leptin and Hypertrophy

This review concerns the influence of leptin on vascular smooth muscle cells (VSMC). VSMC express different isoforms of the leptin receptor (Ob-R) able to activate a wide range of intracellular signalling pathways, mediating many relevant biological actions. In particular, leptin promotes processes deeply involved in atherogenesis, such as VSMC migration, hypertrophy, proliferation, osteogenic differentiation and metalloproteinase expression. The intracellular signalling molecules involved are JAK/STAT, PI3K/Akt, ERK 1/2, p38 MAPK, mTOR, and RhoA/ROCK. Some of these leptin actions are particularly evident in stretching conditions; others are mediated by the NAD(P)H-induced increase of Reactive Oxygen Species. A leptin-induced activation of angiotensin and endothelin systems, with up-regulation of the synthesis of the two hormones and of their receptors, has also been demonstrated. Other studies, however, showed that leptin increases in VSMC the nitric oxide production by activating the inducible nitric oxide synthase, and, via nitric oxide, exerts a vasodilating effect and impairs the proliferative and vasoconstricting actions of angiotensin II. Both the potentially harmful and the potentially beneficial effects exerted by leptin in VSMC are lost in VSMC from animal models of genetically determined leptinresistance. Cultured VSMC from leptin-resistant animals are also resistant to insulin and to nitric oxide. It is not known, however, whether in human obesity, a condition characterized by hypothalamic leptin resistance and by compensatory hyperleptinemia, VSMC are sensitive or resistant to leptin: only in the first case the predictive role of circulating leptin on cardiovascular events could support a pathogenetic influence of the hormone on atherosclerosis.

Topics: Animals; Atherosclerosis; Cell Movement; Cell Proliferation; Humans; Hypertrophy; Leptin; Models, Cardiovascular; Muscle, Smooth, Vascular; Protein Isoforms; Receptors, Leptin; Signal Transduction; Up-Regulation

Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells, are involved in these manifestations of IBD. Among adipokines leptin, adiponectin and resistin hold a fundamental role while the role of ghrelin in inflammation is not well established. Preliminary studies have shown overexpression of leptin, adiponectin, and resistin in mesenteric WAT of patients with Crohn's disease (CD) and significant alterations of circulating serum levels of these adipokines in IBD. It has also been demonstrated that intestinal inflammation causes an increase in endogenous ghrelin production. In animal models of intestinal inflammation, existing data suggest that leptin, adiponectin, and resistin are pivotal mediators of inflammation. Interesting therapeutic interventions based on these data have been suggested. A specific role for hypertrophic WAT has also been implicated in CD. Further efforts with experimental and clinical studies are needed to better understand the role of adipokines in IBD.

Topics: Adiponectin; Adipose Tissue, White; Animals; Colitis, Ulcerative; Crohn Disease; Cytokines; Ghrelin; Humans; Hypertrophy; Inflammatory Bowel Diseases; Leptin; Resistin

Topics: Abnormalities, Multiple; Diabetes Mellitus; Diagnosis, Differential; Humans; Hypertrophy; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Mutation; Pineal Gland; Prognosis; Receptor, Insulin; Recombinant Proteins; Syndrome

The correlation between total testosterone levels, exercise capacity, and metabolic and echocardiographic parameters was studied in 1097 male subjects with coronary artery disease (CAD) and different stages of glucose tolerance.. Testosterone level was the lowest among diabetics as compared to prediabetics or controls (P < 0.001). Total and abdominal adiposity were the highest in the subjects with the lowest testosterone. Independent of adiposity, fasting glucose, insulin, and leptin were higher (P < 0.03 to < 0.001) among diabetic and control groups in the lowest, and HbA1c values (P < 0.001) higher among diabetics in the lowest, than in the highest testosterone tertile. Controls and prediabetic subjects with the lowest testosterone levels had the lowest HDL-cholesterol levels, and controls also the highest triglycerides. An association between low testosterone level and low maximal exercise capacity was observed in diabetics (P < 0.001) and controls (P < 0.03). Independent of adiposity and metabolic parameters, low testosterone levels were associated with the highest septal wall thickness (P < 0.03) among diabetics.. A negative correlation between low testosterone and dysmetabolic features was observed. Independent of metabolic status, low plasma testosterone seems to be an indicator of impaired maximal exercise capacity and cardiac hypertrophy among CAD patients with type II diabetes.

Topics: Analysis of Variance; Blood Glucose; Body Mass Index; Cholesterol, HDL; Coronary Artery Disease; Diabetes Mellitus, Type 2; Echocardiography, Doppler; Exercise Tolerance; Glycated Hemoglobin; Heart Septum; Humans; Hypertrophy; Insulin; Leptin; Male; Prediabetic State; Testosterone; Triglycerides; Waist Circumference

This study examined the acute effects of maximum strength (MS), muscular hypertrophy (MH), and strength endurance (SE) resistance exercise protocols on serum leptin. Ten young lean men (age = 23 +/- 4 yr; body weight = 79.6 +/- 5.2 kg; body fat = 10.2 +/- 3.9%) participated in MS [4 sets x 5 repetitions (reps) at 88% of 1 repetition maximum (1 RM) with 3 min of rest between sets], MH (4 sets x 10 reps at 75% of 1 RM with 2 min of rest between sets), SE (4 sets x 15 reps at 60% of 1 RM with 1 min of rest between sets), and control (C) sessions. Blood samples were collected before and immediately after exercise and after 30 min of recovery. Serum leptin at 30 min of recovery exhibited similar reductions from baseline after the MS (-20 +/- 5%), MH (-20 +/- 4%), and SE (-15 +/- 6%) protocols that were comparable to fasting-induced reduction in the C session (-12 +/- 3%) (P < 0.05). Furthermore, no differences were found in serum leptin among the MS, MH, SE, and C sessions immediately after exercise and at 30 min of recovery (P > 0.05). Cortisol was higher (P < 0.05) after the MH and SE protocols than after the MS and C sessions. Glucose and growth hormone were higher (P < 0.05) after exercise in the MS, MH, and SE protocols than after the C session. In conclusion, typical resistance exercise protocols designed for development of MS, MH, and SE did not result in serum leptin changes when sampled immediately or 30 min postexercise.

Topics: Adult; Blood Glucose; Fatty Acids, Nonesterified; Humans; Hydrocortisone; Hypertrophy; Lactic Acid; Leptin; Male; Muscle, Skeletal; Osmolar Concentration; Physical Endurance; Rest; Weight Lifting

To evaluate the effects of a high-fat diet during post-weaning growth on intermediate metabolism and retroperitoneal adipose tissue, in adult male rats exposed to adequate or deficient zinc intake during prenatal and postnatal life.. Female Wistar rats were fed low- or control-zinc diets from pregnancy to offspring weaning. Male offspring born from control mothers were fed either control or high-fat, control-zinc diets for 60 days. Male offspring born from zinc deficient mothers were fed either low-zinc or high-fat, low-zinc diets for 60 days. At 74 days of life, oral glucose tolerance test was performed. In 81-day-old offspring, blood pressure, lipid profile, plasmatic lipid peroxidation and serum adiponectin level were determined. In retroperitoneal adipose tissue, we evaluated oxidative stress, morphology and adipocytokines mRNA expression. Low-zinc diet induced adipocytes hypertrophy, increased oxidative stress, and decreased adiponectin mRNA expression in adipose tissue. Low-zinc diet increased systolic blood pressure, triglyceridemia, plasmatic lipid peroxidation and glycemia at 3 h after glucose overload. Animals fed high-fat or high-fat, low-zinc diets showed adipocytes hypertrophy, decreased adiponectin mRNA expression, and increased leptin mRNA expression and oxidative stress in adipose tissue. They also exhibited decreased serum adiponectin levels, increased triglyceridemia, plasmatic lipid peroxidation and area under the oral glucose tolerance curve. High-fat, low-zinc diet induced greater alterations in adipocyte hypertrophy, leptin mRNA expression and glucose tolerance test than high-fat diet.. Zinc deficiency since early stages of intrauterine life could increase susceptibility to metabolic alterations induced by high-fat diets during postnatal life.

Topics: Adipocytes; Adiponectin; Animals; Diet, High-Fat; Female; Hypertrophy; Leptin; Male; Malnutrition; Pregnancy; Rats; Rats, Wistar; RNA, Messenger; Zinc

To explore how systemic factors that modify knee osteoarthritis risk are connected to 'whole-joint' structural changes by evaluating the effects of high-fat diet and wheel running exercise on synovial fluid (SF) metabolomics.. Male mice were fed a defined control or high-fat (60% kcal fat) diet from 6 to 52 weeks of age, and half the animals were housed with running wheels from 26 to 52 weeks of age (n = 9-13 per group). Joint tissue structure and osteoarthritis pathology were evaluated by histology and micro-computed tomography. Systemic metabolic and inflammatory changes were evaluated by body composition, glucose tolerance testing, and serum biomarkers. SF metabolites were analyzed by high performance-liquid chromatography mass spectrometry. We built correlation-based network models to evaluate the connectivity between systemic and local metabolic biomarkers and osteoarthritis structural pathology within each experimental group.. High-fat diet caused moderate osteoarthritis, including cartilage pathology, synovitis and increased subchondral bone density. In contrast, voluntary exercise had a negligible effect on these joint structure components. 1,412 SF metabolite features were detected, with high-fat sedentary mice being the most distinct. Diet and activity uniquely altered SF metabolites attributed to amino acids, lipids, and steroids. Notably, high-fat diet increased network connections to systemic biomarkers such as interleukin-1β and glucose intolerance. In contrast, exercise increased local joint-level network connections, especially among subchondral bone features and SF metabolites.. Network mapping showed that obesity strengthened SF metabolite links to blood glucose and inflammation, whereas exercise strengthened SF metabolite links to subchondral bone structure.

Topics: Animals; Biomarkers; Chemokine CCL2; Chondrocytes; Diet, High-Fat; Glucose Intolerance; Hypertrophy; Interleukin-10; Interleukin-1beta; Interleukin-8; Leptin; Metabolomics; Mice, Inbred C57BL; Osteoarthritis; Physical Conditioning, Animal; Stifle; Synovial Fluid; X-Ray Microtomography

Developmental and growth retardation is a condition that is often encountered among children with adenotonsillar hypertrophy (ATH). Leptin, ghrelin and IGF-1 are important factors in growth and development for children. The aim of the study was to investigate serum leptin, ghrelin and IGF-1 levels in children with ATH compare with healthy controls.. 82 children between ages 6-12 were included in this study, divided into two groups. The first group being the study-group consisted of 42 children with obstructive adenotonsillar hypertrophy and the second group being the control-group consisted of 40 healthy children. At 08:30 a.m., peripheral blood samples were extracted from children from both groups to examine the serum levels, and kept in -40 °C until the Elisa test.. Leptin serum level of the control-group was found to be statistically significantly higher than the serum leptin level of the ATH group (p = 0,049; p < 0.05). Body mass indexes of the children with ATH were found to be statistically significantly lower than the body mass index (BMI) of the control group (p = 0,001; p < 0.05). In contrast, there was no statistically significant difference between ghrelin and IGF-1 levels between the ATH and control group (p = 0.193, p > 0.05 and p = 0.478, p > 0.05, respectively).. Upper airway infections are common in children with ATH. Increased airway infections and obstructive enlarged adenotonsillar lymphoid tissue which are caused swallowing difficulties can lead to reduced oral intake and fat tissue. It has led us to think that, ghrelin levels may be increasing secondary to these problems in children with ATH. Furthermore, BMI and leptin would be lower in children with ATH, considering adipose tissue was lesser and leptin was being synthesized and oscillated out of the fat cells of the tissue in these children.

Topics: Adenoids; Body Mass Index; Child; Female; Ghrelin; Growth; Growth and Development; Humans; Hypertrophy; Insulin-Like Growth Factor I; Leptin; Male; Palatine Tonsil

Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb-/-) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb-/- adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb-/- zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb-/- adult zebrafish display the features of T2DM. Furthermore, we showed that lepb-/- adult zebrafish had glomerular hypertrophy and thickening of the glomerular basement membrane, compared to control zebrafish, suggesting that lepb-/- adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb-/- mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; CRISPR-Cas Systems; Gene Deletion; Glucose; Homeostasis; Hypertrophy; Kidney Glomerulus; Leptin; Zebrafish

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.

Topics: 3T3-L1 Cells; Adenylate Kinase; Adipocytes; Adipose Tissue, Beige; Adipose Tissue, White; Adult; Animals; Enzyme Activation; Fatty Acids, Nonesterified; Female; Humans; Hypertrophy; Hyperuricemia; Insulin Resistance; Leptin; Lipogenesis; Lipolysis; Male; Metformin; Mice; Mice, Inbred C57BL; Middle Aged; Signal Transduction; Triglycerides; Uric Acid

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.

Topics: Adipocytes, Brown; Adiposity; Alleles; Animals; Cell Differentiation; Cell Line; Cells, Cultured; Diet, High-Fat; Energy Metabolism; Epigenesis, Genetic; Genetic Loci; Glucose; Homeostasis; Humans; Hypertrophy; Insulin Resistance; Leptin; Male; Mammals; Metabolic Diseases; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Obesity; Oligonucleotides; Species Specificity

The aim of this study was to investigate the effects of medium-chain triglycerides (MCTs) on chemically-induced hepatic carcinogenesis (HCC) in mice.. In a first set of experiments, mice were treated with diethylnitrosoamine intraperitoneally at two weeks of age. They were fed chow containing MCT or a normal chow diet and sacrificed after 28 weeks. Incidence of hepatic tumor was compared between the two groups. Expression of oxidative stress, and inflammatory cytokines and chemokines in liver tissues were examined. In a second set of experiments, the histopathological findings of the intraperitoneal adipose tissue were assessed, and expression of adipocytokines in the fat tissue was measured. In a third set of experiments, plasma β-hydroxybutyrate (HB) concentration was measured in both animals fed chow containing MCT and a normal chow diet. Mouse HCC cells were co-cultured with β-HB, and the numbers of tumor cells were counted at days 3 and 7.. In the first set of experiments, the tumor count observed in the control group was significantly blunted in the MCT group. Maximum tumor diameter also decreased in the MCT group compared to the control group. The expression of inflammatory cytokines and chemokines was significantly decreased by MCT. Furthermore, expression of 4-hydroxynonenal was lower in the MCT group compared to the control group. In the second set of experiments, hypertrophy of the adipocytes was suppressed, and the concentration of adiponectin and leptin in the adipose tissue decreased by MCT. In the third set of experiments, plasma β-HB concentration increased in the MCT group as expected. β-HB significantly inhibited the proliferation of HCC cells.. MCT administration markedly suppresses the incidence of chemically-induced HCC by inhibition of inflammation and increase of ketone bodies.

Topics: 3-Hydroxybutyric Acid; Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Aldehydes; Animal Feed; Animals; Carcinogens; Carcinoma, Hepatocellular; Cell Count; Cell Proliferation; Chemokines; Cytokines; Diethylnitrosamine; Hypertrophy; Inflammation; Leptin; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C3H; Oxidative Stress; Triglycerides

Cardiac pathology including hypertrophy has been associated with an imbalance between mitochondrial fission and fusion. Generally, well-balanced mitochondrial fission and fusion are essential for proper functions of mitochondria. Leptin is a 16-kDa appetite-suppressing protein which has been shown to induce cardiomyocyte hypertrophy. In the present study, we determined whether leptin can influence mitochondrial fission or fusion and whether this can be related to its hypertrophic effect. Cardiomyocytes treated for 24 h with 3.1 nM leptin (50 ng/ml), a concentration representing plasma levels in obese individuals, demonstrated an increase in surface area and a significant 1.6-fold increase in the expression of the β-myosin heavy chain. Mitochondrial staining with MitoTracker Green dye showed elongated structures in control cells with an average length of 4.5 µm. Leptin produced a time-dependent increase in mitochondrial fragmentation with decreasing mitochondrial length. The hypertrophic response to leptin was also associated with increased protein levels of the mitochondrial fission protein dynamin-related protein1 (Drp1) although gene expression of Drp1 was unaffected possibly suggesting post-translational modifications of Drp1. Indeed, leptin treatment was associated with decreased levels of phosphorylated Drp1 and increased translocation of Drp1 to the mitochondria thereby demonstrating a pro-fission effect of leptin. As calcineurin may dephosphorylate Drp1, we determined the effect of a calcineurin inhibitor, FK506, which prevented leptin-induced hypertrophy as well as mitochondrial fission and mitochondrial dysfunction. In conclusion, our data show that leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission via a calcineurin-mediated pathway. The ability of leptin to stimulate mitochondrial fission may be important in understanding the role of this protein in cardiac pathology especially that related to mitochondrial dysfunction.

Topics: Animals; Calcineurin; Dynamins; Gene Expression Regulation; Hypertrophy; Leptin; Mitochondria; Mitochondrial Dynamics; Myocytes, Cardiac; Obesity; Phosphorylation; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley

The ongoing chronic inflammation and subsequent fibrosis play an important role in ligamentum flavum (LF) fibrosis and hypertrophy in patients with lumbar spinal canal stenosis (LSCS). Leptin is a chronic inflammatory mediator and involved in the fibrotic process in multiple organ systems. The present study aimed to investigate the role of leptin in LF fibrosis and its related regulatory mechanisms. The LF specimens were obtained during the surgery from 12 patients with LSCS (LSCS group) and 12 control patients with lumbar disc herniation (LDH) group. The morphologic changes and fibrosis score of LF were assessed by Hematoxylin and eosin (H&E) and Masson's trichrome staining respectively. The location and expression of leptin in LF tissues were determined. Then, the LF cells were cultured and exposed to recombinant human leptin (rhleptin). Collagen I and III were used as fibrosis markers and IL-6 was used as the inflammatory factor. As a result, the LF thickness and fibrosis score in the LSCS group were significantly higher than those in the LDH group (

Topics: Aged; Cells, Cultured; Female; Fibrosis; Humans; Hypertrophy; Interleukin-6; Leptin; Ligamentum Flavum; Lumbar Vertebrae; Male; Middle Aged; Prospective Studies; Spinal Canal; Spinal Stenosis

Increased adiposity, through adipocyte hypertrophy, and/or hyperplasia, characterizes aging and obesity. Both are leptin-resistant states, associated with disturbed lipid metabolism, reduced insulin sensitivity and inflammation. Nevertheless, fat tissue dysfunction appears earlier in obesity than in normal aging. In contrast, lipodystrophy is accompanied by diabetes, and improving the fat cell capacity to expand rescues the diabetic phenotype. Fat tissue dysfunction is extensively studied in the diet-induced obesity, but remains relatively neglected in the aging-associated obesity. In the Wistar rat, as occurs in humans, early or middle aging is accompanied by an increase in adiposity. Using this experimental model, we describe the molecular mechanisms contributing to the white adipose tissue (WAT) hypertrophy. WAT from middle-old age rats is characterized by decreased basal lipogenesis and lipolysis, increased esterification, as demonstrated by the higher TAG and cholesterol content in visceral WAT, and the maintenance of total ceramide levels within normal values. In addition, we describe alterations in the adipose tissue plasma membrane lipid composition, as increased total ether-phosphatidylcholine, sphingomyelin, and free cholesterol levels that favor an enlarged fat cell size with aging. All these metabolic changes may be regarded as a survival advantage that prevents the aged rats from becoming overtly diabetic.

Topics: Adipocytes; Adipose Tissue, White; Adiposity; Aging; Animals; Diabetes Mellitus; Disease Models, Animal; Hypertrophy; Leptin; Lipid Metabolism; Male; Obesity; Rats; Rats, Wistar

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty in storing lipids in adipocytes, low body fat mass, hypoleptinemia, and hyperinsulinemia. Sclerostin is a product of SOST gene that blocks the Wnt/β-catenin pathway, decreasing bone formation and enhancing adipogenesis. There are no data about sclerostin in people with BSCL.. We aimed to evaluate serum sclerostin, bone mineral density (BMD), and L1-L4 Trabecular Bone Score (TBS) in BSCL patients, generating new knowledge about potential mechanisms involved in the bone alterations of these patients.. In this cross-sectional study, we included 11 diabetic patients with BSCL (age 24.7±8.1years; 6 females). Sclerostin, leptin, L1-L4 TBS, BMD were measured. Potential pathophysiological mechanisms have been suggested.. Mean serum sclerostin was elevated (44.7±13.4pmol/L) and was higher in men than women (55.3±9.0 vs. 35.1±8.4pmol/L, p=0.004). Median of serum leptin was low [0.9ng/mL (0.5-1.9)]. Seven out of 11 patients had normal BMD, while four patients had high bone mass (defined as Z-score>+2.5SD). Patients on insulin had lower sclerostin (37.3±9.2 vs. 52.6±13.4pmol/L, p=0.05). The mean TBS was 1.402±0.106, and it was higher than 1.300 in nine patients.. Patients with lipoatrophic diabetes (BSCL) have high serum concentrations of sclerostin, normal or high BMD, and reasonable trabecular bone mass measured by TBS. This is the first report of high sclerostin and good bone microarchitecture (TBS) in BSCL patients.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Bone Density; Bone Morphogenetic Proteins; Cancellous Bone; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genetic Markers; Humans; Hyperinsulinism; Hypertrophy; Insulin; Leptin; Lipodystrophy, Congenital Generalized; Male; Muscular Diseases; Young Adult

To analyze changes in fat cell size, macrophage infiltration, and local adipose tissue adipokine profiles in different fat depots in patients with active Cushing's syndrome.. Subcutaneous (SC) and perirenal (PR) adipose tissue of 10 patients with Cushing's syndrome was compared to adipose tissue of 10 gender-, age-, and BMI-matched controls with regard to adipocyte size determined by digital image analysis on hematoxylin and eosin stainings, macrophage infiltration determined by digital image analysis on CD68 stainings, and adipose tissue leptin and adiponectin levels using fluorescent bead immunoassays and ELISA techniques.. Compared to the controls, mean adipocyte size was larger in PR adipose tissue in patients. The percentage of macrophage infiltration of the PR adipose tissue and PR adipose tissue lysate leptin levels were higher and adiponectin levels were lower in SC and PR adipose tissue lysates in patients. The adiponectin levels were also lower in the SC adipose tissue supernatants of patients. Associations were found between the severity of hypercortisolism and PR adipocyte size.. Cushing's syndrome is associated with hypertrophy of PR adipocytes and a higher percentage of macrophage infiltration in PR adipose tissue. These changes are associated with an adverse local adipokine profile.

Topics: Adipocytes; Adipokines; Adult; Aged; Body Mass Index; Cell Size; Cross-Sectional Studies; Cushing Syndrome; Female; Humans; Hypertrophy; Intra-Abdominal Fat; Leptin; Macrophages; Male; Middle Aged; Young Adult

The trace element zinc plays an important role in human life. Zinc deficiency impairs growth, reproduction, metabolism and immunity in both human and animals. Thus, zinc supplementation is recommended in daily life. However, the effect of long-term chronic zinc supplementation on adipose homeostasis has not been well elucidated. In the current study, mice were supplemented with zinc sulfate in the drinking water for 20 weeks. The results suggested that chronic zinc supplementation impaired systemic glucose clearance after exogenous insulin or glucose challenges, as compared to the control mice. Further study revealed that chronic zinc supplementation made no difference to body weight, but increased visceral adipose tissue weight and adipocyte size. In addition, gene expression of leptin and IL6 in the visceral adipose tissue of zinc-supplemented mice were higher than those of control mice. Moreover, serum level of leptin of the zinc-supplemented mice was twice as high as that of the control mice. Besides, phosphorylation level of AKT T308 was attenuated in the perirenal adipose tissue of zinc-supplemented mice. In comparison, the expression of macrophage marker genes and lipogenic genes were not affected by chronic zinc supplementation, but the protein levels of FAS and SCD1 decreased or tended to decrease in the perirenal adipose tissue of zinc-supplemented mice, as compared to the control mice. Our findings suggest that chronic high dose zinc supplementation induces visceral adipose tissue hypertrophy and impairs AKT signaling in perirenal adipose tissue.

Topics: 3T3-L1 Cells; Adipocytes; Adiposity; Animals; Blood Glucose; Cell Size; Dietary Supplements; Drug Administration Schedule; fas Receptor; Hypertrophy; Interleukin-6; Intra-Abdominal Fat; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Proto-Oncogene Proteins c-akt; Stearoyl-CoA Desaturase; Time Factors; Zinc Sulfate

To test the hypothesis that high-fat (HF) diet-induced obesity increases proinflammatory cytokine expression, macrophage infiltration, and M1 polarization in the infrapatellar fat pad (IFP) prior to knee cartilage degeneration.. We characterized the effect of HF feeding on knee OA pathology, body adiposity, and glucose intolerance in male C57BL/6J mice and identified a diet duration that induces metabolic dysfunction prior to cartilage degeneration. Magnetic resonance imaging and histomorphology were used to quantify changes in the epididymal, subcutaneous, and infrapatellar fat pads and in adipocyte sizes. Finally, we used targeted gene expression and protein arrays, immunohistochemistry, and flow cytometry to quantify differences in fat pad markers of inflammation and immune cell populations.. Twenty weeks of feeding with an HF diet induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased the IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein levels were reduced. This protection from obesity-induced inflammation corresponded to increased IFP fibrosis and the absence of adipocyte hypertrophy.. The IFP does not recapitulate classic abdominal adipose tissue inflammation during the early stages of knee OA in an HF diet-induced model of obesity. Consequently, these findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity-induced knee OA. Furthermore, the profibrotic and antihypertrophic responses of IFP adipocytes to HF feeding suggest that intraarticular adipocytes are subject to distinct spatiotemporal structural and metabolic regulation among fat pads.

Topics: Abdominal Fat; Adipocytes; Adipose Tissue; Animals; Diet, High-Fat; Fibrosis; Glucose Intolerance; Hypertrophy; Inflammation Mediators; Knee Joint; Leptin; Macrophages; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis, Knee; Time Factors

Zinc is a signaling molecule in numerous metabolic pathways, the coordination of which occurs through activity of zinc transporters. The expression of zinc transporter Zip14 (Slc39a14), a zinc importer of the solute carrier 39 family, is stimulated under proinflammatory conditions. Adipose tissue upregulates Zip14 during lipopolysaccharide-induced endotoxemia. A null mutation of Zip14 (KO) revealed that phenotypic changes in adipose include increased cytokine production, increased plasma leptin, hypertrophied adipocytes, and dampened insulin signaling. Adipose tissue from KO mice had increased levels of preadipocyte markers, lower expression of the differentiation marker (PPARγ), and activation of NF-κB and STAT3 pathways. Our overall hypothesis was that ZIP14 would play a role in adipocyte differentiation and inflammatory obesity. Global Zip14 KO causes systemic endotoxemia. The observed metabolic changes in adipose metabolism were reversed when oral antibiotics were administrated, indicating that circulating levels of endotoxin were in part responsible for the adipose phenotype. To evaluate a mechanism, 3T3-L1 cells were differentiated into adipocytes and treated with siRNA to knock down Zip14. These cells had an impaired ability to mobilize zinc, which caused dysregulation of inflammatory pathways (JAK2/STAT3 and NF-κB). The Zip14 deletion may limit the availability of intracellular zinc, yielding the unique phenotype of inflammation coupled with hypertrophy. Taken together, these results suggest that aberrant zinc distribution observed with Zip14 ablation impacts adipose cytokine production and metabolism, ultimately increasing fat deposition when exposed to endotoxin. To our knowledge, this is the first investigation into the mechanistic role of ZIP14 in adipose tissue regulation and metabolism.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Adipose Tissue, White; Adiposity; Animals; Blotting, Western; Cation Transport Proteins; Cell Differentiation; Cytokines; Endotoxemia; Gene Knockdown Techniques; Hypertrophy; Inflammation; Janus Kinase 2; Leptin; Lipopolysaccharides; Mice; Mice, Knockout; Microscopy, Confocal; NF-kappa B; PPAR gamma; Signal Transduction; STAT3 Transcription Factor

Adipose tissue (AT)-thyrocyte interaction is largely unknown. Here we described the interaction in a co-culture system, in which thyrocytes were cultured on AT fragment (ATF)-embedded collagen gel, using electron microscopy, immunocytochemistry, real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). ATFs promoted the hypertrophy, polarization and lipid accumulation of thyrocytes. ATFs did not affect the growth of thyroyctes, and inhibited their apoptosis. ATFs increased the protein expression of thyroglobulin (Tg) and paired box gene 8 (PAX8) in thyrocytes. In turn, thyrocytes decreased the concentration of leptin and adiponectin, and increased the expression of these mRNAs in ATFs. Thyrotropin (TSH) enhanced the ATF-induced nuclear hypertrophy and Tg protein expression in thyrocytes, while TSH enhanced the thyrocyte-induced expression of leptin and adiponectin mRNAs in ATFs. Finally, leptin promoted the hypertrophy and Tg protein expression in thyrocytes. TSH enhanced these leptin-induced effects. The data indicate an active interaction between thyrocytes and AT, suggesting that (i) ATFs may serve to regulate the morphology, survival and differentiation of thyrocytes probably through lipid accumulation partly in a TSH-synergistic way; (ii) thyrocytes may affect adipokine production from ATFs in a TSH-independent manner; and (3) leptin may be related to the hypertrophy and differentiation of thyrocytes in a TSH-synergistic way.

Topics: Adiponectin; Adipose Tissue; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Coculture Techniques; Collagen; Humans; Hypertrophy; Leptin; Lipid Metabolism; Male; PAX8 Transcription Factor; Rats, Wistar; RNA, Messenger; Thyroglobulin; Thyroid Epithelial Cells; Thyrotropin

Adipose tissue (AT) expansion is the result of two processes: hyperplasia and hypertrophy; and both, directly or indirectly, depend on the adipogenic potential of adipocyte precursor cells (APCs). Glucocorticoids (GCs) have a potent stimulatory effect on terminal adipogenesis; while their effects on early stages of adipogenesis are largely unknown. In the present work, we study, in a model of high GC levels, the adipogenic potential of APCs from retroperitoneal AT (RPAT) and its relationship with RPAT mass expansion. We employed a model of hyper-adiposity (30- and 60-day-old rats) due to high endogenous GC levels induced by neonatal treatment with l-monosodium glutamate (MSG). We found that the RPAT APCs from 30-day-old MSG rats showed an increased adipogenic capacity, depending on the APCs' competency, but not in their number. Analyses of RPAT adipocyte diameter revealed an increase in cell size, regardless of the rat age, indicating the prevalence of a hypertrophic process. Moreover, functional RPAT alterations worsened in 60-day-old rats, suggesting that the hyperplastic AT expansion found in 30-day-old animals might have a protective role. We conclude that GCs chronic excess affects APCs' adipogenic capacity, modifying their competency. This change would modulate the hyperplastic/hypertrophic balance determining healthy or unhealthy RPAT expansion and, therefore, its functionality.

Topics: Adipocytes; Adipogenesis; Adiposity; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Corticosterone; Disease Models, Animal; Glucocorticoids; Hyperplasia; Hypertrophy; Insulin; Intra-Abdominal Fat; Leptin; Male; Malonates; Obesity; Rats; Rats, Sprague-Dawley

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca(2+)-triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model.

Topics: Adipocytes; Adipose Tissue, White; Adiposity; Animals; Blood Glucose; Body Weight; Dyslipidemias; Energy Intake; Energy Metabolism; Feeding Behavior; Female; Homeostasis; Hypertrophy; Hypothalamus; Insulin; Insulin Secretion; Leptin; Liver; Male; Metabolic Diseases; Mice, Obese; Phenotype; Receptors, Leptin; Synaptosomal-Associated Protein 25

The purpose of this study was to search for the effects of adenotonsillectomy (A&T) on height, weight, and body mass index (BMI), as well as changes in ghrelin, leptin, and insulin-like growth factor 1 (IGF-1) levels in children with adenotonsillar hypertrophy (ATH)-related sleep-disordered breathing (SDB).. A study cohort of 39 children clinically diagnosed with ATH-related SDB was included in this study. Twenty-three healthy children were included as controls. Height and weight standard deviation scores (SDS) and ghrelin, leptin, and IGF-1 levels of the controls were determined once; in the study group, they were determined preoperatively and in the third month postoperatively.. Preoperative IGF-1 (ng/mL) and ghrelin (pg/mL) levels were significantly higher in the patients than in the controls (322.51±113.10 vs. 256.96±176.73, p<0.05 and 106.08±9.75 vs. 80.11±28.50, p<0.001, respectively). The preoperative height and weight SDS values of the patients were lower than those of the controls (-0.67±1.36 vs. 0.13±1.13, p<0.05 and -0.38±1.35 vs. -0.20±1.29, respectively). The patients' postoperative height and weight SDS values were significantly higher than their preoperative values (-0.05±1.08 vs. -0.67±1.36, p<0.0001 and 0.00±1.28 vs. -0.38±1.35, p<0.0001, respectively). The mean postoperative IGF-1 levels also were significantly higher than preoperative levels (386.05±130.06 vs. 322.51±113.10, p<0.05, respectively).. Plasma IGF-1 levels are lower in malnourished children, and plasma ghrelin levels are decreased after acute oral food intake and are increased in cachexia and fasting. Therefore, increased serum IGF-1 levels, height and weight SDS values, and decreased ghrelin levels detected postoperatively are useful parameters that help to monitor the development of children with adequate oral intakes.

Topics: Adenoidectomy; Adenoids; Body Height; Child; Child, Preschool; Female; Ghrelin; Humans; Hyperplasia; Hypertrophy; Insulin-Like Growth Factor I; Leptin; Male; Palatine Tonsil; Tonsillectomy

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.

Topics: Animals; Body Weight; Eating; Enzyme Activation; Fatty Liver; Glucose Intolerance; Hypertrophy; Insulin; Insulin Resistance; Islets of Langerhans; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Mutation; Obesity; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Serotonin Plasma Membrane Transport Proteins

We recently identified leptin as a downstream factor mediating the hypertrophic effects of both angiotensin II and endothelin-1 in cardiomyocytes, an effect dependent on increased leptin biosynthesis, however, the mechanism for such increased leptin production is not known. This study was designed to elucidate the mechanisms underlying angiotensin II- and endothelin-1-stimulated synthesis in cultured ventricular myocytes. The hypertrophic effects of both angiotensin II (100 nM) and endothelin-1 (10 nM) were associated with increased leptin secretion and gene expression by 40 and 50 %, and 86 and 68 %, respectively. These effects were associated with significantly increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation by 34 and 52 %, as well as enhanced translocation of NF-κB into nuclei and also the NF-κB-DNA binding activity by 35 and 31 % induced by angiotensin II and endothelin-1, respectively. On their own, 24 h treatment with either angiotensin II or endothelin-1 increased cell surface area by 30 and 40 %, protein synthesis by 30 % and the α-skeletal actin gene by 53 and 68 %, respectively, indicating a robust hypertrophic effect whereas this was completely prevented by NF-κB inhibition. In addition, NF-κB inhibition significantly attenuated angiotensin II and endothelin-1-induced p38 MAPK activation whereas inhibition of p38 MAPK blocked both angiotensin II- and endothelin-1-induced increases in leptin secretion. The ability of both angiotensin II- and endothelin-1 to increase leptin production in cardiomyocytes and the resultant hypertrophic response are mediated by NF-κB and dependent on p38 MAPK activation.

Topics: Active Transport, Cell Nucleus; Angiotensin II; Animals; Cell Enlargement; Cell Nucleus; Cell Size; Cells, Cultured; Endothelin-1; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hypertrophy; Leptin; Myocytes, Cardiac; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Primary Cell Culture; Rats; Rats, Sprague-Dawley

The obesity-related 16 kDa peptide leptin is synthesized primarily in white adipocytes although its production has been reported in other tissues including the heart. There is emerging evidence that leptin may contribute to cardiac pathology especially that related to myocardial remodelling and heart failure. In view of the importance of mitochondria to these processes, the goal of the present study is to determine the effect of leptin on mitochondria permeability transition pore opening and the potential consequence in terms of development of apoptosis. Experiments were performed using neonatal rat ventricular myocytes exposed to 3.1 nM (50 ng/ml) leptin for 24 hours. Mitochondrial transition pore opening was analyzed as the capacity of mitochondria to retain the dye calcein-AM in presence of 200 µM CaCl2. Leptin significantly increased pore opening although the effect was markedly more pronounced in digitonin-permeabilized myocytes in the presence of calcium with both effects prevented by the transition pore inhibitor sanglifehrin A. These effects were associated with increased apoptosis as evidenced by increased TUNEL staining and caspase 3 activity, both of which were prevented by the transition pore inhibitor sanglifehrin A. Leptin enhanced Stat3 activation whereas a Stat 3 inhibitor peptide prevented leptin-induced mitochondrial transition pore opening as well as the hypertrophic and pro-apoptotic effects of the peptide. Inhibition of the RhoA/ROCK pathway prevented the hypertrophic response to leptin but had no effect on increased pore opening following leptin administration. We conclude that leptin can enhance calcium-mediated, Stat3-dependent pro-apoptotic effects as a result of increased mitochondrial transition pore opening and independently of its hypertrophic actions. Leptin may therefore contribute to mitochondrial dysfunction and the development of apoptosis in the diseased myocardium particularly under conditions of excessive intracellular calcium accumulation.

Topics: Animals; Apoptosis; Calcium; Digitonin; Hypertrophy; Leptin; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocytes, Cardiac; Obesity; Protein Conformation; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; STAT3 Transcription Factor; Time Factors

Hyperleptinemia is known to participate in cardiac hypertrophy and hypertension, but the relationship between pressure overload and leptin is poorly understood. We therefore examined the expression of leptin (ob) and the leptin receptor (ob-R) in the pressure-overloaded rat heart. We also examined gene expressions in culture cardiac myocytes to clarify which hypertension-related stimulus induces these genes.. Pressure overload was produced by ligation of the rat abdominal aorta, and ob and ob-R isoform mRNAs were measured using a real-time polymerase chain reaction (PCR). We also measured these gene expressions in neonatal rat cardiac myocytes treated with angiotensin II (ANGII), endothelin-1 (ET-1), or cyclic mechanical stretch. Leptin and the long form of the leptin receptor (ob-Rb) gene were significantly increased 4 weeks after banding, but expression of the short form of the leptin receptor (ob-Ra) was unchanged. ob-Rb protein expression was also detected by immunohistochemistry in hypertrophied cardiac myocytes after banding. Meanwhile, plasma leptin concentrations were not different between the control and banding groups. In cultured myocytes, ANGII and ET-1 increased only ob mRNA expression. However, mechanical stretch activated both ob and ob-Rb mRNA expression in a time-dependent manner, but ob-Ra mRNA was unchanged by any stress.. We first demonstrated that both pressure mediated hypertrophy and mechanical stretch up-regulate ob-Rb gene expression in heart and cardiac myocytes, which are thought to be important for leptin action in cardiac myocytes. These results suggest a new local mechanism by which leptin affects cardiac remodeling in pressure-overloaded hearts.

Topics: Angiotensin II; Animals; Cells, Cultured; Endothelin-1; Hypertrophy; Leptin; Male; Myocytes, Cardiac; Pressure; Protein Isoforms; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; STAT3 Transcription Factor; Stress, Mechanical; Up-Regulation

Improved glycaemic control during pregnancy in mothers with type 1 diabetes (T1DM) and gestational diabetes (GDM) has resulted in a marked reduction of perinatal mortality and morbidity, but the prevalence of macrosomia is usually high.. We used non-invasive anthropometric methods to estimate the body composition and the thickness of the interventricular heart septum in 18 infants of mothers with well-controlled T1DM, 10 infants of mothers with GDM and 28 infants of healthy control mothers matched for gestational age and mode of delivery.. Skinfold measurements were obtained with a Harpenden calliper within 48 h after delivery. Echocardiography was also performed to measure the thickness of the interventricular septum. Cord blood was sampled for assays of C-peptide, leptin and IGF-I.. The rates of macrosomia (gestational age-adjusted birth weight >2 standard deviation score, SDS) were 56 and 30% in infants of mothers with T1DM and GDM, respectively, compared to 10% in control infants. The body fat content was 40% (0.2 kg) higher and the interventricular heart septum thickness was increased by 20% in both groups of infants of diabetic mothers. We found no associations between maternal levels of HbA1c during pregnancy and body composition or interventricular heart septum thickness. Cord levels of C-peptide and leptin were significantly higher in infants of T1DM mothers than in control infants. Cord leptin level was associated with birth weight SDS and percent body fat in infants of T1DM mothers. IGF-I was associated with percent body fat in infants of GDM mothers and control mothers. A multiple-regression analysis showed that 50% of the variation in body weight SDS could be determined, with IGF-I, leptin and C-peptide as independent variables.. Both fat mass and cardiac septal thickness are increased in newborn infants of women with T1DM and GDM in spite of efforts to achieve good glycaemic control during pregnancy.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Macrosomia; Glycated Hemoglobin; Heart Septum; Humans; Hypertrophy; Infant, Newborn; Insulin-Like Growth Factor I; Leptin; Pregnancy; Prevalence; Regression Analysis

Maternal nicotine (NIC) exposure during lactation leads to overweight, hyperleptinemia, and hypothyroidism in adult rat offspring. In this model, we analyzed adipocyte morphology, glucose homeostasis (serum insulin and adiponectin; liver and muscle glycogen), serum lipid, and the leptin signaling pathway. After birth, osmotic minipumps were implanted in lactating rats, which were divided into the groups NIC (6 mg/kg per day s.c. for 14 days) and control (C, saline). NIC and C offspring were killed at the age of 180 days. Adult NIC rats showed higher total body fat (+10%, P<0.05), visceral fat mass (+12%, P<0.05), and cross-sectional area of adipocytes (epididymal: +12% and inguinal: +43%, P<0.05). Serum lipid profile showed no alteration except for apolipoprotein AI, which was lower. We detected a lower adiponectin:fat mass ratio (-24%, P<0.05) and higher insulinemia (+56%, P<0.05), insulin resistance index (+43%, P<0.05), leptinemia (+113%, P<0.05), and leptin:adiponectin ratio (+98%, P<0.05) in the adult NIC group. These rats presented lower hypothalamic contents of the proteins of the leptin signaling pathway (leptin receptor (OB-R): -61%, janus tyrosine kinase 2: -41%, and p-signal transducer and activator of transcription 3: -56%, P<0.05), but higher suppressor of cytokine signaling 3 (+81%, P<0.05). Therefore, NIC exposure only during lactation programs rats for adipocyte hypertrophy in adult life, as well as for leptin and insulin resistance. Through the effects of NIC, perinatal maternal cigarette smoking may be responsible for the future development of some components of the metabolic syndrome in the offspring.

Topics: Adipocytes; Adiponectin; Animals; Animals, Newborn; Blood Glucose; Cotinine; Drug Resistance; Female; Glycogen; Homeostasis; Hypertrophy; Hypothalamus; Insulin; Insulin Resistance; Lactation; Leptin; Lipids; Liver; Male; Milk; Muscle, Skeletal; Nicotine; Rats; Signal Transduction

The Ca(2+)/calmodulin stimulated adenylyl cylcase 8 (AC8) is a pure Ca(2+) sensor, catalyzing the conversion of ATP to cAMP, with a critical role in neuronal plasticity. A role for AC8 in modulating complex behavioral outcomes has been demonstrated in AC8 knock out (KO) mouse models in which anxiety-like responses were differentially modulated following repeated stress experiences, suggesting an involvement of AC8 in stress adaptation and mood disorders. To further investigate the role of this enzyme in phenotypes relevant for psychiatric conditions, AC8 KO mice were assessed for baseline behavioral and hormonal parameters, responses to repeated restraint stress experience, and long-term effects of chronic social defeat stress. The lack of AC8 conferred a hyperactive-phenotype both in home-cage behaviors and the forced swim test response as well as lower leptin plasma levels and adrenal hypertrophy. AC8 KO mice showed baseline "anxiety" levels similar to wild type littermates in a variety of procedures, but displayed decreased anxiety-like responses following repeated restraint stress. This increased stress resilience was not seen during the chronic social defeat procedure. AC8 KO did not differ from wild type mice in response to social stress; similar alterations in body weight, food intake and increased social avoidance were found in all defeated subjects. Altogether these results support a complex role of cAMP signaling pathways confirming the involvement of AC8 in the modulation of stress responses. Furthermore, the hyperactivity and the increased risk taking behavior observed in AC8 KO mice could be related to a manic-like behavioral phenotype that warrants further investigation.

Topics: Adenylyl Cyclases; Adrenal Glands; Animals; Behavior, Animal; Biomarkers; Disease Models, Animal; Hypertrophy; Leptin; Male; Mice; Mice, Knockout; Mood Disorders; Stress, Psychological

Excess lipid accumulation resulting from an elevated supply of plasma fatty acids is linked to the pathogenesis of the metabolic syndrome and heart disease. The term 'lipotoxicity' was coined to describe how lipid accumulation leads to cellular dysfunction and death in non-adipose tissues including the heart, pancreas and liver. While lipotoxicity has been shown in cultured skeletal muscle cells, the degree of lipotoxicity in vivo and the functional consequences are unresolved. We studied three models of fatty acid overload in male mice: 5 h Intralipid((R)) and heparin infusion, prolonged high fat feeding (HFF) and genetic obesity induced by leptin deficiency (ob/ob mice). Markers of apoptosis, proteolysis and autophagy were assessed as readouts of lipotoxicity. The Intralipid((R)) infusion increased caspase 3 activity in skeletal muscle, demonstrating that enhancing fatty acid flux activates pro-apoptotic pathways. HFF and genetic obesity increased tissue lipid content but did not influence apoptosis. Gene array analysis revealed that HFF reduced the expression of 31 pro-apoptotic genes. Markers of autophagy (LC3beta and beclin-1 expression) were unaffected by HFF and were associated with enhanced Bcl(2) protein expression. Proteolytic activity was similarly unaffected by HFF or in ob/ob mice. Thus, contrary to our previous findings in muscle culture in vitro and in other non-adipose tissues in vivo, lipid overload did not induce apoptosis, autophagy or proteolysis in skeletal muscle. A broad transcriptional suppression of pro-apoptotic proteins may explain this resistance to lipid-induced cell death in skeletal muscle.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Caspase 3; Dietary Fats; Disease Models, Animal; Down-Regulation; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Gene Expression Profiling; Hypertrophy; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Obesity; Oligonucleotide Array Sequence Analysis; Proteasome Endopeptidase Complex; Time Factors; Transcription, Genetic

Obesity is a leading cause of diabetes mellitus and hypertension. Molecular signals produced by adipose tissue may contribute to the pathogenesis of these two disorders. We showed previously that a specific segment of rat chromosome 20 (RNO20) contains a gene(s) regulating the degree of obesity, glucose intolerance, and hypertension in response to a chronic high-fat diet (HFD). Here we examined microarray gene expression profiles and cellular morphology of adipose tissues and whole body energy expenditure in this model. Adult male spontaneously hypertensive rats (SHR) and a congenic strain (SHR.1N) that differs from SHR by the above-mentioned segment of RNO20 were fed for 12 wk with HFD or a normal diet. At the end of this period, whole body energy expenditure was measured with indirect calorimetry. In response to HFD, body weight, fat pad weights, adipocyte size, and serum leptin levels increased significantly more in SHR.1N than SHR. Microarray gene expression profiles [Affymetrix, 15,923 genes and expressed sequence tags (ESTs)] showed that multiple genes of molecular pathways involved in lipogenesis were downregulated to a similar level in both strains, whereas genes involved in fatty acid oxidation and energy dissipation were upregulated less in SHR.1N than SHR. This was associated with lower whole body energy expenditure in SHR.1N than SHR at the end of the 12-wk HFD. Our results suggest that a gene(s) within the RNO20 segment regulate(s) HFD-induced increases in adiposity, and that this effect may be mediated, at least in part, by the impact of that gene(s) on fat burning and energy expenditure.

Topics: Adipocytes; Animals; Chromosome Mapping; Dietary Fats; Energy Metabolism; Gene Expression Profiling; Hypertrophy; Leptin; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Inbred SHR

We investigated the role of leptin and its interaction with endothelin 1 (ET-1) in fibronectin (FN) synthesis and cardiomyocyte hypertrophy, two characteristic features of diabetic cardiomyopathy.. Endothelial cells [human umbilical vein endothelial cells (HUVECs)] were examined for FN production and neonatal rat cardiomyocytes for hypertrophy, following incubation with glucose, ET-1, leptin and specific blockers. FN, ET-1, leptin and leptin receptors mRNA expression and FN protein were measured. Myocytes were also morphometrically examined. Furthermore, hearts from streptozotocin-diabetic rats were analysed.. Glucose caused increased FN mRNA and protein expression in HUVECs and cardiomyocytes hypertrophy along with upregulation of ET-1 mRNA, leptin mRNA and protein. Glucosemimetic effects were seen with leptin and ET-1. Leptin receptor antagonist (leptin quadruple mutant) and dual endothelin A endothelin B (ETA/ETB) receptor blocker bosentan normalized such abnormalities. Hearts from the diabetic animals showed hypertrophy and similar mRNA changes.. These data indicate that in diabetes increased FN production and cardiomyocyte hypertrophy may be mediated through leptin with its interaction with ET-1.

Topics: Analysis of Variance; Animals; Cells, Cultured; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Extracellular Matrix Proteins; Fibronectins; Humans; Hypertrophy; Leptin; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Statistics, Nonparametric; Umbilical Veins

This study investigated the effects of rosiglitazone on nutritionally programmed chronic disease, with a focus on blood pressure (BP) and aortic wall structural remodeling. Wistar pregnant rats were fed one of two diets: a normal protein diet (19% protein; NP rats) or low-protein diet (5% protein; LP rats). Male offspring at 3 months of age were randomly divided into four groups: NP offspring treated with rosiglitazone (NPR); untreated NP offspring (NP); LP offspring treated with rosiglitazone (LPR); untreated LP offspring (LP). Rosiglitazone was administered at a dose of 5 mg/kg/d until 6 months of age. BP was elevated in LP offspring. Rosiglitazone reduced BP beginning in the first week of treatment in the LPR offspring. The insulin sensitivity was increased in LP offspring, and was not altered by rosiglitazone. LP offspring exhibited a 40% reduction in the amount of elastic fibers in the aorta wall compared with NP offspring (p < 0.01), and the quantity of elastic fibers was not altered by rosiglitazone. The smooth muscle cells, elastic lamellae, circumferential wall tension (CWT) and tensile stress (TS) were increased in LP offspring, indicating increased blood flow in the aorta. Rosiglitazone reduced both CWT and TS by 30% compared to the levels in untreated LP offspring (p < 0.01 for both). Rosiglitazone restored the expressions of angiotensin II type 1 receptor and endothelial nitric oxide synthase nearly to the levels in the NP offspring. ANOVA disclosed a significant two-factor interaction between protein content in the diet and rosiglitazone treatment (p < 0.001 for CWT and p < 0.00001 for TS, two-way ANOVA). We conclude that rosiglitazone has beneficial effects in reducing the BP and the aortic tunica media hypertrophy with consequent balance of the wall stress in metabolically programmed offspring.

Topics: Animals; Aorta; Blood Glucose; Blood Pressure; Carbohydrate Metabolism; Diet, Protein-Restricted; Disease Models, Animal; Elasticity; Female; Hypertension; Hypertrophy; Insulin; Leptin; Male; Nitric Oxide Synthase Type III; PPAR gamma; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Rosiglitazone; Thiazolidinediones; Tunica Media

The effect of 40% food restriction (FR) and replenishment on the growth hormone (GH) and insulin-like growth factor-I (IGF-I) axis in the epiphyseal growth plate (EGP) was examined in a mouse model. Changes in RNA and protein levels were evaluated with real time PCR and immunohistochemistry, respectively, and serum levels of IGF-I and leptin were measured with radioimmunoassay. Dramatic changes in weight, tibial length and EGP height were observed following 10 days of 40% FR. The protein levels of IGF-I receptor (IGF-IR) and GH receptor (GHR), which were reduced during FR, increased during catch-up growth without an apparent change in the level of their RNA. The levels of type II and X collagens were unchanged. Serum IGF-I and leptin levels were reduced during FR and increased during catch-up growth. Following 40% FR, there was a significant decrease in the level of GHR and IGF-IR in the EGP which may explain the reduced effect of GH treatment in malnourished animals and children.

Topics: Animals; Body Weight; Cell Proliferation; Chondrocytes; Eating; Growth Hormone; Growth Plate; Hypertrophy; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred ICR; Nutritional Physiological Phenomena; Receptor, IGF Type 1; Receptors, Somatotropin; Tibia

To understand the adaptation to lactation of obese rats, by studying the interplay among the gut hormone cholecystokinin (CCK), the adiposity hormone leptin and the affiliation hormone oxytocin in modulating body mass and fat storage.. Strain differences were examined between Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking expression of functional CCK-1 receptors and Long Evans Tokushima Otsuka (LETO) controls, tested as nulliparous dams, at the 7 and 15th lactation day, at weaning (lactation day 22) or 8 weeks postweaning.. We measured body mass, fat pads (brown, retroperitoneal and inguinal) and inguinal adipocytes. Plasma levels of leptin and oxytocin were determined.. Fat depots of LETO female rats were larger during lactation compared to the levels found in postweaning and nulliparous female rats. LETO female rats gained weight and accumulated fat during pregnancy and lactation, returning to their normal fat levels postweaning. In contrast, OLETF female rats presented lower body weight and fat depots during the lactation period than nulliparous dams, and regained the weight and fat postweaning. Plasma leptin and oxytocin were highly correlated and followed the same pattern. OLETF leptin levels were highly correlated with fat depot and inguinal cell surface. No significant correlation was found for LETO parameters.. Pregnancy and lactation are energy-consuming events, which naturally induce female rats to increase food intake and accumulate fat. When challenged by the demands of rapidly growing preobese OLETF pups, OLETF dams' fat stores are reduced to lean, LETO levels. During lactation, sensitivity of the oxytocinergic neurons descending from the paraventricular nuclei to the nucleus of the solitary tract to CCK is reduced. We theorized that this pathway is not available to OLETF female rats that lack functional CCK-1 receptors to mediate the signal. The current study contributes to the understanding of the female body's adaptation to lactation.

Topics: Adaptation, Physiological; Adipocytes; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Female; Hypertrophy; Lactation; Leptin; Mutation; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Receptors, Cholecystokinin; Weaning; Weight Gain

Obesity is associated with increased leptin production that may contribute to cardiovascular pathology through a multiplicity of effects. Leptin has been shown to contribute to vascular remodeling through various mechanisms, including production of vascular smooth muscle (VSMC) hypertrophy; however, the mechanisms underlying the vascular hypertrophic effect of leptin remain unknown. In the present study, we investigated the contributions of the RhoA/Rho kinase (ROCK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways, actin dynamics, and the expression of serum-response factor (SRF) in the hypertrophic effects of leptin on vascular tissue. Strips of rat portal vein (RPV) were cultured with or without leptin at 3.1 nM for 1 to 3 days. Leptin significantly increased RhoA activity by 163 +/- 20%, whereas phosphorylation of downstream factors, including LIM kinase 1 and cofilin-2, was increased by 160 +/- 25 and 290 +/- 25%, respectively. Leptin also significantly phosphorylated Akt by 130 +/- 30%, which was inhibited by the PI3K inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). RhoA/ROCK and PI3K/Akt activation was associated with a significant increase in RPV wet weight (11 +/- 1%), protein synthesis (45 +/- 7%), SRF expression (136 +/- 11%), and polymerization of actin, as reflected by an increase in the F-/G-actin ratio, effects that were significantly attenuated by a leptin receptor (leptin obese receptor) antibody, the ROCK inhibitor (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) (Y-27632) as well as the PI3K inhibitor LY294002. Our results indicate that the activation of RhoA/ROCK and PI3K/Akt plays a pivotal role in leptin signaling, leading to the development of VSMC hypertrophy through a mechanism involving altered actin dynamics.

Topics: Actins; Animals; Cytoskeleton; Hypertrophy; Intracellular Signaling Peptides and Proteins; Leptin; Muscle, Smooth, Vascular; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction

Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+/-3.54 microm) and large cells (mean 100.1+/-3.94 microm). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.

Topics: Adipocytes; Cell Size; Female; Gene Expression Regulation; Humans; Hypertrophy; Insulin Resistance; Leptin; Male; Postmenopause; Reverse Transcriptase Polymerase Chain Reaction

Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2-/- mice, whereas that of DGAT1 was down-regulated. This reciprocal expression of DGAT1 and DGAT2 was also observed in WAT of leptin-deficient ob/ob mice. A high fat diet also resulted in increased DGAT2 and reduced DGAT1 in the WAT of C57BL/6 mice. Induction of adipocyte hypertrophy in vitro up-regulated both DGAT1 and DGAT2 expression in 3T3-L1 cells, suggesting that adipocyte non-autonomous mechanism in vivo is required for the reciprocal changes in expression of DGAT1 and DGAT2. In fact, intracerebroventricular infusion of leptin reduced DGAT2 expression in WAT of Irs2-/- mice and ob/ob mice, independently of DGAT1 expression. We propose the hypothesis that leptin regulates adipocyte size by altering expression patterns of DGAT via central nervous system to determine the levels of triglyceride synthesis.

Topics: 3T3-L1 Cells; Acyltransferases; Adipocytes; Adipose Tissue; Animals; CCAAT-Enhancer-Binding Proteins; Diacylglycerol O-Acyltransferase; Dietary Fats; DNA-Binding Proteins; Gene Expression; Hypertrophy; Injections, Intraventricular; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Mutant Strains; Mice, Obese; Obesity; Phosphoproteins; Sterol Regulatory Element Binding Protein 1; Transcription Factors

The hypertrophy of vascular smooth muscle cells (VSMCs) is critical in vascular remodeling associated with hypertension, atherosclerosis, and restenosis. Recently, leptin has appeared to play a pivotal role in vascular remodeling. However, the mechanism by which leptin induces hypertrophy in vascular smooth muscle cells is still unknown. We studied the role of leptin as a potential hypertrophic factor in rat VSMCs. In the present study, leptin significantly increased [(3)H]leucine incorporation and the total protein/DNA ratio in VSMCs. The maximal hypertrophic effect was at 100ng/ml of leptin. Leptin induced phosphorylation and activation of p38 mitogen-activated protein (p38 MAP) kinase and of signal transducers and activators of transcription 3 in a concentration- and time-dependent manner. A p38 MAP kinase inhibitor SB203580 significantly inhibited leptin-induced hypertrophy, AG490 (a JAK2 inhibitor) partially inhibited it, and other MAP kinase inhibitors, PD98059 (an ERK inhibitor) and SP600125 (a JNK inhibitor), had no effect. These results indicate that leptin directly stimulates cellular hypertrophy via p38 MAP kinase in rat VSMCs.

Topics: Animals; Anthracenes; Aorta; Arteriosclerosis; Blotting, Western; Cells, Cultured; DNA; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Hypertrophy; Leptin; Leucine; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Time Factors; Trans-Activators; Tyrphostins

There is an increased incidence of renal glomerulosclerosis in obese individuals. One of the major structural changes observed in nephropathy is the increase in kidney size, which may occur due to hypertrophy or changes in the rate of hyperplasia or apoptosis. Here we investigated whether leptin, the product of the obese (ob) gene which is found at high plasma levels in obese and diabetic individuals, alters any of these parameters.. We show that leptin increased hypertrophy of these cells. This was indicated by an approximately 33% increase in cell size and 40% increase in leucine incorporation. Furthermore, we show that the hypertrophic effect of leptin was mediated via PI 3-kinase and ERK1/2 by using the inhibitors LY294002 and PD98059, respectively. We also confirm that leptin activates both PI 3-kinase and ERK1/2 in these cells. We show that hyperplasia was not affected by leptin by measuring rat glomerular mesangial cell number and by assessing bromodeoxyuridine uptake. Leptin also did not alter caspase 3-like activity under control conditions or upon induction of apoptosis by ultraviolet light, suggesting that apoptosis was not regulated by leptin in these cells.. Our results show that leptin induced glomerular mesangial cell hypertrophy via PI 3-kinase and ERK1/2, and that hyperplasia and apoptosis were not altered by leptin. The hypertrophic effect of leptin may play a role in the pathophysiology of nephropathy associated with obesity.

Topics: Animals; Apoptosis; Cell Size; Cells, Cultured; Chromones; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Glomerular Mesangium; Hyperplasia; Hypertrophy; Kidney; Leptin; Leucine; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Rats

Various cardiovascular pathologies are associated with vascular smooth muscle cell (VSMC) hypertrophy and elevated plasma leptin levels. We used the rat portal vein (RPV) cultured for three days to investigate the effect of mechanical stretch on autocrine secretion of leptin and the effect of exogenous leptin (3.1 nM) on VSMC. Stretching the RPV significantly up-regulated leptin production by greater than 100-fold and leptin receptor expression by up to 10-fold. In addition, stretch increased tissue weight by 23 +/- 1.3 and 30 +/- 1% (P < 0.05), respectively, in the absence or presence of leptin, although this was significantly attenuated by an antileptin antibody (166 ng/ml). Unstretched RPV weight decreased by 7.5 +/- 1.8% in the absence of leptin, whereas in the presence of leptin, weight increased by 6.5 +/- 1.8% (P < 0.05). VSMC size and [3H]leucine incorporation rates were significantly increased by leptin in stretched and unstretched tissues. Leptin-induced hypertrophy was associated with significant extracellular signal-regulated kinase (ERK1/2) activation as well as increased expression of angiotensinogen, the angiotensin type 1 receptor as well as preproendothelin-1, and the endothelin type A receptor, whereas ERK inhibition or inhibition of either the angiotensin II or endothelin-1 systems at both the synthesis and receptor levels blocked the hypertrophic response. The effects of leptin were also completely blocked by the cholesterol-chelating agent methyl-beta-cyclodextrin. Therefore, our study demonstrates stretch-dependent leptin release and a direct hypertrophic effect of leptin on RPV, the latter likely dependent on intact cholesterol-rich membrane microdomains and locally produced paracrine factors.

Topics: Angiotensin II; Animals; Cell Culture Techniques; Cells, Cultured; Culture Media; Endothelin-1; Hypertrophy; Leptin; Male; Models, Biological; Muscle, Smooth, Vascular; Organ Size; Portal Vein; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Stress, Mechanical; Up-Regulation

Degeneration of the ovary in middle-aged women results in castrate levels of ovarian steroids and increased gonadotropin secretion from the anterior pituitary gland. Ageing in women is also accompanied by significant changes in energy homeostasis. We have observed alterations in hypothalamic morphology and gene expression in older women, including hypertrophy and increased gene expression of neurokinin B (NKB) neurones, elevated levels of gonadotropin releasing-hormone (GnRH) mRNA and decreased numbers of neurones expressing pro-opiomelanocortin (POMC) mRNA. To determine if loss of ovarian steroids could produce comparable changes in gene expression in young primates, we measured the effects of ovariectomy on NKB, GnRH and POMC gene expression in young cynomolgus monkeys. We also measured serum leptin and body weight to examine the consequences of ovariectomy on energy balance. NKB neurones in the infundibular nucleus of ovariectomized monkeys were larger, more numerous and displayed increased levels of NKB mRNA compared to those of intact controls. Moreover, ovariectomy increased the number of neurones expressing GnRH gene transcripts and elevated serum luteinizing hormone. By contrast, several parameters related to energy balance, including POMC gene expression, serum leptin and body weights, were unchanged by ovariectomy. Thus, the rise in NKB and GnRH gene expression in older women was simulated by ovariectomy in monkeys, but the changes in POMC gene expression and energy balance were not. This study provides strong support for the hypothesis that ovarian failure contributes to the increased NKB and GnRH gene expression observed in postmenopausal women.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Disease Models, Animal; Energy Metabolism; Female; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hypertrophy; Leptin; Macaca fascicularis; Menopause; Neurokinin B; Neurons; Neurosecretory Systems; Ovariectomy; Ovary; Pro-Opiomelanocortin; Random Allocation; RNA, Messenger

Both diabetes (db/db) and obese (ob/ob) genotype mutations induce a hyperglycemic-hyperinsulinemic endometabolic state in C57BL mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) in these leptin ligand/receptor-deficient models. The severity of the DOS induced by these single gene, homozygous-recessive mutations may be moderated by the background genome on which the mutation is expressed. The current studies define the phenotypic, systemic, cytochemical and cellular metabolic responses to db/db and ob/ob mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (+/?) indices. Both db/db and ob/ob mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to +/? indices when expressed on either the C57BL/KsJ (-/KsJ) or C57BL/6 (-/6) backgrounds. However, the -/KsJ background enhanced the severity of expression of these DOS indices relative to the -/6 strain. Similarly, the -/KsJ genome suppressed cellular glucose uptake rates, pancreatic tissue weights and insulin concentrations in both db/db and ob/ob mutants relative to /6 background strain influences or +/? indices. Concurrent enhancement of tissue and cellular lipogenic metabolism and islet cytolipid depositions were exaggerated when the mutations were expressed on the -/KsJ background relative to the -/6 genome. Pancreatic islet B-cell lipodeposition was markedly enhanced in ob/ob and db/db mutants expressed on either the -/KsJ or -/6 background. In both ob/ob and db/db models, B-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets when the mutations were expressed on the -/6 background. In contrast, the severity of the DOS state expressed on the -/KsJ background resulted in pronounced B-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both ob/ob and db/db mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in ob/ob and db/db mutants were exaggerated by the -/KsJ genome as compared to -/6 or control indices. The influences of the -/KsJ genome on the progressive expression of tissue NE counter-regulatory responses to enhanced cytolipidemic indices were inversely related, with cytochemical lipodeposition occurring under conditions of diminished adrenergic responses to the DOS indices.

Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Size; Diabetes Mellitus, Type 2; Female; Genotype; Hyperinsulinism; Hypertrophy; Insulin; Islets of Langerhans; Leptin; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Norepinephrine; Obesity; Organ Size; Oxidative Stress; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Species Specificity

The relationship between the adipocyte-derived hormone leptin, insulin resistance, and fat redistribution in patients with human immunodeficiency virus (HIV) infection has not been established. We classified a cohort of HIV type 1 (HIV-1)-infected patients with >or=6 months of antiretroviral exposure as having no lipodystrophy (51 patients [43% of the cohort]), lipoatrophy (23 patients [19% of the cohort]), mixed lipodystrophy (29 patients [24% of the cohort]), or lipohypertrophy (17 patients [14% of the cohort]), on the basis of physical examination, anthropometric measurements, and the findings of dual-emission x-ray absorptiometry and computed tomography. Measurements of insulin resistance were higher for patients with each category of lipodystrophy, compared with those observed for patients with no lipodystrophy (P<.001). Mean leptin levels (+/- standard deviation) were lowest in patients with lipoatrophy (1.76+/-1.20 ng/mL), highest in patients with lipohypertrophy (9.10+/-6.86 ng/mL), and significantly different from those in patients without lipodystrophy (3.14+/-2.30 ng/mL; both P<.01). In this cohort of antiretroviral-experienced HIV-infected patients, a low serum level of leptin was independently associated with insulin resistance in patients with lipoatrophy, after controlling for total and regional body fat.

Topics: Adult; Atrophy; Female; HIV Infections; HIV-1; Humans; Hypertrophy; Leptin; Male; Middle Aged; Regression Analysis

High-salt diet is known to induce or aggravate hypertension in animal models of hypertension and in humans. When Sprague-Dawley rats (n = 60) are fed a moderately high-fat diet (32% kcal fat, 0.8% NaCl) for 10 wk, about one-half develop obesity [obesity prone (OP)] and mild hypertension, whereas the other half [obesity resistant (OR)] maintain body weight equivalent to a low-fat control (C) and are normotensive. The aim of this study was to test the effect of high-NaCl diets (2 and 4% NaCl) on the development of hypertension and obesity, oxidative stress, and renal function. Both 2 and 4% NaCl induced an early increase in systolic blood pressure of OP but not OR or C rats. High-salt intake induced an increase in the size and reduction in number of adipocytes, concomitant to a twofold increase in circulating leptin in OP rats. Aortic superoxide generation indicated a 2.8-fold increase in the OP high-salt vs. normal-salt groups, whereas urine isoprostanes were not significantly increased. Also, hydroxynonenal protein adducts in the kidney were highly increased in OP rats on 2 and 4% NaCl, indicating oxidative stress in the renal tissue. Urine albumin was increased threefold in the OP on 2% NaCl and fourfold in the same group on 4% NaCl vs. 0.8% NaCl. Kidney histology indicated a higher degree of glomerulosclerosis in OP rats on high-salt diets. In summary, high-salt diet accelerated the development but did not increase the severity of hypertension; high salt increased oxidative stress in the vasculature and kidney and induced kidney glomerulosclerosis and microalbuminuria. Also, the OP rats on high salt displayed adipocyte hypertrophy and increased leptin production.

Topics: Adipocytes; Adipose Tissue; Animals; Aorta; Blood Pressure; Body Weight; Diet; Disease Susceptibility; Diuresis; Hypertension; Hypertrophy; Kidney; Leptin; Male; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renin; Sclerosis; Sodium Chloride, Dietary

Adipose tissue glyceroneogenesis generates glycerol 3-phosphate, which could be used for fatty acid esterification during starvation. To determine whether increased glyceroneogenesis leads to increased fat mass and to explore the role of obesity in the development of insulin resistance, we overexpressed PEPCK, a regulatory enzyme of glyceroneogenesis in adipose tissue. Transgenic mice showed a chronic increase in PEPCK activity, which led to increased glyceroneogenesis, re-esterification of free fatty acids (FFAs), increased adipocyte size and fat mass, and higher body weight. In spite of increased fat mass, transgenic mice showed decreased circulating FFAs and normal leptin levels. Moreover, glucose tolerance and whole-body insulin sensitivity were preserved. Skeletal muscle basal and insulin-stimulated glucose uptake and glycogen content were not affected, suggesting that skeletal muscle insulin sensitivity is normal in transgenic obese mice. Our results indicate the key role of PEPCK in the control of FFA re-esterification in adipose tissue and, thus, the contribution of glyceroneogenesis to fat accumulation. Moreover, they suggest that higher fat mass without increased circulating FFAs does not lead to insulin resistance or type 2 diabetes in these mice.

Topics: Adipocytes; Adipose Tissue; Animals; Carbon Radioisotopes; Deoxyglucose; Esterification; Fatty Acids; Fatty Acids, Nonesterified; Gene Expression; Glycerol; Glycerophosphates; Heterozygote; Homozygote; Hypertrophy; Insulin Resistance; Leptin; Male; Mice; Mice, Transgenic; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); RNA, Messenger; Tumor Necrosis Factor-alpha

Morbid obesity is the result of massive expansion of white adipose tissue (WAT) and requires recruitment of adipocyte precursor cells and their supporting infrastructure. To characterize the change in the expression profile of the preexisting WAT at the start of obesity, when adipocyte hypertrophy is present but hyperplasia is still minimal, we employed a cDNA subtraction screen for genes differentially expressed in epididymal fat pads harvested 1 wk after the start of a 60% fat diet. Ninety-six genes were upregulated by at least 50% above the WAT of control rats receiving a 4% fat diet. Of these genes, 30 had not previously been identified. Sixteen of the 96 genes, including leptin, adipocyte complement-related protein 30 kDa, and resistin, were predicted to encode a signal peptide. Ten of the 16 had been previously identified in other tissues and implicated in cell growth, proliferation, differentiation, cell cycle control, and angiogenesis. One was a novel gene. Twenty-nine novel fragments were identified. Thus, at the onset of high-fat-diet-induced obesity in rats, adipose tissue increases its expression of factors previously implicated in the expansion of nonadipocyte tissues and of several uncharacterized novel factors. The only one of these thus far characterized functionally was found to promote lipogenesis.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Blood Proteins; Cytoskeletal Proteins; Dietary Fats; Gene Expression Profiling; Hormones, Ectopic; Hyperplasia; Hypertrophy; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Mitochondria; Nerve Growth Factor; Nutritional Physiological Phenomena; Obesity; Oxygen Consumption; Proteins; Rats; Rats, Sprague-Dawley; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha

Topics: Adolescent; Age Factors; Analysis of Variance; Animals; Atrophy; Autopsy; Breast Feeding; Child; Cytokines; Data Interpretation, Statistical; Humans; Hypertrophy; Infant; Infant Food; Infant, Newborn; Leptin; Mice; Starvation; Sudden Infant Death; Thymus Gland; Ultrasonography

To investigate the relationships of fat cell weight (FCW) as well as of estimated total adipose cell number to fasting plasma leptin concentration.. Cross-sectional correlational study.. A sample of 63 men (mean age+/-s.d.: 36+/-4 y) and 42 premenopausal women (35+/-5 y).. Adipose tissue (AT) biopsies were obtained in order to determine FCW as well as estimated adipose cell number. Fasting plasma leptin and insulin concentrations as well as various fatness and body fat distribution variables (underwater weighing and computed tomography) were also measured.. In both genders, mean FCW as well as the estimated adipose cell number were significantly correlated with body fatness and AT distribution variables (0.41

Topics: Adipocytes; Adipose Tissue; Adult; Biopsy; Body Composition; Cell Count; Cell Size; Cross-Sectional Studies; Fasting; Female; Humans; Hyperplasia; Hypertrophy; Insulin; Leptin; Male; Regression Analysis

The relationship between interscapular brown adipose tissue (IBAT) thermogenic potential and vitamin A status was investigated by studying the effects of feeding a vitamin A-deficient diet and all-trans retinoic acid (tRA) treatment on body weight and IBAT parameters in mice. Feeding a vitamin A-deficient diet tended to trigger opposite effects to those of tRA treatment, namely increased body weight, IBAT weight, adiposity and leptin mRNA expression, and reduced IBAT thermogenic potential in terms of uncoupling protein 1 (UCP1) mRNA and UCP2 mRNA expression. The results emphasize the importance of retinoids as physiological regulators of brown adipose tissue.

Topics: Adipose Tissue, Brown; Animals; Blotting, Northern; Body Temperature Regulation; Body Weight; Carrier Proteins; Hypertrophy; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Proteins; RNA, Messenger; Tretinoin; Uncoupling Protein 1; Uncoupling Protein 2; Vitamin A Deficiency

The biological role of peroxisome proliferator-activated receptor gamma (PPARgamma) was investigated by gene targeting and case-control study of the Pro12Ala PPARgamma2 polymorphism. Homozygous PPARgamma-deficient embryos died at 10.5-11.5 days post conception (dpc) due to placental dysfunction. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARgamma agonist treatment. Heterozygous PPARgamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARgamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARgamma. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against type 2 diabetes. These results revealed that in both mice and humans, PPARgamma is a thrifty gene mediating type 2 diabetes.

Topics: Adipose Tissue; Animals; Case-Control Studies; Diabetes Mellitus, Type 2; Dietary Fats; Humans; Hypertrophy; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Biological; Obesity; Polymorphism, Genetic; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors