leptin and Hypothermia

Prevailing changes in the feeding status or the nutritional status, in general, can modify the expression of many orexigenic and anorexigenic peptides, which influence hypothalamic functions. These peptides usually adjust body temperature according to anabolic (increased appetite with suppressed metabolic rate and body temperature) or catabolic (anorexia with enhanced metabolism and temperature) patterns. It was plausible to presume that such peptides contribute to regulated changes of body temperature (either fever or hypothermia) in systemic inflammation, particularly since anorexia is a common feature in inflammatory processes. No consistent, common, or uniform way of action was, however, demonstrated, which could have described the effects of various peptides. With the exception of cholecystokinin (CCK), all investigated peptides were devoid of real thermoregulatory actions: they influenced the metabolic rate (and consequently body temperature), but not the mechanisms of heat loss. Central CCK is indeed catabolic and may participate in febrigenesis. Leptin may activate various cytokines, catabolic peptides and may inhibit anabolic peptides, but it probably has no direct febrigenic effect and it is not indispensable in fever. Melanocortins and corticotropin-releasing factor provide catabolic adaptive mechanisms to food intake (diet induced thermogenesis) and environmental stress, respectively, but they act rather as endogenous antipyretic substances during systemic inflammation, possibly contributing to the mechanisms of limitation of fever. Bacterial lipopolysaccharides enhance the expression of most of these catabolic peptides. In contrast, neuropeptide Y (NPY) expression may not be changed, only its release is decreased at specific nuclei, a defective NPY effect may also contribute to the febrile rise in body temperature. The data provide no clear-cut explanation for the mechanism of hypothermia seen in systemic inflammation. According to speculations, a presumed, overflow,-type release of NPY from the hypothalamic nuclei, as well as a suppression of the activity of catabolic peptides, could possibly cause hypothermia. There are no cues, however, referring to the identity of factors that could trigger such changes during systemic inflammation in order to induce hypothermia.

Topics: alpha-MSH; Animals; Body Temperature; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Endotoxins; Fever; Humans; Hypothermia; Inflammation; Leptin; Mice; Neuropeptide Y; Peptides; Rats

Amino-acid (AA) infusions promote thermogenesis and prevent perioperative hypothermia, but the mechanism of action is unknown. We sought to verify the hypothesis that AA infusions stimulate the release of metabolic hormones during surgery and increase energy expenditure, resulting in thermogenesis.. Twenty-four patients were randomly assigned to receive AA (4 kJ x kg(-1) x h(-1)) or saline, which was infused for 2 h during off-pump coronary artery bypass surgery (OPCABS). Arterial adrenaline, thyroid hormone, insulin, and leptin levels were determined at five defined times during surgery. Oxygen consumption was measured 3 h after the start of infusion.. AA infusion maintained the body core temperature during OPCABS. This effect was accompanied by an increase in oxygen consumption, which depended on increased heart rate. AA infusion prominently stimulated the secretion of insulin and leptin; the insulin level increased rapidly within 2 h after the start of infusion, whereas leptin levels increased gradually over a 6-h period after the start of infusion.. AA infusion significantly increased body core temperature and oxygen consumption during surgery. Given the release of insulin and leptin in response to AA infusion, it is likely that these hormonal signaling pathways may, in part, have contributed to the thermogenic response that occurred during the surgery.

Topics: Aged; Amino Acids; Anesthesia, General; Blood Glucose; Blood Urea Nitrogen; Body Temperature Regulation; Coronary Artery Bypass, Off-Pump; Epinephrine; Female; Hemodynamics; Hormones; Humans; Hypothermia; Infusions, Intravenous; Insulin; Intraoperative Complications; Leptin; Male; Middle Aged; Triiodothyronine

Thyroid hormones (TH) are essential for the homeostatic control of energy metabolism and the regulation of body temperature. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback mechanisms, ensuring that TH levels are maintained at a constant level. However, the feedback mechanisms underlying the resetting of the HPT axis regulation in the control of body temperature are still not fully understood. Here, we aimed to determine the thermoregulatory response in hypothyroid mice to different environmental temperatures and the underlying mechanisms.. Distinct thermogenic challenges were induced in hypothyroid female C57BL/6N and leptin-deficient ob/ob mice through housing at either room temperature or thermoneutrality. The thermogenic and metabolic effects were analyzed through metabolic chambers, 18F-FDG-PET/MRI, infrared thermography, metabolic profiling, histology, gene expression and Western blot analysis.. In hypothyroid mice maintained at room temperature, high leptin serum levels induce a pyrexic effect leading to the stabilization of body temperature through brown adipose tissue thermogenesis and white adipose tissue browning. Housing at thermoneutrality leads to the normalization of leptin levels and a reduction of the central temperature set point, resulting in decreased thermogenesis in brown and white adipose tissue and skeletal muscle and a significant decline in body temperature. Furthermore, anapyrexia in hypothyroid leptin-deficient ob/ob mice indicates that besides its pyrexic actions, leptin exerts a stimulatory effect on the HPT axis to stabilize the remaining TH serum levels in hypothyroid mice.. This study led to the identification of a previously unknown endocrine loop in which leptin acts in concert with the HPT axis to stabilize body temperature in hypothyroid mice.

Topics: Animals; Female; Hypothermia; Hypothyroidism; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Protein Stability; Thyroid Hormones

Adipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored.. Our study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults.. Nineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity.. Plasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA).. Plasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P  = 0.03), and inversely correlated with MR sFF (coefficient, -404; P  = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects.. Higher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.. A higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.

Topics: Acute Disease; Adiponectin; Adipose Tissue, Brown; Adult; Body Composition; Calorimetry; Clavicle; Cold Temperature; Energy Metabolism; Female; Fibroblast Growth Factors; Fluorodeoxyglucose F18; Humans; Hypothermia; Leptin; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Thermography; Time Factors; Young Adult

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

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia. Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.

Topics: Alzheimer Disease; Animals; Body Temperature; Body Temperature Regulation; Caffeine; Central Nervous System Stimulants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hippocampus; Hypothermia; Leptin; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Phosphorylation; tau Proteins

Recent experimental evidence suggests that lipopolysaccharide (LPS)-induced hypothermia is an adaptive thermoregulatory strategy against immunological challenge in rats. We hypothesized that the hormones which are predominantly responsible for energy homeostasis may have efferent signaling roles for development of the hypothermia.. The aim of the study was to evaluate the changes of hypothalamic-pituitary-thyroid (HPT) and hypothalamic- pituitary-adrenal (HPA) axis hormones, leptin and erythropoietin at various phases of LPS-induced hypothermia such as the initial phase, nadir and the end of the response in blood sampled rats.. Body temperature of adult male albino Wistar rats was recorded by biotelemetry. E. coli O111:B4 LPS (250 μg/kg, ip) was injected alone or with SC-560, a cyclooxygenase-1 selective inhibitor (1 mg/kg, sc).. Serum FT4 levels elevated at the initial phase, but FT3 levels decreased at nadir and remained low at the end of the response. Meanwhile, no change was observed in TSH levels. Serum adrenocorticotropic hormone (ACTH) levels reduced at the initial phase and serum corticosterone levels decreased at nadir without any change in serum corticotropin-releasing hormone (CRH) levels throughout the hypothermia. Serum leptin levels increased only at the end of the response. No change was observed in the levels of serum erythropoietin. SC-560 treatment abolished both LPS-induced hypothermia and respective hormonal changes.. Data suggest that HPT axis hormones may contribute to development of LPS-induced hypothermia in rats. Data also support the view that leptin may have a role for the recovery of hypothermic response.

Topics: Adrenocorticotropic Hormone; Animals; Biomarkers; Body Temperature; Corticosterone; Cyclooxygenase Inhibitors; Erythropoietin; Humans; Hypothalamo-Hypophyseal System; Hypothermia; Leptin; Lipopolysaccharides; Male; Mice; Pituitary-Adrenal System; Pyrazoles; Rats, Wistar; Thyrotropin; Thyroxine

Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.

Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Biomarkers; Body Weight; Central Nervous System; Cholesterol; Diet, High-Fat; Energy Intake; Gastrointestinal Transit; Hypothermia; Insulin; Leptin; Mice; Mice, Knockout; Mice, Transgenic; MicroRNAs; Mutation; Obesity; Peripheral Nervous System; Phenotype; Piperidines; Promoter Regions, Genetic; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Triglycerides

The role of the nuclear receptor FXR in adaptive thermogenesis was investigated using FXR-deficient mice. Despite elevated serum bile acid concentrations and increased mRNA expression profiles of thermogenic genes in brown adipose tissue, FXR-deficiency did not alter energy expenditure under basal conditions. However, FXR-deficiency accelerated the fasting-induced entry into torpor in a leptin-dependent manner. FXR-deficient mice were also extremely cold-intolerant. These altered responses may be linked to a more rapid decrease in plasma concentrations of metabolic fuels (glucose, triglycerides) thus impairing uncoupling protein 1-driven thermogenesis. These results identify FXR as a modulator of energy homeostasis.

Topics: Acclimatization; Adipose Tissue, Brown; Animals; Base Sequence; Bile Acids and Salts; Body Temperature Regulation; DNA Primers; DNA-Binding Proteins; Fasting; Female; Homeostasis; Hypothermia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Transcription Factors

Mice lacking either bombesin receptor subtype (BRS)-3 or gastrin-releasing peptide receptor (GRP-R) exhibit feeding abnormalities. However, it is unclear how these receptors are associated with feeding regulation. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia, and brain leptin resistance that occurred after the onset of obesity. To explore the cause of this phenomenon, we examined changes in feeding responses to appetite-related neuropeptides in BRS-3-deficient, GRP-R-deficient, and wild-type littermate mice. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice but not in GRP-R-deficient mice. In addition, the levels of MCH-R and prepro-MCH mRNAs in the hypothalamus of BRS-3-deficient mice were significantly more elevated than those of wild-type littermates. There was no significant difference in feeding between BRS-3-deficient and wild-type littermate mice after treatment with bombesin (BN), although the hypophagic response to low-dose BN was significantly suppressed in the GRP-R-deficient mice. These results suggest that upregulation of MCH-R and MCH triggers hyperphagia in BRS-3-deficient mice. From these results, we assume that the BRS-3 gene deletion upsets the mechanism by which leptin decreases the expression of MCH-R and that this effect may be mediated through neural networks independent of BN-related peptides such as GRP-R.

Topics: Animals; Base Sequence; Body Weight; Bombesin; DNA Primers; Eating; Female; Hypothalamic Hormones; Hypothermia; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Knockout; Pituitary Hormones; Receptors, Bombesin; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Leptin contributes to the regulation of thermogenesis. In rodents, sympathetic nerve activity efferent to interscapular brown adipose tissue (IBAT-SNA) is involved. On the basis of the hypotheses that 1) leptin acutely potentiates hypothermia-induced increases in IBAT-SNA; 2) this action of leptin is specific to IBAT-SNA, i.e., it does not occur with renal sympathetic nerve activity (R-SNA); and 3) this effect of leptin depends on intact and functional leptin receptors, we measured IBAT-SNA and R-SNA in anesthetized lean and diet-induced obese Sprague-Dawley and in obese Zucker rats, randomly assigned to low-dose leptin or vehicle. Before the start of leptin or vehicle and 5 min, 90 min, and 180 min after, hypothermia (30 degrees C) was induced. Compared with vehicle, leptin did not significantly alter baseline R-SNA or IBAT-SNA. In lean Sprague-Dawley rats, hypothermia-induced increases in IBAT-SNA were significantly augmented by leptin but not by vehicle. In obese Sprague-Dawley rats, leptin did not potentiate hypothermia-induced increases in IBAT-SNA. In Zucker rats, IBAT-SNA did not increase with hypothermia and leptin was not able to induce sympathoactivation with cooling. Changes in R-SNA during hypothermia were not significantly modified by leptin in either group. Thus, low-dose leptin, although not altering baseline SNA, acutely enhances hypothermia-induced sympathetic outflow to IBAT in lean rats. This effect is specific for thermogenic SNA because leptin does not significantly alter the response of R-SNA to hypothermia. The effect depends on intact and functional leptin receptors because it occurs neither in rats with a leptin receptor defect nor in rats with acquired leptin resistance.

Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Carrier Proteins; Hypothermia; Kidney; Leptin; Male; Models, Biological; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Sympathetic Nervous System

Acute immunoneutralization of circulating leptin, with an anti-leptin antibody, significantly reduced rectal temperature at 30 min and 75 min post-injection in overnight fasted and at 30 min in overnight fed mice, while no effects in metabolic and ponderal indicators were observed after antibody administration for 22 days. Furthermore, hyperinsulinemia and hypoglycemia were induced by passive immunization against leptin, being both influenced by the post-prandrial status. These experiments confirm through an indirect approach that leptin is involved in energy, but also in glucose homeostasis.

Topics: Animals; Antibodies, Monoclonal; Blood Glucose; Eating; Fasting; Hyperinsulinism; Hypoglycemia; Hypothermia; Immunization, Passive; Insulin; Leptin; Mice; Mice, Inbred BALB C; Proteins; Triglycerides; Weight Gain