Regulation Of Adipose Tissue Mass Research Articles

AGPAT3 deficiency impairs adipocyte differentiation and leads to a lean phenotype in mice.

Acylglycerophosphate acyltransferases (AGPATs) catalyze the de novo formation of phosphatidic acid to synthesize glycerophospholipids and triglycerides. AGPATs demonstrate unique physiological roles despite a similar biochemical function. AGPAT3 is highly expressed in the testis, kidney, and liver, with intermediate expression in adipose tissue. Loss of AGPAT3 is associated with reproductive abnormalities and visual dysfunction. However, the role of AGPAT3 in adipose tissue and whole body metabolism has not been investigated. We found that male Agpat3 knockout (KO) mice exhibited reduced body weights with decreased white and brown adipose tissue mass. Such changes were less pronounced in the female Agpat3-KO mice. Agpat3-KO mice have reduced plasma insulin growth factor 1 (IGF1) and insulin levels and diminished circulating lipid metabolites. They manifested intact glucose homeostasis and insulin sensitivity despite a lean phenotype. Agpat3-KO mice maintained an energy balance with normal food intake, energy expenditure, and physical activity, except for increased water intake. Their adaptive thermogenesis was also normal despite reduced brown adipose mass and triglyceride content. Mechanistically, Agpat3 was elevated during mouse and human adipogenesis and enriched in adipocytes. Agpat3-knockdown 3T3-L1 cells and Agpat3-deficient mouse embryonic fibroblasts (MEFs) have impaired adipogenesis in vitro. Interestingly, pioglitazone treatment rescued the adipogenic deficiency in Agpat3-deficient cells. We conclude that AGPAT3 regulates adipogenesis and adipose development. It is possible that adipogenic impairment in Agpat3-deficient cells potentially leads to reduced adipose mass. Findings from this work support the unique role of AGPAT3 in adipose tissue.NEW & NOTEWORTHY AGPAT3 deficiency results in male-specific growth retardation. It reduces adipose tissue mass but does not significantly impact glucose homeostasis or energy balance, except for influencing water intake in mice. Like AGPAT2, AGPAT3 is upregulated during adipogenesis, potentially by peroxisome proliferator-activated receptor gamma (PPARγ). Loss of AGPAT3 impairs adipocyte differentiation, which could be rescued by pioglitazone. Overall, AGPAT3 plays a significant role in regulating adipose tissue mass, partially involving its influence on adipocyte differentiation.

Alcoholic fatty liver is blunted by rFGF21 administration in mice lacking adipose FGFR1: The role of FGF21 in PPARα-mediated regulation of adipose tissue mass

Fibroblast growth factor 21 (FGF21) is regulated by peroxisome proliferator activated receptor α (PPARα) in the liver. FGF21 regulates lipid metabolism via fibroblast growth factor receptor 1 (FGFR1). FGF21 protect against alcoholic fatty liver (AFL), however, FGF21 does not exert protective effect through liver FGFR1. We have previously shown that PPARα agonist WY-14,643 induces FGF21 and adipose atrophy but fails to protect against chronic ethanol-induced AFL in mice lacking adipose FGFR1. In this study we tested the direct role of the FGF21 in regulation of adipose tissue mass and ethanol induced-hepatic triglyceride (TG) accumulation in normal control (fgfr1fl/fl) mice and in adipose FGFR1 knockout mice (fgfr1adipoQ-cre). First, we tested whether WY-14,643 effects on adipose atrophy and AFL can be recapitulated in binge alcohol model. As in chronic model, adipose tissue mass and serum free fatty acid (FFA) were decreased by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. However, in contrast to the chronic model, binge ethanol-induced AFL was blunted by WY-14,643 to a greater extent in the fgfr1adipoQ-cre mice than in the fgfr1fl/fl mice. Similarly, circulating FGF21 was elevated by binge ethanol to a greater extent in the fgfr1adipoQ-cre mice than in the fgfr1fl/fl mice on top of WY-14,643 treatment. Accordingly, we tested the involvement of the FGF21 in adipose atrophy and AFL. Consistent with FGFR1-dependent effects of WY-14,643 on adipose atrophy and AFL, recombinant mouse FGF21 (rFGF21) injection induced adipose atrophy, blunted AFL and serum TG elevation to a greater extent in the fgfr1adipoQ-cre mice than in the fgfr1fl/fl mice. These results indicated the consistency of adipose FGFR1 dependent effect of WY-14,643 and FGF21 in PPARα-mediated regulation of adipose tissue mass and fat mobilization from adipose tissues to the liver, suggesting that adipose tissues crosstalk with liver through an interaction between liver PPARα-FGF21 and adipose FGFR1 to maintain adipose tissue mass.

Alcoholic fatty liver is blunted by rFGF21 administration in mice lacking adipose FGFR1: the role of FGF21 in PPARα‐mediated regulation of adipose tissue mass

Fibroblast growth factor 21 (FGF21) regulates lipid metabolism via fibroblast growth factor receptor 1 (FGFR1). FGF21 protects against alcoholic fatty liver, which is still observed in mice lacking liver FGFR1, suggesting the involvement of extra‐hepatic FGFR1 in mediating alcoholic fatty liver. We have previously shown that, in a chronic Lieber‐DeCarli model, the peroxisome proliferator‐activated receptor‐α (PPARα) agonist WY‐14,643 induced FGF21 and adipose atrophy but failed to protect against alcoholic fatty liver in mice lacking adipose FGFR1. In this study we tested the role of the FGF21 in regulation of adipose tissue mass and ethanol induced‐hepatic fat (triglyceride, TG) accumulation in mice lacking adipose FGFR1. In binge alcohol model, male adipose FGFR1 knockout mice (fgfr1adipoQ‐cre) and corresponding normal control (fgfr1fl/fl) mice were fed liquid control diet with or without 20 mg/L WY‐14,643 for 2 weeks followed by a binge ethanol gavage at 5 g/kg, adipose tissue mass and serum free fatty acid were decreased by WY‐14,643 in the fgfr1adipoQ‐cremice but not in the fgfr1fl/flmice. However, in contrast to the chronic model, the binge ethanol‐induced liver TG accumulation was blunted by WY‐14,643 to a greater extent in the fgfr1adipoQ‐cremice than in the fgfr1fl/flmice. Consistently, on top of WY‐14,643 feeding, circulating FGF21 was elevated by binge ethanol to a greater extent in the fgfr1adipoQ‐cre mice than in the fgfr1fl/fl mice. To test the involvement of the FGF21 in adipose atrophy and the less extent of hepatic fat accumulation in the fgfr1adipoQ‐cremice, recombinant mouse FGF21 (rFGF21) was injected intraperitoneally at 0.4 mg/kg to the 3‐week ethanol fed fgfr1adipoQ‐cre mice and fgfr1fl/fl mice during the last 10 days of the ethanol feeding. Consistent with FGFR1‐dependent effects of WY‐14,643 on adipose atrophy and liver fat accumulation, on the top of chronic ethanol diet, rFGF21 administration induced adipose atrophy, blunted liver TG accumulation and serum TG elevation to a greater extent in the fgfr1adipoQ‐cre mice than in the fgfr1fl/fl mice. These results indicated the consistency of adipose FGFR1 dependent effect of WY‐14,643 and FGF21 in PPARα‐mediated regulation of adipose tissue mass and fat mobilization from adipose tissues to the liver.

Subcutaneous adipose tissue sclerostin is reduced and Wnt signaling is enhanced following 4-weeks of sprint interval training in young men with obesity.

Sclerostin is a Wnt/β‐catenin antagonist, mainly secreted by osteocytes, and most known for its role in reducing bone formation. Studies in rodents suggest sclerostin can also regulate adipose tissue mass and metabolism, representing bone–adipose tissue crosstalk. Exercise training has been shown to reduce plasma sclerostin levels; but the effects of exercise on sclerostin and Wnt/β‐catenin signaling specifically within adipose tissue has yet to be examined. The purpose of this study was to examine subcutaneous WAT (scWAT) sclerostin content and Wnt signaling in response to exercise training in young men with obesity. To this end, 7 male participants (BMI = 35 ± 4; 25 ± 4 years) underwent 4 weeks of sprint interval training (SIT) involving 4 weekly sessions consisting of a 5‐min warmup, followed by 8 × 20 s intervals at 170% of work rate at VO2peak, separated by 10 s of rest. Serum and scWAT were sampled at rest both pre‐ and post‐SIT. Despite no changes in serum sclerostin levels, we found a significant decrease in adipose sclerostin content (−37%, p = 0.04), an increase in total β‐catenin (+52%, p = 0.03), and no changes in GSK3β serine 9 phosphorylation. There were also concomitant reductions in serum TNF‐α (−0.36 pg/ml, p = 0.03) and IL‐6 (−1.44 pg/ml, p = 0.05) as well as an increase in VO2peak (+5%, p = 0.03) and scWAT COXIV protein content (+95%, p = 0.04). In conclusion, scWAT sclerostin content was reduced and β‐catenin content was increased following SIT in young men with excess adiposity, suggesting a role of sclerostin in regulating human adipose tissue in response to exercise training.

PPARα agonist WY-14,643 induces adipose atrophy and fails to blunt chronic ethanol-induced hepatic fat accumulation in mice lacking adipose FGFR1

Fibroblast growth factor 21 (FGF21) is mainly regulated by peroxisome proliferator-activated receptor α (PPARα) in liver. The PPARα-FGF21 axis protects against alcohol-related liver disease (ALD). FGF21 exerts its effect via FGF receptor 1 (FGFR1). However, liver specific FGFR1 abrogation had no effect on ALD. Adipose tissues highly express FGFR1. When adipocyte specific FGFR1 knockout (fgfr1adipoQ-cre) mice and corresponding normal control (fgfr1fl/fl) mice were fed with Lieber-DeCarli ethanol liquid diet for 3 weeks, liver triglyceride (TG) accumulation was increased in the fgfr1fl/fl mice to a greater extent than in the fgfr1adipoQ-cre mice. When PPARα agonist WY-14,643 was added in the liquid ethanol diet at 10 mg/L, the ethanol-induced liver TG accumulation was blunted in the fgfr1fl/fl mice but not in the fgfr1adipoQ-cre mice. There was no significant difference in WY-14,643-induced fatty acid oxidation, ethanol metabolism, and oxidative stress between the fgfr1fl/fl and fgfr1adipoQ-cre mice. Interestingly, adipose atrophy was induced by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. Serum free fatty acid was also decreased by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. These results suggest that WY-14,643 inhibits alcoholic fatty liver and regulates adipose tissue mass and fat mobilization from adipose tissues to liver in an adipocyte FGFR1-dependent manner.

TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice.

TL1A is a pro-inflammatory cytokine that is homologous to TNFα and connected with the development of several chronic inflammatory disorders. The preliminary results of this study indicated reduced fat accumulation in 9-month-old TL1A-deficient mice at steady state. Thus, the objective was to investigate whether TL1A-deficient mice are resistant to the development of high-fat (HF) diet-induced obesity and to investigate the impact on lymphocyte infiltration in adipose tissue. TL1A-deficient and TL1A-sufficient male BALB/cJ littermate mice were fed a 60% HF diet or a 10% low-fat control diet for 22 weeks. Mouse body composition and weight were monitored, and tissues were processed and evaluated by flow cytometry, qPCR, and histology. In this study, the TL1A-deficient HF-diet-fed mice had reduced whole-body weight gain, which was directly explained by a corresponding fat mass reduction (average 37.2%), compared with that of their TL1A-sufficient littermates. Despite previous data showing marked changes in the gut microbial community, TL1A-deficient GF mice also displayed reduced adiposity. Furthermore, the TL1A-deficient mice were resistant to hepatic steatosis and were shown to have improved glucose tolerance, as determined by oral glucose tolerance test (OGTT), and greater insulin sensitivity. In the epididymal white adipose tissue (eWAT), TL1A deficiency in HF-diet-fed mice resulted in a reduced abundance of IL-18Ra+ type-1 ILCs and γδT cells as well as markedly reduced expression of the mitochondria-regulating genes Ucp1, Ucp2, Ucp3, and Prdm16. Finally, to investigate the link of TL1A to obesity in humans, we identified a noncoding polymorphism (rs4979453) close to the TL1A locus that is associated with waist circumference in men (p = 0.00096, n = 60586). These findings indicate that TL1A plays an important role in regulating adipose tissue mass and that this role is independent of the gut microbiota. Furthermore, we show that TL1A regulates adipose-resident innate lymphocytes and mitochondria-mediated oxidative stress in eWAT.

Study of serum leptin level in children with cyanotic and acyanotic congenital heart disease

Objective The aim of this study was to measure serum leptin levels in children with cyanotic and acyanotic congenital heart disease and to examine its possible role in growth in these children. Background Leptin has been shown to be an integral component of energy homeostasis and regulation of body weight. Leptin regulates adipose tissue mass and correlates with the fat mass. Research on the physiological function of leptin has primarily focused on its role in the pathogenesis of obesity. Children with congenital heart disease are at increased risk for poor growth. Several factors may play a role in poor growth, including feeding difficulties, increased caloric requirements, and the effects of cardiac lesions on growth regulation. Patients and methods This study was carried out over 1 year on 35 patients with congenital heart disease [20 patients were acyanotic (12 boys, 8 girls) and 15 patients were cyanotic (9 boys, 6 girls)] in the Pediatric Cardiology Department in Menoufia University Hospital and 35 apparently healthy children of the same age (range: 3 months–12 years), sex, and socioeconomic status. All patients and controls were subjected to a complete assessment of history, a thorough clinical examination, chest radiograph, ECG, echocardiography, and measurement of serum leptin level. Results Children with cyanotic congenital heart disease had statistically significant lower weight, length, mid-arm circumference, and BMI. There was no statistically significant difference in serum leptin levels in the cyanotic, acyanotic, and control groups. Serum leptin level was correlated positively with BMI and mid-arm circumference in all groups. Conclusion Serum leptin level did not change in children with acyanotic and cyanotic congenital heart disease, suggesting that other factors may regulate nutrient intake, growth, weight, and energy input and output in these children.

Adipose lipid turnover and long-term changes in body weight.

The worldwide obesity epidemic1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates2,3. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.

Dietary protein restriction increases hepatic leptin receptor mRNA and plasma soluble leptin receptor in male rodents.

Leptin is an adipokine that regulates adipose tissue mass through membrane-anchored leptin receptor (Ob-R). Extracellular domain of Ob-R in plasma is called soluble leptin receptor (sOb-R), and is the main leptin-binding protein. Based on a previous DNA microarray analysis that showed induction of hepatic Ob-R mRNA in low-protein diet-fed mice, this study aimed to clarify the effect of dietary protein restriction on hepatic Ob-R mRNA and plasma sOb-R levels. First, the effect of protein restriction on hepatic Ob-R mRNA level was examined together with fasting and food restriction using male rats as common experimental model for nutritional research. Hepatic Ob-R mRNA level was increased by feeding low-protein diet for 7 d, although not significantly influenced by 12-h fasting and sixty percent restriction in food consumption. Then, effect of protein restriction on liver Ob-R and plasma sOb-R was investigated using male mice because specific sOb-R ELISA was more available for mice. Hepatic Ob-R mRNA level was also increased in protein restricted-mice although it did not increase in hypothalamus. Hepatic Ob-R protein was decreased, whereas plasma sOb-R was increased by protein restriction. Because the concentration of sOb-R increased without changing plasma leptin concentration, free leptin in plasma was significantly reduced. The direct effect of amino acid deprivation on Ob-R mRNA level was not observed in rat hepatoma cells H4IIE cultured in amino acid deprived medium. In conclusion, dietary protein restriction increased hepatic Ob-R mRNA, resulting in increased plasma sOb-R concentration, which in turn, reduces plasma free leptin level and may modulate leptin activity.

142-OR: Unique Role of the a4 Component for S6-Kinase Activity in Metabolic Regulation and Anti-apoptotic Effect in Brown Adipose Tissue

Insulin and IGF1 signaling regulate function of brown and white adipose tissues. Recently we created adipocyte-specific inducible IR/IGF1R knockout mouse (Ai-DKO) and demonstrated the critical role of insulin signaling in maintenance of BAT and WAT. To further investigate downstream targets of these hormones regulating adipose tissue mass in adult animals, we compared gene expression patterns in WAT and BAT by using Ai-DKO mice, and found α4 expression was significantly reduced in Ai-DKO BAT but not in WAT compared with those of control. Knockdown of α4 in brown preadipocytecell lines using shRNA did not affect insulin-stimulated phosphorylation of IR, IRS1 or Akt; however, phosphorylation of ribosomal S6 protein was significantly increased in α4 KD cells after insulin stimulation. To investigate the impact of α4in mature adipocytesin vivo, we created inducible adipocyte-specific knockout of α4 gene (Ai-α4 KO) using floxed mice and mice carrying a tamoxifen-inducible Cre-ERT2transgene on the adiponectin promoter. Within 7 days, Ai-α4KO displayed an apparent decrease in SC-WAT and BAT mass, but not a significant effect on PG-WAT mass. Ai-α4 KO revealed extensive losses of adipocytes in SC-WAT and BAT depots with a significant increase in stromovascular cells in histological analysis with elevation of F4/80, TNF-α and IL-6, while no apparent changes were observed in PG-WAT. This appears to be due to a rapid development of an apoptotic process with increased TUNEL and cleaved caspase-3.Interestingly, Ai-α4KO showed marked reduction of BAT-associated functional gene UCP1 as well as PRDM16, Tfam and PGC1α mRNA compared to control. Consistent with these changes in mRNA and the decrease in BAT mass, Ai-α4 KO mice showed marked cold intolerance, glucose intolerance and insulin resistance. Thus, α4 is one of the components in control of insulin signaling and preferentially BAT mass, and has a unique role in regulating anti-apoptotic effect in brown adipocytes. Disclosure M. Sakaguchi: None. S. Okagawa: None. S. Kitano: None. T. Kondo: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi. Funding Japan Society for the Promotion of Science; Takeda Foundation; MSD Foundation; Kenzou Suzuki Foundation; Ono Foundation; Motida Foundation

Insulin Signaling in Adipocytes Controls Systemic Insulin Sensitivity through the 5-LO-LTB4 Axis

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis has been unclear. To provide insight into the role of insulin action in adipocytes, we generated mice that lack 3'-phosphoinositide-dependent kinase1 (PDK1) specifically in adipocytes (A-PDK1KO mice). These mice manifest impairment of metabolic actions of insulin in adipose tissue and a reduction in adipose tissue mass. The mice developed insulin resistance, glucose intolerance, and hepatic steatosis, all of which were markedly attenuated by additional ablation of FoxO1 specifically in adipocytes without an effect on adipose tissue mass, indicating that the PDK1-FoxO1 axis in adipocytes plays an important role in systemic metabolic homeostasis through a mechanism independent of the regulation of adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammation in adipose tissue differed between A-PDK1KO mice and adipocyte-specific PDK1/FoxO1 deficient mice (A-PDK1/FoxO1KO mice), indicating that those factors did not account for the difference in metabolic phenotypes of the two genotypes of mice. Microarray and lipidomics analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissues as well as the expression of 5-lipoxygenase (5-LO), a rate limiting enzyme for LTB4 production, in adipose tissues were increased and normalized in A-PDK1KO and A-PDK1/FoxO1KO mice, respectively. Administration of a 5-LO inhibitor reduced plasma levels of LTB4 and ameliorated insulin resistance and glucose intolerance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through downregulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. These results thus indicate that insulin signaling via the PDK1-FoxO1 pathway negatively regulates the production of LTB4 through the suppression of 5-LO in adipocytes and thereby maintains systemic insulin sensitivity. Disclosure T. Hosooka: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. W. Ogawa: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Abbott.

Antiangiogenic Herbal Composition Ob-X Reduces Abdominal Visceral Fat in Humans: A Randomized, Double-Blind, Placebo-Controlled Study.

Adipose tissue growth is angiogenesis-dependent, and angiogenesis inhibitors can regulate adipose tissue mass by cutting off the blood supply. We examined whether antiangiogenic herbal composition Ob-X can reduce fast-growing abdominal fat, especially visceral fat in humans by inhibiting angiogenesis. Eighty abdominally obese subjects (body mass index: 25-29.9 kg/m2, waist circumference: exceeding 90 cm for males and 85 cm for females) participated in a 12-week randomized, double-blind, placebo-controlled human study to evaluate the efficacy and safety of Ob-X. 690 mg of Ob-X was administered orally twice a day. The Ob-X group showed a noticeable reduction in visceral fat of 20.5% after the 12-week treatment as compared to baseline measured by computed tomography. The change in visceral fat in the Ob-X group was statistically significant as compared to the placebo group (p = 0.0495) and 1.9 times higher than in the placebo group. Therefore, angiogenesis inhibitor Ob-X has the potential to improve obesity-related metabolic syndrome by reducing dangerous visceral fat.

Changes in Body Mass Index, Leptin, and Leptin Receptor Polymorphisms and Breast Cancer Risk.

Obesity is a strong risk factor for breast cancer. The polymorphisms of leptin (LEP) and leptin receptor (LEPR) may be associated with breast cancer by regulator of adipose tissue mass and tumor cell growth. A total of 794 cases and 805 matched controls were sequentially enrolled. Time-of-flight mass spectrometry was used to determine the LEPrs7799039, LEPRrs1137100, and LEPRrs1137101 genotypes for each participant. Associations between polymorphisms of these genes, change in body mass index (BMI), and breast cancer risk were assessed by unconditional multivariable logistic regression models. The unconditional logistic regression model showed that persistent overweight (BMI ≥24 kg/m2) over the preceding 10 years was associated with increased breast cancer risk in premenopausal women (odds ratio [OR] = 1.67, 95% confidence interval [CI]: 1.19-2.35). No associations between LEPrs7799039, LEPRrs1137100, or LEPRrs1137101 polymorphisms alone and breast cancer risk were found. Persistent overweight over the preceding 10 years and carrying the LEPrs7799039 AA genotype together increased breast cancer risk in premenopausal women (ORadj = 2.00, 95% CI: 1.26-3.16). Persistent overweight over the preceding 10 years and carrying the LEPRrs1137100 GG genotype increased breast cancer risk in premenopausal women (ORadj = 1.68, 95% CI: 1.06-2.68). In premenopausal women, persistent overweight (BMI ≥24 kg/m2) over the preceding 10 years increases breast cancer risk. Persistent overweight along with LEPrs7799039 AA or LEPRrs1137100 GG genotypes synergistically increase risk of breast cancer among premenopausal women.

Ovarian hormones and obesity.

Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

The obese child in the Intensive Care Unit. Update.

Given that childhood obesity is an epidemic, the frequency of critically-ill patients who are overweight or obese seen at intensive care units has increased rapidly. Adipose tissue is an endocrine organ that secretes a number of protein hormones, including leptin, which stands out because it regulates adipose tissue mass. The presence of arterial hypertension, metabolic syndrome, diabetes mellitus, respiratory disease and chronic kidney disease may become apparent and complicate the course of obese pediatric patients in the Intensive Care Unit. Obesity management is complex and should involve patients, their families and the medical community. It should be coordinated with comprehensive government health policies and implemented in conjunction with a change in cultural context.

Association of polymorphism in adiponectin (+45 T/G) and leptin (-2548 G/A) genes with type 2 diabetes mellitus in male Egyptians.

IntroductionAdiponectin is an adipose tissue-specific protein with insulin-sensitizing properties. Many investigators have explored the association between adiponectin single nucleotide polymorphisms (SNPs) and type 2 diabetes mellitus (T2DM) in different ethnic populations from different regions. Leptin is a protein hormone constituting an important signal in the regulation of adipose tissue mass and body weight. The aim of this study was to explore potential associations between SNP +45 T>G of the adiponectin gene and SNP 2548G/A of leptin with T2DM and the effect of SNPs on serum adiponectin and leptin levels.Material and methodsFrom the Egyptian population, we enrolled 110 T2DM patients and 90 non-diabetic controls. Serum lipid profile, blood glucose, serum adiponectin, and leptin were measured. Genotyping for two common SNPs of the adiponectin and leptin genes was performed by polymerase chain reaction–restriction fragment length polymorphism.ResultsThe G allele and TG/GG genotype of SNP 45 occurred more frequently than the T allele and TT genotype in T2DM patients compares to the controls. Subjects with the GG + TG genotype of SNP 45 were at increased risk for T2DM (OR = 6.476; 95% CI: 3.401–12.33) and associated with a low serum adiponectin level compared with the TT genotype. The serum leptin concentration of GA + AA genotype carriers was not significantly different from that of the GG genotype in the diabetic group.ConclusionsThe G allele carriers who have reduced plasma concentrations of adiponectin may have an association with T2DM, while leptin SNP 2548 G/A is not associated with the risk of development of T2DM in the Egyptian population.

SRA Gene Knockout Protects against Diet-induced Obesity and Improves Glucose Tolerance

We have recently shown that the non-coding RNA, steroid receptor RNA activator (SRA), functions as a transcriptional coactivator of PPARγ and promotes adipocyte differentiation in vitro. To assess SRA function in vivo, we have generated a whole mouse Sra1 gene knock-out (SRA(-/-)). Here, we show that the Sra1 gene is an important regulator of adipose tissue mass and function. SRA is expressed at a higher level in adipose tissue than other organs in wild type mice. SRA(-/-) mice are resistant to high fat diet-induced obesity, with decreased fat mass and increased lean content. This lean phenotype of SRA(-/-) mice is associated with decreased expression of a subset of adipocyte marker genes and reduced plasma TNFα levels. The SRA(-/-) mice are more insulin sensitive, as evidenced by reduced fasting insulin, and lower blood glucoses in response to IP glucose and insulin. In addition, the livers of SRA(-/-) mice have fewer lipid droplets after high fat diet feeding, and the expression of lipogenesis-associated genes is decreased. To our knowledge, these data are the first to indicate a functional role for SRA in adipose tissue biology and glucose homeostasis in vivo.

Up-regulation of Bcl-2 during adipogenesis mediates apoptosis resistance in human adipocytes

Targeting apoptotic pathways in adipocytes has been suggested as a pharmacological approach to treat obesity. However, adipocyte apoptosis was identified as a cause for macrophage infiltration into adipose tissue. Previous studies suggest that mature adipocytes are less sensitive to apoptotic stimuli as compared to preadipocytes. Here, we aimed to identify proteins mediating apoptosis resistance in adipocytes.Our data revealed that the anti-apoptotic protein Bcl-2 (B-cell lymphoma 2) is up-regulated during adipogenic differentiation. Bcl-2 overexpression in preadipocytes lowers their apoptosis sensitivity to the level of mature adipocytes. Vice versa Bcl-2 knockdown in adipocytes sensitizes these cells to CD95-induced apoptosis. Taken together, our findings suggest a shift in the balance of pro-apoptotic and anti-apoptotic molecules during adipogenesis resulting in a higher apoptosis resistance. This study sheds new light on the apoptotic process in human fat cells and may constitute a new possible target for the specific regulation of adipose tissue mass.

Role of leptin in legg–calvé–perthes disease

Obesity is considered a clinical risk sign for Legg-Calvé-Perthes disease (LCPD). Leptin is primarily secreted by adipocytes, and it regulates adipose tissue mass and body weight. Furthermore, obesity is clearly associated with increased leptin levels. We investigated the roles of leptin and the soluble leptin receptor (sOB-R) in LCPD. This matched case-control study included 38 male and 3 female patients with LCPD, and an equal number of age-(range was 4-12) and sex-matched control patients with healthy fractures. Serum leptin and sOB-R levels were quantified with ELISA. The free leptin index (FLI) was defined as the ratio of leptin to sOB-R levels. Serum leptin levels, sOB-R, and FLI were compared between groups. The relationship between leptin, disease severity, and treatment outcomes were analyzed in the LCPD group. There were no significant differences between groups in terms of age, sex, and body mass index (BMI) percentile. Mean leptin levels (p = 0.042), sOB-R levels (p = 0.003), and FLI (p = 0.013) differed significantly between groups. In the LCPD group, the serum leptin levels, sOB-R levels, and FLI differed significantly between the lateral pillar and Stulberg classification groups (p < 0.05). Also, the leptin levels and FLI increased significantly according to the lateral pillar and Stulberg classifications even after adjusting for age and BMI percentile (p < 0.05). Circulating leptin and FLI were significantly higher in the LCPD group. Furthermore, leptin, disease severity, and treatment outcomes were associated. This correlation suggests that leptin might play an important role in LCPD pathogenesis.

Interleukin-7 Regulates Adipose Tissue Mass and Insulin Sensitivity in High-Fat Diet-Fed Mice through Lymphocyte-Dependent and Independent Mechanisms

Although interleukin (IL)-7 is mostly known as a key regulator of lymphocyte homeostasis, we recently demonstrated that it also contributes to body weight regulation through a hypothalamic control. Previous studies have shown that IL-7 is produced by the human obese white adipose tissue (WAT) yet its potential role on WAT development and function in obesity remains unknown. Here, we first show that transgenic mice overexpressing IL-7 have reduced adipose tissue mass associated with glucose and insulin resistance. Moreover, in the high-fat diet (HFD)-induced obesity model, a single administration of IL-7 to C57BL/6 mice is sufficient to prevent HFD-induced WAT mass increase and glucose intolerance. This metabolic protective effect is accompanied by a significant decreased inflammation in WAT. In lymphocyte-deficient HFD-fed SCID mice, IL-7 injection still protects from WAT mass gain. However, IL-7-triggered resistance against WAT inflammation and glucose intolerance is lost in SCID mice. These results suggest that IL-7 regulates adipose tissue mass through a lymphocyte-independent mechanism while its protective role on glucose homeostasis would be relayed by immune cells that participate to WAT inflammation. Our observations establish a key role for IL-7 in the complex mechanisms by which immune mediators modulate metabolic functions.