Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn−/− mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn−/− mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn−/− mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn−/− mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn−/− mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn−/− mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

While erythropoietin is the cytokine known that regulates erythropoiesis, erythropoietin receptor (EpoR) expression and associated activity beyond hematopoietic tissue remain uncertain. Here we show that mice with EpoR expression restricted to hematopoietic tissues (Tg) develop obesity and insulin resistance. Tg-mice exhibit a decrease in energy expenditure and an increase in white fat mass and adipocyte number. Conversely, erythropoietin treatment of wild-type mice increases energy expenditure and reduces food intake and fat mass accumulation but showed no effect in body weight of Tg-mice. EpoR is expressed at a high level in white adipose tissue and in the proopiomelanocortin neurons of the hypothalamus. While Epo treatment in wild-type mice induces the expression of the polypeptide hormone precursor gene, proopiomelanocortin, mice lacking EpoR show reduced levels of proopiomelanocortin in the hypothalamus. This study provides the first evidence that mice lacking EpoR in nonhematopoietic tissue become obese and insulin resistant with loss of erythropoietin regulation of energy homeostasis.

OBJECTIVEObesity, insulin resistance, and type 2 diabetes form a tightly correlated cluster of metabolic disorders in which adipose is one of the first affected tissues. The role of hypoxia and hypoxia-inducible factor 1 (HIF1) in the development of high-fat diet (HFD)–induced obesity and insulin resistance was investigated using animal models.RESEARCH DESIGN AND METHODSMice with adipocyte-specific targeted disruption of the genes encoding the HIF1 obligatory subunits Hif1α or Arnt (Hif1β) were generated using an aP2-Cre transgene with the Cre/LoxP system. The mice were fed an HFD for 12 weeks and their metabolic phenotypes were determined. Gene expression patterns in adipose tissues were also determined by microarray and quantitative PCR.RESULTSOn an HFD, adipocyte-specific ARNT knockout mice and adipocyte-specific HIF1α knockout mice exhibit similar metabolic phenotypes, including reduced fat formation, protection from HFD-induced obesity, and insulin resistance compared with similarly fed wild-type controls. The cumulative food intake remained similar; however, the metabolic efficiency was lower in adipocyte-specific HIF1α knockout mice. Moreover, indirect calorimetry revealed respiratory exchange ratios were reduced in adipocyte-specific HIF1α knockout mice. Hyperinsulinemic-euglycemic clamp studies demonstrated that targeted disruption of HIF1α in adipocytes enhanced whole-body insulin sensitivity. The improvement of insulin resistance is associated with decreased expression of Socs3 and induction of adiponectin.CONCLUSIONSInhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance. This study reveals that HIF1 could provide a novel potential therapeutic target for obesity and type 2 diabetes.

Summary Lipid droplet (LD) lipolysis in brown adipose tissue (BAT) is generally considered to be required for cold-induced nonshivering thermogenesis. Here we show that mice lacking BAT Comparative Gene Identification-58 (CGI-58), a lipolytic activator essential for the stimulated LD lipolysis, have normal thermogenic capacity and are not cold sensitive. Relative to littermate controls, these animals had higher body temperatures when they were provided food during cold exposure. The increase in body temperature in the fed, cold-exposed knockout mice was associated with increased energy expenditure and increased sympathetic innervation and browning of white adipose tissue (WAT). Mice lacking CGI-58 in both BAT and WAT were cold sensitive, but only in the fasted state. Thus, LD lipolysis in BAT is not essential for cold-induced nonshivering thermogenesis in vivo. Rather CGI-58-dependent LD lipolysis in BAT regulates WAT thermogenesis, and our data uncover an essential role of WAT lipolysis in fueling thermogenesis during fasting.

Background:The chemical uncoupler 2,4-dinitrophenol was widely used as a treatment for obesity in the past. Results: In mice, 2,4-dinitrophenol generates heat and turns off brown fat heat production. It reduces weight gain at thermoneutrality but not at cooler ambient temperatures. Conclusion: Environmental temperature should be considered when assessing anti-obesity drugs in mice. Significance: Chemical uncouplers deserve further investigation for the treatment of obesity.

Background: FSP27 contributes to unilocular lipid droplet formation in adipocytes. Results: Adipocyte-specific FSP27 disruption in mice produced small white adipose mass, hepatosteatosis, and insulin resistance upon high-fat diet feeding. Conclusion: Adipose FSP27 plays a critical role in minimizing ectopic fat accumulation. Significance: This mouse model is useful for understanding the significance of fat storage in adipose tissue.

Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (Mф) infiltration and phenotypic shift from “anti-inflammatory” M2-like to predominantly “proinflammatory” M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to nonerythroid tissues, including antiapoptotic and anti-inflammatory effects. Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance. We investigated EPO receptor (EPO-R) expression in WAT and characterized the role of its signaling during obesity-induced inflammation. Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes. These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6. Using obese ∆EpoR mice with EPO-R restricted to erythroid cells, we demonstrated an anti-inflammatory role for endogenous EPO. Collectively, our findings identify EPO-R signaling as a novel regulator of WAT inflammation, extending its nonerythroid activity to encompass effects on both Mф infiltration and subset composition in WAT.

G s α, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with G s α deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant. Despite the presence of these abnormalities, Ad-GsKO mice maintained normal energy balance on both standard and high-fat diets, associated with decreases in both lipolysis and lipid synthesis. In addition, Ad-GsKO mice maintained at thermoneutrality on a standard diet also had normal energy balance. Ad-GsKO mice had improved insulin sensitivity and glucose metabolism, possibly secondary to the effects of reduced lipolysis and lower circulating fatty acid binding protein 4 levels. G s α signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight. T he sympathetic nervous system (SNS) regulates energy homeostasis and adiposity through several mechanisms, including activation of nonshivering thermogenesis in brown adipose tissue (BAT), browning (formation of BAT-like "beige" cells) of white adipose tissue (WAT), and stimulation of lipolysis. Although these processes have been shown to be potential targets in treating obesity and diabetes (1-3), ablation of sympathetic nerves (4-6) or their main effectors (norepinephrine and epinephrine) (7) does not result in obesity or insulin resistance. Although mice lacking β adrenergic receptors (β-less mice) do develop obesity (8), it is likely that this effect is not due only to loss of β-adrenergic signaling in adipose tissue.The main mediator of SNS function in adipose tissues is G s α (9, 10), a ubiquitously expressed G protein α-subunit that in adipose tissue couples adrenergic and other receptors, such as the adenosine A2A receptor (11), to the generation of intracellular cAMP. We have previously generated adipose-specific G s α knockout mice (FGsKO) using fatty acid binding protein 4 (FABP4) (aP2)-cre and showed these mice to have significant early mortality and a severely lean phenotype (12). However, the usefulness of this model to examine the role of G s α in mature adipocytes is limited due to both the lack of specificity of FABP4-cre expression in adipose tissue and the presence of a severe defect in adipogenesis due to expression of FABP4, and therefore loss of G s α, during an early step in adipocyte differentiation.Adiponectin is a mature adipocyte marker expressed late in adipocyte differentiation (13). The more recent availability of adiponectin-cre mouse lines (14, 15) has enabled us to generate adipose-specific G s α knockout mice (Ad-GsKO) in which G s α deletion is restricted to mature adipocytes. Despite having loss of BAT function or browning of WAT, Ad-GsKO mice failed to develop obesity on either ...