Increased Adipose Tissue Mass Research Articles

Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial beta-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial beta-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial beta-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.

The metabolic syndrome of ω3-depleted rats. II. Body weight, adipose tissue mass and glycemic homeostasis

Exposure of 7-week-old normal rats for 3-7 months to a diet deprived of long-chain polyunsaturated omega3 fatty acids was recently reported to induce changes in the fatty acid content and pattern of liver phospholipids and triglycerides similar to those otherwise found in second generation omega3-depleted rats. In the present study, the changes in body weight, parametrial adipose tissue mass, plasma glucose and insulin concentrations and insulin resistance index were investigated in the same control and omega3-depleted rats, which were then given access for 2 to 4-5 weeks to either a flaxseed oil-enriched diet (control and omega3-depleted rats) or a soybean oil-enriched diet (control rats). The body weight failed to differ between control and omega3-depleted rats. The latter rats, however, displayed increases in adipose tissue mass, plasma glucose and insulin concentrations, and insulin resistance index. In the control rats given access to the soybean or flaxseed oil-enriched diet, body weight and adipose tissue mass were little affected, but both the plasma glucose concentration and insulin resistance index decreased. In the omega3-depleted rats given access to the flaxseed oil-enriched diet, both body weight and adipose tissue mass underwent a rapid, pronounced and sustained increase, whilst the plasma glucose concentration and insulin resistance index decreased similarly to those in the control rats. The present design of omega3 fatty acid dietary deprivation thus reproduces the visceral obesity and insulin resistance otherwise observed in second-generation omega3-depleted rats. However, the supply of exogenous omega3 fatty acids to the omega3-depleted rats failed to oppose visceral obesity, possibly as a result of the orexigenic effects of these omega3 fatty acids.

Leptin and insulin sensitivity: reply to Oral and Burant

present data that support the hypothesis that the increase in insulin sensitivity, while off recombinant methionyl human leptin, can be attributed to the rapid expansion of the adipose tissue mass. Furthermore, these authors cite the positive effects of leptin therapy on insulin sensitivity of lipodystrophic patients and of patients with mutations of the insulin receptor. As discussed in our article (7), there are limitations to those examples. In lipodystrophic patients there is marked insulin resistance, which is absent in leptin deficiency; on the contrary, prior to treatment our patients did not exhibit pronounced insulin resistance, even in the context of morbid obesity (4). In mutations of the insulin receptor there is defective signaling, which again is absent in leptin deficiency. Therefore, those examples cannot be directly compared with our data. We agree that our study does not allow us to conclude that leptin therapy by itself has a direct effect, worsening insulin sensitivity; as we discussed extensively, such an effect could be indirect through other actions of leptin. Additionally, as commented extensively in our paper, rapid weight gain is a confounding factor that needs to be minimized in future studies. Nevertheless, the uniqueness of our patients (complete absence of leptin and of leptin resistance and normal insulin sensitivity) allows us to suggest that leptin may worsen insulin sensitivity either directly or indirectly. The adipoinsular axis has many complex interactions that need to be elucidated (1). It is possible that leptin may lead to changes in insulin sensitivity but not to overall glucose homeostasis. In clinical research studies, the weight of leptindeficient patients should ideally be kept stable during the onand off-leptin euglycemic hyperinsulinemic clamps. However, it is unethical to allow excessive weight regain after leptin therapy is temporarily discontinued. Alternatively, one could restrict the patients to a rigid isocaloric diet at all times. However, it is virtually impossible for leptin-deficient patients to maintain such a diet while off leptin. The limitations of clinical research in living patients are such that not all possible variables can be controlled for at the same time. Given the constraints of patient-oriented investigation, we still believe that our results provide some of the clearest evidence that in humans leptin worsens insulin resistance, and we stand by our comment that hyperleptinemia may mediate the increased insulin resistance of obesity. Others have independently come to the same conclusion (2). We agree that further studies are needed to clarify the acute and chronic effects of leptin on insulin sensitivity. To determine whether the rapid increase in adipose tissue mass is responsible for the increase in insulin sensitivity, we plan to determine glucose uptake by performing euglycemic hyperinsulinemic clamps with radiolabeled glucose. In addition, patients will be advised to maintain isocaloric diets as much as possible. By continuing to investigate the effects of leptin on insulin sensitivity, we may be able to elucidate the roles of leptin on the adipoinsular axis. As a last word, the regulation of human glucose homeostasis is of fundamental relevance to the survival of our species. Therefore, the hallmark of such regulation is extensive redundancy, as evidenced by a vast network of signals that determine overall glucose utilization (3, 5). The specific contribution of each signal to glucose homeostasis is not necessarily fixed and immutable but may vary across time and across individuals or groups of individuals with different disorders in the context of their overall metabolic milieu.

Impact of increased adipose tissue mass on inflammation, insulin resistance, and dyslipidemia

Obesity is associated with increased prevalence of metabolic disorders, such as inflammation, insulin resistance, and dyslipidemia, which can predispose an individual to develop diabetes and cardiovascular disease. Adipose tissue (AT) is now recognized as a metabolically active organ that controls plasma free fatty acid levels and contributes to systemic metabolic homeostasis by secreting adipokines. In obesity, the recruitment of immune cells, such as T cells and macrophages, to AT causes inflammation, which is thought to contribute to local insulin resistance. This loss of insulin sensitivity within AT can lead to uncontrolled release of fatty acids, secretion of inflammatory cytokines, and alterations in the balance of adipokines, which ultimately impact lipoprotein metabolism and insulin sensitivity systemically. Thus, AT itself plays an important role in the increased risk of diabetes and cardiovascular disease that is associated with obesity.

Reduced Energy Expenditure and Increased Inflammation Are Early Events in the Development of Ovariectomy-Induced Obesity

Menopause, an age-related loss of ovarian hormone production, promotes increased adiposity and insulin resistance. However, the diet-independent mechanism by which loss of ovarian function promotes increased adipose tissue mass and associated metabolic pathologies remains unclear. To address this question, we monitored food intake and weight gain of ovariectomized (OVX) mice and sham OVX (SHM) mice for 12 wk. Although food intake was similar, OVX mice gained 25% more weight than SHM mice. Moreover, the OVX mice accumulated 4.7- and 4.4-fold more perigonadal and inguinal adipose tissue by weight, respectively, with 4.4-fold (perigonadal, P < 0.001) and 5.3-fold (inguinal, P < 0.01) larger adipocytes and no change in adipocyte cell number. OVX-induced adiposity was coincident with an 18% decrease in metabolic rate during the dark phase (P = 0.001) as well as an 11% decrease during the light phase (P = 0.03). In addition, ambulatory activity levels of OVX mice were decreased only during the dark phase (40%, P = 0.008). OVX mice displayed evidence of immune infiltration and inflammation in adipose tissue, because perigonadal and inguinal adipose depots from OVX mice had increased expression of TNFalpha, iNOS, CD11c, and other hallmarks of adipose tissue inflammation. In contrast, expression of the T cell marker CD3 (3.5-fold, P = 0.03) and Th1 cytokine interferon-gamma (IFNgamma) (2.6-fold, P = 0.02) were elevated in perigonadal but not sc fat. Finally, histology revealed OVX-specific liver hepatic steatosis, coincident with increased PPARgamma gene expression and downstream lipogenic gene expression. In summary, OVX in mice decreases energy expenditure, without altering energy intake, resulting in adipocyte hypertrophy, adipose tissue inflammation, and hepatic steatosis.

Ex vivo study of incorporation into adipocytes and lipolysis-inhibition effect of polycyclic aromatic hydrocarbons

We have previously shown that benzo[a]pyrene (B[a]P) administrated at extremely low dose can cause weight gain in mice and that the increase in adipose tissue mass is due to inhibition of beta-adrenergic stimulation of lipolysis. Moreover we have suggested that in addition to its endocrine properties, adipose tissue act as a reservoir for many chemical carcinogens including Polycyclic Aromatic Hydrocarbons (PAHs). In this paper we show that B[a]P as well as the two C4 PAHs, pyrene and phenanthrene can bioaccumulate into adipocytes in a similar manner, but that at the difference of B[a]P, have no impact on epinephrine-induced lipolysis. On the basis of this ex vivo study, we therefore suggest that B[a]P may play a central role in carcinogenesis not only by inducing cancer through its mutagenic properties, but also by increasing the bioaccumulation capacity of the adipose tissue mass.

Relationship between Total and High Molecular Weight Adiponectin Levels and Plasma Nonesterified Fatty Acid Tolerance during Enhanced Intravascular Triacylglycerol Lipolysis in Men

Increased plasma nonesterified fatty acid (NEFA) appearance during enhanced intravascular triacylglycerol (TG) lipolysis is a marker of metabolic adipose tissue dysfunction and may lead to the development of insulin resistance. The relationship between total and high molecular weight (HMW) adiponectin levels, NEFA appearance, and total TG lipolytic capacity has not been previously studied in humans. Our objective was to determine whether total and HMW adiponectin plasma levels are associated with plasma NEFA level and appearance, and with total TG lipolytic rate during enhanced intravascular TG lipolysis in men. This was a cross-sectional metabolic study. The study was performed at an academic clinical research center. There were 15 healthy men (mean +/- sd body mass index 25.5 +/- 4.7 kg/m(2)) aged 21-50 yr (mean +/- sd 31.1 +/- 10.2) without first-degree relatives with type 2 diabetes included in the study. Pancreatic clamps and iv infusion of stable isotopic tracers ([1,1,2,3,3-(2)H(5)]glycerol and [U-(13)C]palmitate) were performed, whereas intravascular TG lipolysis was clamped by iv infusion of heparin plus Intralipid at low (fasting) and high insulin levels. Total and HMW adiponectin levels were measured using an ELISA. Levels of total and HMW adiponectin, palmitate appearance (plasma palmitate appearance rate), and glycerol appearance (plasma glycerol appearance rate) were calculated. During heparin plus Intralipid infusion, total and HMW adiponectin was inversely correlated with plasma palmitate appearance rate (r = -0.65; P = 0.01), but this association was lost when expressed per nonlean weight. Adiponectin levels were positively associated with plasma glycerol appearance rate per nonlean weight (r = 0.71 and r = 0.66, respectively; P < or = 0.01). Increased adipose tissue mass likely explains the association between low adiponectin and reduced NEFA tolerance. Adiponectin level is a marker of total TG lipolytic rate per adipose tissue mass in men.

Postnatal Catch‐up Growth After Fetal Protein Restriction Programs Proliferation of Rat Preadipocytes

We studied the in vitro proliferation and differentiation of rat preadipocytes to investigate whether catch-up growth after prenatal protein restriction may program adipose precursor cells leading to development of increased adipose tissue mass. Pregnant rat dams were fed either an isocaloric low-protein diet (LP-8%) or control diet (C-20%). During lactation, in order to induce catch-up growth, dams from LP group were fed with the C diet and litter size was reduced to four pups instead of eight. Preadipocytes were isolated from weanling male pups (28 days of age). Differentiation and proliferation were assessed across time. At late stages of preadipocyte differentiation, no difference was observed in lipid accumulation of C or LP cultures but the mRNA expression of leptin was enhanced in LP cells. At early stages of culture, a higher DNA and protein content accompanied by a higher rate of proliferation was measured in adipocytes from LP cultures. Moreover, the mRNA expression of cyclin D1 was increased in these cells whereas the expression of peroxisome proliferators-activated receptor gamma (PPARgamma) and steroyl regulatory element binding protein (SREBP-1c) was significantly reduced during early stages. The results suggest that prenatal exposure to a LP followed by rapid catch-up growth is associated with a higher rate for proliferation in preadipocytes.

Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes

Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF; AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.

Enhanced angiogenesis in obesity and in response to PPARγ activators through adipocyte VEGF and ANGPTL4 production

PPARgamma activators such as rosiglitazone (RSG) stimulate adipocyte differentiation and increase subcutaneous adipose tissue mass. However, in addition to preadipocyte differentiation, adipose tissue expansion requires neovascularization to support increased adipocyte numbers. Paradoxically, endothelial cell growth and differentiation is potently inhibited by RSG in vitro, raising the question of how this drug can induce an increase in adipose tissue mass while inhibiting angiogenesis. We find that adipose tissue from mice treated with RSG have increased capillary density. To determine whether adipose tissue angiogenesis was stimulated by RSG, we developed a novel assay to study angiogenic sprout formation ex vivo. Angiogenic sprout formation from equally sized adipose tissue fragments, but not from aorta rings, was greatly increased by obesity and by TZD treatment in vivo. To define the mechanism involved in RSG-stimulated angiogenesis in adipose tissue, the expression of proangiogenic factors by adipocytes was examined. Expression of VEGFA and VEGFB, as well as of the angiopoietin-like factor-4 (ANGPTL4), was stimulated by in vivo treatment with RSG. To define the potential role of these factors, we analyzed their effects on endothelial cell growth and differentiation in vitro. We found that ANGPTL4 stimulates endothelial cell growth and tubule formation, albeit more weakly than VEGF. However, ANGPTL4 mitigates the growth inhibitory actions of RSG on endothelial cells in the presence or absence of VEGF. Thus, the interplay between VEGF and ANGPTL4 could lead to a net expansion of the adipose tissue capillary network, required for adipose tissue growth, in response to PPARgamma activators.

IFATS Collection: Stem Cell Antigen-1-Positive Ear Mesenchymal Stem Cells Display Enhanced Adipogenic Potential

Abstract Hyperplasia is a major contributor to the increase in adipose tissue mass that is characteristic of obesity. However, the identity and characteristics of cells that can be committed into adipocyte lineage remain unclear. Stem cell antigen 1 (Sca-1) has been used recently as a candidate marker in the search for tissue-resident stem cells. In our quest for biomarkers of cells that can become adipocytes, we analyzed ear mesenchymal stem cells (EMSC), which can differentiate into adipocytes, osteocytes, chondrocytes, and myocytes. Our previous studies have demonstrated that EMSC abundantly expressed Sca-1. In the present study, we have analyzed the expression of adipogenic transcription factors and adipocyte-specific genes in Sca-1-enriched and Sca-1-depleted EMSC fractions. Sca-1-enriched EMSC accumulated more lipid droplets during adipogenic differentiation than Sca-1-depleted. Similarly, EMSC isolated from Sca-1−/− mice displayed reduced lipid accumulation relative to EMSC from wild-type controls (p &amp;lt; .01). Comparative analysis of the adipogenic differentiation process between Sca-1-enriched and Sca-1-depleted populations of EMSC revealed substantial differences in the gene expression. Preadipocyte factor 1, CCAAT enhancer-binding protein (C/EBP) β, C/EBPα, peroxisome proliferator-activated receptor γ2, lipoprotein lipase, and adipocyte fatty acid binding protein were expressed at significantly higher levels in the Sca-1-enriched EMSC fraction. However, the most striking observation was that leptin was detected only in the conditioned medium of Sca-1-enriched EMSC. In addition, we performed loss-of-function (Sca-1 morpholino oligonucleotide) experiments. The data presented here suggest that Sca-1 is a biomarker for EMSC with the potential to become functionally active adipocytes. Disclosure of potential conflicts of interest is found at the end of this article.

Gene expression microarray analysis of the effects of grape anthocyanins in mice: a test of a hypothesis-generating paradigm

The mechanism(s) through which fruits, vegetables, and whole grains favorably affect health is not well established. Using an anthocyanin-rich grape as a model, we examined the ability of an agnostic analytical approach using gene expression microarrays to generate novel testable hypotheses regarding the mechanisms of action of potentially healthful foods and food components. C57BL/6 mice were divided into 2 groups and fed a proatherogenic diet with or without a semipurified anthocyanin extract (70% anthocyanins) incorporated at a level of 0.1 mg/mL into the drinking water. After 6 weeks, compared with control mice, mice supplemented with anthocyanins tended to gain more weight and have increased adipose tissue mass, although these effects did not achieve statistical significance. Anthocyanin-supplemented mice had significantly reduced relative liver weights and heart weights. Serum lipids and inflammatory cytokines were not different between the groups. Gene expression microarray analysis of the liver and skeletal muscle identified a number of molecular pathways significantly affected by anthocyanin treatment. Two distinct clusters emerged. The first cluster included down-regulated pathways in both muscle and liver involving cellular defense, whereas the second included hepatic genes involved in energy metabolism. From these data, 3 hypotheses were developed for future investigation.

Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth

OBJECTIVE—IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro.RESEARCH DESIGN AND METHODS—To investigate the role of IGF-1 receptor in vivo, we have inactivated the Igf-1r gene in adipose tissue (IGF-1RaP2Cre mice) using conditional gene targeting strategies.RESULTS—Conditional IGF-1R inactivation resulted in increased adipose tissue mass with a predominantly increased lipid accumulation in epigonadal fat pads. However, insulin-stimulated glucose uptake into adipocytes was unaffected by the deletion of the IGF-1R. Surprisingly, IGF-1RaP2Cre mice exhibited markedly increased somatic growth in the presence of elevated IGF-1 serum concentrations, and IGF-1 mRNA expression was significantly increased in liver and adipose tissue. IGF-1 stimulation of wild-type adipocytes significantly decreased IGF-1 mRNA expression, whereas the opposite effect was observed in IGF-1R–deficient adipocytes.CONCLUSIONS—IGF-1R signaling in adipocytes does not appear to be crucial for the development and differentiation of adipose tissue in vivo, but we identified a negative IGF-1R–mediated feedback mechanism of IGF-1 on its own gene expression in adipocytes, indicating an unexpected role for adipose tissue IGF-1 signaling in the regulation of IGF-1 serum concentrations in control of somatic growth.

Effects of adjuvant aromatase inhibitors on bone mineral density -observations from clinical practice

Obesity is becoming increasingly prevalent and it has been linked to poor breast cancer outcomes. Because obesity is associated with increased adipose tissue mass and aromatase activity [the target of aromatase inhibitors (AIs)], there is concern that these agents may be less effective in women who are overweight or obese. Four of the randomized trials of AIs vs. tamoxifen conducted in the adjuvant breast cancer setting (ATAC, BIG 1-98 and TEAM in the postmenopausal setting and ABCSG-12 in the premenopausal setting) have reported effects of body mass index (BMI) on the relative effectiveness of an AI vs. tamoxifen. Obesity was confirmed as an adverse prognostic factor in ATAC and BIG 1-98 but not the TEAM study; in ABSCG-12, obesity was associated with poor outcomes in the anastrozole arm only. In the three postmenopausal trials, the use of an AI vs. tamoxifen was associated with better outcomes at all levels of BMI [all hazard ratios for recurrence <1, although 95% confidence intervals often included 1 due to lower power and smaller reductions in risk]. Of note, there was no significant interaction of BMI with letrozole (vs. tamoxifen) in the BIG 1-98 trial; while ATAC investigators concluded that the relative benefit of anastrozole (vs. tamoxifen) might be better in thinner (vs. heavier) women. In ABCSG-12, the use of anastrozole (vs. tamoxifen) was associated with significantly worse outcomes in women with BMI ≥25 kg/m2 (similar to the detrimental effect of anastrozole on overall survival seen in the parent trial). These findings do not support the use of BMI as a predictor of AI (vs. tamoxifen) benefit in the adjuvant setting in postmenopausal breast cancer.

The latest on adipokines

Adipose tissue is now recognized as an organ synthesizing and secreting numerous factors called adipokines. Increases in adipose tissue mass during obesity largely modify adipokine production. Several adipokines have been shown to link obesity with insulin resistance or type 2 diabetes. This review addresses the role of “new” adipokines in adipose tissue growth and energy metabolism. Thus, the study of adipokine characteristics and functions will enable the development of new pharmacological targets and therapeutic strategies.

Serum concentrations and expressions of serum amyloid A and leptin in adipose tissue are interrelated: the Genobin Study

Serum amyloid A (SAA) is a novel link between increased adipose tissue mass and low-grade inflammation in obesity. Little is known about the factors regulating its serum concentration and mRNA levels. We investigated the association between SAA and leptin in obese and normal weight subjects and analyzed the effect of weight reduction on serum SAA concentration and gene expression in adipose tissue of the obese subjects. Seventy-five obese subjects (60+/-7 years, body mass index (BMI) 32.9+/-2.8 kg/m(2), mean+/-s.d.) with impaired fasting plasma glucose or impaired glucose tolerance and other features of metabolic syndrome, and 11 normal weight control subjects (48+/-9 years, BMI 23.7+/-1.9 kg/m(2)) were studied at the baseline. Twenty-eight obese subjects underwent a 12-week intensive weight reduction program followed by 5 months of weight maintenance. Blood samples and abdominal s.c. adipose tissue biopsies were taken at the baseline and after the follow-up. Gene expression was studied using real-time quantitative PCR. The gene expressions in women and serum concentrations of leptin and SAA were interrelated independently of body fat mass in the obese subjects (r=0.54, P=0.001; r=0.24, P=0.039 respectively). In multiple linear regression analyses, leptin mRNA explained 38% of the variance in SAA mRNA (P=0.002) in the obese women. Weight loss of at least 5% increased SAA mRNA expression by 48 and 36% in men and women, but serum SAA concentrations did not change. The association between SAA and leptin suggests an interaction between these two adipokines, which may have implications in inflammatory processes related to obesity and the metabolic syndrome.

Macronutrients and obesity: views, news and reviews

Profound changes in macronutrient composition of food have taken place since the agricultural revolution, leading to a higher dietary intake of carbohydrates at the expense of protein, and a dramatically increased intake of n-6 polyunsaturated fatty acids (PUFAs) at the expense of n-3 PUFAs. This review focuses on how macronutrients impact on molecular processes central to appetite regulation and energy homeostasis. We discuss the effects on transcription factors, implicated as key players in adipocyte differentiation and function, including PPARs, sterol regulatory element binding proteins and liver X receptors. Furthermore, as energy homeostasis is to a large extent orchestrated by the gut–brain axis, we discuss key hormones involved in the regulation of energy balance and appetite. Obesity is rapidly climbing the WHO’s top ten global health problem list. As increased adipose tissue mass is associated with increased adipocyte size and number, understanding of adipocyte differentiation and function in terms of regulation of metabolism is important to curb the obesity epidemic. Genetics may account for an individual’s predisposition to obesity, but habitual food intake in excess of energy expenditure is probably a primary factor in obesity development. In view of huge changes in the human diet and the emerging knowledge concerning the ability of dietary macronutrients to directly or indirectly act as signaling molecules, we review research aimed at elucidating molecular mechanisms governing the effects of macronutrients on the differentiation and function of white fat cells. Furthermore, as nutrient homeostasis is to a large extent orchestrated by the gut–brain axis, we discuss key hormones involved in the regulation of energy balance and appetite. Since a large proportion of the experimental work has been performed using rodent models, including numerous informative transgenic models, this review primarily focuses on data obtained from studies on rodents, but in addition, we also refer readers to

Adipose-Specific Disruption of Signal Transducer and Activator of Transcription 3 Increases Body Weight and Adiposity

To determine the role of STAT3 in adipose tissue, we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre-driven disappearance of STAT3 expression occurred on d 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature but not differentiating adipocytes. Beginning at 9 wk of age, ASKO mice weighed more than their littermate controls and had increased adipose tissue mass, associated with adipocyte hypertrophy, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure. Leptin-induced, but not isoproterenol-induced, lipolysis was impaired in ASKO adipocytes, which may partially explain the increased cell size. Despite reduced adiponectin and increased liver triacylglycerol, ASKO mice displayed normal glucose tolerance. Overall, these findings demonstrate that adipocyte STAT3 regulates body weight homeostasis in part through direct effects of leptin on adipocytes.

The Effects of Epigallocatechin-3-Gallate on Thermogenesis and Fat Oxidation in Obese Men: A Pilot Study

Objectives: The development of obesity is characterized by an increase in adipose tissue mass and by concomitant and profound changes in almost all organ functions leading to diseases such as hypertension, diabetes mellitus and coronary heart disease. Recent data from human studies indicate that the consumption of green tea and green tea extracts may help reduce body weight, mainly body fat, by increasing postprandial thermogenesis and fat oxidation. However, human studies investigating the metabolic effects of the most predominant tea catechin, EGCG, alone are absent.Methods: In a randomized double blind, placebo-controlled, cross-over pilot study, six overweight men were given 300 mg EGCG/d for 2d. Fasting and postprandial changes in energy expenditure (EE) and substrate oxidation were assessed.Results: Resting EE did not differ significantly between EGCG and placebo treatments, although during the first postprandial monitoring phase, respiratory quotient (RQ) values were significantly lower with EGCG compared to the placebo.Conclusions: These findings suggest that EGCG alone has the potential to increase fat oxidation in men and may thereby contribute to the anti-obesity effects of green tea. However, more studies with a greater sample size and a broader range of age and BMI are needed to define the optimum dose.

Retinol Binding Protein 4 and Pathogenesis of Diabetes

Obesity is an important risk factor for a number of chronic diseases that impose a huge burden on individuals and society. Recently it has become clear that adipose tissue-secreted products may play a significant role in mediating many obesity-related diseases including diabetes. Thus, in addition to being an energy depot, the adipocyte is a highly active cell, secreting a plethora of factors with profound effects on a number of organs and systems. The study of these factors and their endocrine effects has become a rapidly evolving and dynamic area of endocrinology. One paradigm for explaining the deleterious effects of adipokines is related to the sheer increase in adipose tissue mass in obesity. When preadipocytes differentiate to become mature adipocytes, they acquire the ability to synthesize numerous proteins, including cytokines, growth factors, and hormones that are involved in overall energy homeostasis and various paracrine effects. In health, these proteins do not spill over significantly into the circulation. In obesity, the massive increase in fat mass leads to a significant increase in circulation of many adipose tissue secreted factors that may have pathogenic effects. For example, the increase in circulating angiotensin II in obesity is related at least in part due to excess adiposity and may mediate hypertension (1). In recent years, adipose tissue has been found to be a major source of many proteins that may directly contribute to vascular injury, diabetes, and atherogenesis (2). These proinflammatory adipokines include TNF-α, IL-6, leptin, plasminogen activator inhibitor-1, angiotensinogen, and resistin, among many others. In contrast, the adipokine adiponectin confers protection against inflammation, atherogenesis, and obesity-linked insulin resistance.