Monosaccharide Transport Proteins; Nerve Tissue Proteins; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic; Trophoblasts; Up-Regulation

Hypoxia leads to a decrease in food intake and attenuated weight gain in rats. The purpose of this study was to measure plasma leptin and insulin in young rats exposed to hypoxia for 7 d as compared to a normoxic control group of the same age. One group was exposed from birth to 7 d of age; the other was exposed from 28 to 35 d of age (weaned at 21 d of age). As expected, body weight was significantly lower in rats of either age exposed to hypoxia for 7 d. Plasma leptin was significantly lower in hypoxic (2.0+/-0.2 ng/mL; n = 41) compared with normoxic (2.6+/-0.3 ng/mL; n = 30) 7-d-old rats. Plasma leptin was also significantly lower in hypoxic (1.1+/-0.1 ng/mL; n = 20) as compared to normoxic (1.5+/-0.1 ng/mL; n = 20) 35-d-old rats. Seven-day-old rats exposed to hypoxia demonstrated significant increases in plasma glucose and insulin whereas 35-d-old rats exhibited a decrease in both variables. We conclude that exposure to hypoxia for 7 d leads to a decrease in body weight and plasma leptin in infant and juvenile rats. The decrease in leptin may be an attempt to reverse hypoxia-induced anorexia.

Topics: Aging; Animals; Animals, Newborn; Blood Glucose; Body Weight; Female; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley

Preeclampsia (PE) is a hypertensive disorder, which develops in late pregnancy and is usually associated with placental hypoxia and dysfunction. We have recently demonstrated that leptin is a novel placenta-derived hormone in humans and suggested its significance in human pregnancy (see Ref. 19). To explore the changes in the leptin production in placenta in PE, we measured the plasma leptin level and placental leptin messenger RNA expression in pregnant women with PE. Plasma leptin levels in preeclamptic women were elevated significantly, compared with gestational age- and body mass index-matched normal pregnant women (P < 0.0001). Plasma leptin levels in the severe PE group were significantly higher than those in the mild PE group (P < 0.0001). Plasma leptin levels in preeclamptic women were reduced, soon after the placental delivery, to those expected for their body mass indices. Northern blot analysis revealed that leptin messenger RNA levels are increased in the placentas from preeclamptic women, compared with normal pregnant women. Leptin secretion was increased significantly in a human trophoblastic cell line (BeWo cells) cultured under hypoxic conditions (5% O2), compared with those cultured under standard conditions (20% O2; P < 0.01). The present study demonstrated that placental production of leptin is augmented in severe PE, probably because of placental hypoxia, thereby suggesting the possible significance of leptin as a marker of placental hypoxia in severe PE.

Topics: Adult; Blotting, Northern; Body Mass Index; Cell Hypoxia; Cell Line; Female; Gene Expression; Gestational Age; Humans; Hypoxia; Leptin; Oxygen; Placenta; Pre-Eclampsia; Pregnancy; Protein Biosynthesis; Proteins; RNA, Messenger; Trophoblasts