Gsα deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight

G_sα, 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_sα 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_sα signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight.The 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_sα (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_sα 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_sα 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_sα, 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_sα knockout mice (Ad-GsKO) in which G_sα 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 standard chow or a high-fat diet (HFD). Moreover, Ad-GsKO mice had improved glucose tolerance and insulin sensitivity associated with a significant reduction of circulating FABP4. Our results show that thermogenesis in BAT and in beige adipocytes is not required for normal weight maintenance and that G_sα signaling in adipose tissue has an effect on whole-body glucose metabolism independent of adiposity.     

Expression of six transmembrane protein of prostate 2 in human adipose tissue associates with adiposity and insulin resistance

CONTEXT: Six transmembrane protein of prostate 2 (STAMP2) is a counterregulator of adipose inflammation and insulin resistance in mice. Our hypothesis was that STAMP2 could be involved in human obesity and insulin resistance. OBJECTIVE: The objective of the study was to elucidate the role of adipose STAMP2 expression in human obesity and insulin resistance. DESIGN: The design was to quantify STAMP2 in human abdominal sc and omental white adipose tissue (WAT), isolated adipocytes, and stroma and in vitro differentiated preadipocytes and relate levels of STAMP2 in sc WAT to clinical and adipocyte phenotypes involved in insulin resistance. PARTICIPANTS: Nonobese and obese women and men (n = 236) recruited from an obesity clinic or through local advertisement. MAIN OUTCOME MEASUREMENT: Clinical measures included body mass index, body fat, total adiponectin, and homeostasis model assessment as measure of overall insulin resistance. In adipocytes we determined cell size, sensitivity of lipolysis and lipogenesis to insulin, adiponectin secretion, and inflammatory gene expression. RESULTS: STAMP2 levels in sc and visceral WAT and adipocytes were increased in obesity (P = 0.0008-0.05) but not influenced by weight loss. Increased WAT STAMP2 levels associated with a high amount of body fat (P = 0.04), high homeostasis model assessment (P = 0.01), and large adipocytes (P = 0.02). Subjects with high STAMP2 levels displayed reduced sensitivity of adipocyte lipogenesis (P = 0.04) and lipolysis (P = 0.03) to insulin but had normal adiponectin levels. WAT STAMP2 levels correlated with expression of the macrophage marker CD68 (P = 0.0006). CONCLUSION: Human WAT STAMP2 associates with obesity and insulin resistance independently of adiponectin, but the role of STAMP2 in obesity and its complications seems different from that in mice.     

From the Cover: Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis

White adipocytes have a unique structure in which nearly the entire cell volume is occupied by one large lipid droplet. However, the molecular and cellular processes involved in the cytoplasmic remodeling necessary to create this structure are poorly defined. Autophagy is a membrane trafficking process leading to lysosomal degradation. Here, we investigated the effect of the deletion of an essential autophagy gene, autophagy-related gene 7 (atg7), on adipogenesis. A mouse model with a targeted deletion of atg7 in adipose tissue was generated. The mutant mice were slim and contained only 20% of the mass of white adipose tissue (WAT) found in wild-type mice. Interestingly, ≈50% of the mutant white adipocytes were multilocular. The mutant white adipocytes were smaller with a larger volume of cytosol and contained more mitochondria. These cells exhibited altered fatty acid metabolism with increased rates of β-oxidation and reduced rates of hormone-induced lipolysis. Consistently, the mutant mice had lower fed plasma concentrations of fatty acids and the levels decreased at faster rates upon insulin stimuli. These mutant mice exhibited increased insulin sensitivity. The mutant mice also exhibited markedly decreased plasma concentrations of leptin but not adiponectin, lower plasma concentrations of triglyceride and cholesterol, and they had higher levels of basal physical activity. Strikingly, these mutant mice were resistant to high-fat-diet-induced obesity. Taken together, our results indicate that atg7, and by inference autophagy, plays an important role in normal adipogenesis and that inhibition of autophagy by disrupting the atg7 gene has a unique anti-obesity and insulin sensitization effect.     

Getting ‘Smad' about obesity and diabetes

Recent findings on the role of transforming growth factor (TGF)-β/Smad3 signaling in the pathogenesis of obesity and type 2 diabetes have underscored its importance in metabolism and adiposity. Indeed, elevated TGF-β has been previously reported in human adipose tissue during morbid obesity and diabetic neuropathy. In this review, we discuss the pleiotropic effects of TGF-β/Smad3 signaling on metabolism and energy homeostasis, all of which has an important part in the etiology and progression of obesity-linked diabetes; these include adipocyte differentiation, white to brown fat phenotypic transition, glucose and lipid metabolism, pancreatic function, insulin signaling, adipocytokine secretion, inflammation and reactive oxygen species production. We summarize the recent in vivo findings on the role of TGF-β/Smad3 signaling in metabolism based on the studies using Smad3^−/− mice. Based on the presence of a dual regulatory effect of Smad3 on peroxisome proliferator-activated receptor (PPAR)β/δ and PPARγ2 promoters, we propose a unifying mechanism by which this signaling pathway contributes to obesity and its associated diabetes. We also discuss how the inhibition of this signaling pathway has been implicated in the amelioration of many facets of metabolic syndromes, thereby offering novel therapeutic avenues for these metabolic conditions.     

Polycystic ovary syndrome and adipose tissue

Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder in women of reproductive age. Typically, it is associated with ovulatory dysfunction: dysovulation or anovulation, and symptoms of hyperandrogenism. It incurs risk of metabolic disorders such as diabetes, dyslipidemia and fatty liver. As a key endocrine organ in metabolic homeostasis, adipose tissue is often implicated in these complications. Studies of white adipose tissue (WAT) in PCOS have focused on the mechanism of insulin resistance in this tissue. Clinically, abnormalities in WAT distribution are seen, with decreased waist-to-hip ratio and increased ratio of adipose to lean mass. Such abnormalities are greater when total circulating androgens are elevated. At tissue level, white adipocyte hyperplasia occurs, along with infiltration of macrophages. Secretion of adipokines, cytokines and chemo-attractant proteins is increased in a pro-inflammatory manner, leading to reduced insulin sensitivity via alteration of glucose transporters, and hence decreased glucose uptake. The kinetics of non-esterified fatty acids (or free fatty acids) is also altered, leading to lipotoxicity. In recent years, brown adipose tissue (BAT) has been studied in women with PCOS. Although abundance is low in the body, BAT appears to play a significant role in energy expenditure and metabolic parameters. Both supra-clavicular skin temperature, which reflects BAT activity, and BAT mass are reduced in women with PCOS. Moreover, BAT mass and body mass index (BMI) are inversely correlated in patients. In the adipocyte, increased total circulating androgen levels reduce expression of uncoupling protein 1 (UCP1), a key protein in the brown adipocyte, leading to reduced biogenesis and mitochondrial respiration and hence a reduction in post-prandial thermogenesis. BAT is currently being investigated as a possible new therapeutic application.     

Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues

Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.Overweight and obesity are global pandemic predisease syndromes that affect a majority of people during their lifetime. Even those who are lean for the time being might have to change their lifestyles to prevent future development of obesity and related disorders, including type 2 diabetes, cardiovascular disease, hypertension, and certain types of malignant disease. It is known that humans and animals at a certain age are more vulnerable to develop obesity. Midaged and elderly populations tend to be more susceptible than younger populations to developing insulin resistance and type 2 diabetes (1). Despite this notion, mechanisms underlying age-related development of obesity and type 2 diabetes are unknown.Current approaches of understanding obesity and diabetes development focus on studying adipocytes per se or adipose-associated inflammatory cells (2–4). However, the role of vascular networks, as one of the most dominant nonadipocyte components in all adipose tissues, in modulation of adipocyte functions is poorly understood. White adipose tissue (WAT) and brown adipose tissue (BAT) are hypervascularized and capillary networks form a “honeycomb-like” structure in which each adipocyte is embedded in a vascular chamber (5–7). The anatomical proximity and intimate interaction between adipocytes and capillaries suggest that microvasculatures are crucial for modulation of adipocyte functions under physiological and pathological conditions. Because adipose tissues undergo expansion and shrinkage during the entire adulthood, adipose vasculatures have to exhibit the same magnitude of plasticity to cope with adipose tissue mass and functional changes. Blood vessels not only provide nutrients and oxygen for adipocytes, cells in the vessel wall are also an important source of stem cells that can differentiate into preadipocytes and adipocytes, and adjust the adipose tissue mass depending on metabolic demands (6, 8–10).To sustain vessel numbers, vascular integrity, and architectures, adipocytes, together with other cell types including inflammatory cells and mesenchymal cells, produce a variety of soluble and nonsoluble factors, cytokines, and adipokines to modulate vascular functions through a paracrine mechanism (7). Among all known vascular factors, VEGF is the most prominently expressed angiogenic factor in adipose tissues and significantly modulates adipose angiogenesis and functions under physiological and pathological conditions (11, 12). VEGF binds to VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2), two tyrosine kinase receptors, primarily expressed in endothelial cells (13, 14). Although VEGFR2-mediated signaling has been associated with VEGF-induced angiogenesis, vascular permeability, and other vasculature-related functions, the functional consequences of the VEGFR1-triggered signaling remain enigmatic. VEGF is also an important vascular survival factor that prevents endothelial cell apoptosis (15). Based on its prominent functions under pathological conditions, antiangiogenic drugs targeting the VEGF–VEGFR2 signaling pathway have been developed for treatment of cancer and ophthalmological disease (16–18).In this paper, we present our findings of age-related vascular changes in adipose tissues and define VEGF as a key factor for maintenance of adipose vascular integrity. Importantly, age-related differential responses of adipose vasculature to anti-VEGF drugs resulted in a significant difference of insulin sensitivity in various age populations. These findings demonstrate that adipose VEGF levels and vascularization are key determinants for modulation of metabolism and insulin sensitivity. Our data also provide information in understanding the role of adipose vasculature in development of obesity and diabetes. Based on our compelling evidence, it is reasonable to speculate that there may be differential responses of metabolic changes in human populations of different ages to clinically available antiangiogenic drugs.     

Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ

In mammals, the adipose organ is a multi-depot organ made of two tissue types, the white and brown adipose tissues, which collaborate in partitioning the energy contained in lipids between thermogenesis and the other metabolic functions. It consists of several sc and visceral depots. Some areas of these depots are brown and correspond to brown adipose tissue, while many are white and correspond to white adipose tissue. White areas contain a variable amount of brown adipocytes and their number varies with age, strain and environmental conditions. Brown and white adipocyte are morphologically different. At light microscopy level, brown adipocytes have cytoplasmic lipids arranged as numerous small droplets (multilocularity), while white adipocytes have cytoplasmic lipids arranged in a unique vacuole (unilocularity). Ultrastructurally, brown adipocytes have numerous big mitochondria packed with cristae and containing the thermogenic uncoupling protein 1 (UCP1). In vivo and in vitro studies have shown that the differentiation process of brown and white adipocytes shows distinctive features. Nevertheless, the origin of the adipocyte precursor is still unknown. Recent data have stressed the plasticity of the adipose organ in adult animals. Indeed, under peculiar conditions fully differentiated, white adipocytes can transdifferentiate into brown adipocytes, and viceversa. The ability of the adipose organ to interconvert its main cytotypes in order to meet changing metabolic needs is highly pertinent to the physiopathology of obesity and related to therapeutic strategies.     

An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)–deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.

Cancer-associated cachexia (CAC) is an energy balance disorder causing unintended loss of body weight due to depletion of white adipose tissue (WAT) and skeletal muscle. This multiorgan and multifactorial syndrome affects up to 80% of cancer patients and is responsible for more than 20% of cancer-associated deaths (1). CAC impedes the effectiveness of anticancer therapies and drastically lowers patients’ quality of life (2).A long list of tumor-borne, often proinflammatory factors, including interleukin-6 (IL-6) (3), parathyroid hormone–related protein (PTHrP) (4), leukemia inhibitory factor (LIF) (5), zinc α-glycoprotein (6), or growth differentiation factor-15 (GDF-15) (7), trigger CAC in mouse models. However, the signaling cascades and catabolic mechanisms that lead to adipose- and muscle tissue wasting remain insufficiently understood (8, 9). IL-6 and PTHrP are among the best studied of these “cachexokines.” Their presence or absence is decisive for the development of CAC in cancer patients and animal models (4, 10–13). Thus, treatment with neutralizing antibodies against IL-6, the IL-6 receptor, or PTHrP ameliorates CAC in various mouse models of CAC (3, 4, 14, 15).CAC-associated WAT atrophy results from a metabolic switch toward decreased lipid synthesis and excessive degradation of lipid stores via enhanced triglyceride degradation (lipolysis) (9, 16). Induced lipolysis is observed in both humans and mice with CAC (17, 18). The absence of metabolic lipases at least partially ameliorates cachexia in murine cancer models (19). The metabolic or catabolic fates of lipolytic products, namely fatty acids (FAs) and glycerol, have not been fully clarified. These may provide energy and/or biosynthetic substrates for cancer cells to promote tumor growth or can be reesterified in WAT, creating an adenosine-triphosphate (ATP)-consuming futile metabolic cycle. Both of these pathways would contribute to the eventual loss of WAT during CAC (20).Another important catabolic pathway in CAC involves the direct oxidation of FAs and glycerol in adipose tissue. This process is promoted by the conversion of white to beige adipocytes called “WAT browning.” During WAT browning, adipocytes adopt a multilocular lipid droplet morphology; express genes that are typical for brown adipocytes, such as uncoupling protein-1 (UCP-1); exhibit elevated substrate oxidation rates; and dissipate energy as heat (21). WAT browning occurs in carcinogen-induced cancer models and genetically engineered mouse models as well as syngeneic and xenogeneic transplant models of murine cancers (3, 4, 22) and depends on the presence of cachexokines. WAT browning also occurs in humans suffering CAC or severe burn trauma (3, 23–25), but the cellular and molecular mechanisms underlying catabolic WAT remodeling in CAC remain unclear.Here, we demonstrate that a macrophage-sympathetic neuron signaling axis generates a high β-adrenergic tone resulting in beige adipogenesis, increased lipid degradation, and WAT atrophy in murine models of CAC. This mechanism triggering hypermetabolism in CAC may offer targets for prevention or treatment of the disease.     

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice

Aims/hypothesis

Obesity-induced inflammation is initiated by the recruitment of macrophages into adipose tissue. The recruited macrophages, called adipose tissue macrophages, secrete several proinflammatory cytokines that cause low-grade systemic inflammation and insulin resistance. The aim of this study was to find macrophage-recruiting factors that are thought to provide a crucial connection between obesity and insulin resistance.

Methods

We used chemotaxis assay, reverse phase HPLC and tandem MS analysis to find chemotactic factors from adipocytes. The expression of chemokines and macrophage markers was evaluated by quantitative RT-PCR, immunohistochemistry and FACS analysis.

Results

We report our finding that the chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1), identified from 3T3-L1 adipocyte conditioned medium, induces monocyte migration via its receptor chemokine (C-X-C motif) receptor 4 (CXCR4). Diet-induced obese mice demonstrated a robust increase of CXCL12 expression in white adipose tissue (WAT). Treatment of obese mice with a CXCR4 antagonist reduced macrophage accumulation and production of proinflammatory cytokines in WAT, and improved systemic insulin sensitivity.

Conclusions/interpretation

In this study we found that CXCL12 is an adipocyte-derived chemotactic factor that recruits macrophages, and that it is a required factor for the establishment of obesity-induced adipose tissue inflammation and systemic insulin resistance.     

Emerging Role of AMPK in Brown and Beige Adipose Tissue (BAT): Implications for Obesity,Insulin Resistance,and Type 2 Diabetes

Purpose of Review

The global prevalence of type 2 diabetes (T2D) is escalating at alarming rates, demanding the development of additional classes of therapeutics to further reduce the burden of disease. Recent studies have indicated that increasing the metabolic activity of brown and beige adipose tissue may represent a novel means to reduce circulating glucose and lipids in people with T2D. The AMP-activated protein kinase (AMPK) is a cellular energy sensor that has recently been demonstrated to be important in potentially regulating the metabolic activity of brown and beige adipose tissue. The goal of this review is to summarize recent work describing the role of AMPK in brown and beige adipose tissue, focusing on its role in adipogenesis and non-shivering thermogenesis.

Recent Findings

Ablation of AMPK in mouse adipocytes results in cold intolerance, a reduction in non-shivering thermogenesis in brown adipose tissue (BAT), and the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance; effects associated with a defect in mitochondrial specific autophagy (mitophagy) within BAT. The effects of a β3-adrenergic agonist on the induction of BAT thermogenesis and the browning of white adipose tissue (WAT) are also blunted in mice lacking adipose tissue AMPK. A specific AMPK activator, A-769662, also results in the activation of BAT and the browning of WAT, effects which may involve demethylation of the PR domain containing 16 (Prdm16) promoter region, which is important for BAT development.

Summary

AMPK plays an important role in the development and maintenance of brown and beige adipose tissue. Adipose tissue AMPK is reduced in people with insulin resistance, consistent with findings that mice lacking adipocyte AMPK develop greater NAFLD and insulin resistance. These data suggest that pharmacologically targeting adipose tissue AMPK may represent a promising strategy to enhance energy expenditure and reduce circulating glucose and lipids, which may be effective for the treatment of NAFLD and T2D.

     

Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.The metabolic syndrome is a constellation of related disorders (obesity, insulin resistance, dyslipidemia, fatty liver, hypertension, and atherosclerosis) (1–3). Of note, obesity, which is attributable to the chronic imbalance between energy intake and energy expenditure, is an epidemic, for which there is no effective therapy (4). A major challenge in battling this epidemic is to identify a target that can either decrease energy intake or increase energy expenditure. There is great research interest in brown adipose tissue (BAT), which is specialized for the dissipation of chemical energy in the form of heat (4, 5). BAT defends mammals against hypothermia, obesity, and type 2 diabetes; however, adult humans lack this thermogenic interscapular organ (6). Recently, studies have demonstrated that adult humans harbor a distinct cold-inducible depot of brown adipocytes that are expressed in WAT in the supraclavicular, paraaortic, and suprarenal regions (7–9). These cells, called beige or brite fat cells because of their beige color, undergo a browning process following cold stimulus and share some molecular, histologic and functional characteristics with beige adipocytes found in the subcutaneous white adipose tissue (SAT) of mice (7, 10, 11). The discovery of beige cells has raised clinical interest in the potential of these cells in the treatment of obesity.Uncoupling protein-1 (UCP1), which dissipates the mitochondrial electrochemical gradient which is the key for ATP formation, mediates the thermogenic activity of brown and beige adipocytes (12). Cell death-inducing DNA fragmentation factor α-like effector A (CIDEA), a member of a novel family of proapoptotic proteins, is expressed abundantly in both BAT and beige cells (10). Despite the similarity in thermogenic function, multiple lines of evidence indicate that they have unique expression profiles and distinct characters that likely contribute to their tissue-specific functions (4). Several genes such as Prdm16 (PR domain containing 16), Tbx1 (T-box 1), Tmem26 (transmembrane 26), pRb (protein retinoblastoma), Foxc2 (forkhead box protein C2), and CD137 [also know as TNFRSF9 (tumor necrosis factor receptor superfamily, member 9)] are preferentially expressed in beige adipocytes and ablation of some of these genes or of beige cells make mice more prone to develop obesity and metabolic dysfunction (10, 13, 14). Although recent evidence suggested that beige and brown adipocytes are likely to function in the maintenance of energy balance and thermogenesis, the safety of therapeutic stimulation of the browning process in treatment of obesity has not been established partly because the mechanisms underlying this process are not understood.Liver X receptors (LXRs) α and β are two members of the nuclear receptor family involved in multiple metabolic pathways, including insulin sensitivity; metabolism of glucose, lipid, and cholesterol; and energy expenditure (15). Our team has shown that LXR participates in regulation of key genes of energy pathways in the BAT in female rodents (16, 17). Genetic knock out of LXRs in both male and female mice provided them protection from diet-induced obesity, which was consistent with findings observed by other research groups using different LXR knockout mice (18, 19). These phenomena were explained by an ectopic expression of UCP1 in visceral white adipose and skeletal muscles or increased fat oxidation (18, 20). However, we have speculated that alteration of the browning process in LXR knockout mice could contribute to the metabolic protection against obesity and type 2 diabetes. We now present the evidence that this is the case.We found that depletion of LXRs in male mice reduced fat content and body weight. This finding was associated with an increased browning of SAT and consequently increased energy expenditure. Meanwhile, activated TSH-releasing hormone (TRH) signaling in the paraventricular nucleus (PVN) area of the hypothalamus in LXRαβ^−/− mice increased the activity of the hypothalamic–pituitary–thyroid (HPT) axis, which ultimately led to the enhanced browning of SAT.     

Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice

To elucidate the role of neuropeptide Y (NPY)-Y1 receptor (Y1-R) in food intake, energy expenditure, and other possible functions, we have generated Y1-R-deficient mice (Y1-R^−/−) by gene targeting. Contrary to our hypothesis that the lack of NPY signaling via Y1-R would result in impaired feeding and weight loss, Y1-R^−/− mice showed a moderate obesity and mild hyperinsulinemia without hyperphagia. Although there was some variation between males and females, typical characteristics of Y1-R^−/− mice include: greater body weight (females more than males), an increase in the weight of white adipose tissue (WAT) (approximately 4-fold in females), an elevated basal level of plasma insulin (approximately 2-fold), impaired insulin secretion in response to glucose administration, and a significant changes in mitochondrial uncoupling protein (UCP) gene expression (up-regulation of UCP1 in brown adipose tissue and down-regulation of UCP2 in WAT). These results suggest either that the Y1-R in the hypothalamus is not a key molecule in the leptin/NPY pathway, which controls feeding behavior, or that its deficiency is compensated by other receptors, such as NPY-Y5 receptor. We believe that the mild obesity found in Y1-R^−/− mice (especially females) was caused by the impaired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT. This model will be useful for studying the mechanism of mild obesity and abnormal insulin metabolism in noninsulin-dependent diabetes mellitus.     

De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age,adipose depot,and gender specific

It is generally assumed that white adipocytes arise from resident adipose tissue mesenchymal progenitor cells. We challenge this paradigm by defining a hematopoietic origin for both the de novo development of a subset of white adipocytes in adults and a previously uncharacterized adipose tissue resident mesenchymal progenitor population. Lineage and cytogenetic analysis revealed that bone marrow progenitor (BMP)-derived adipocytes and adipocyte progenitors arise from hematopoietic cells via the myeloid lineage in the absence of cell fusion. Global gene expression analysis indicated that the BMP-derived fat cells are bona fide adipocytes but differ from conventional white or brown adipocytes in decreased expression of genes involved in mitochondrial biogenesis and lipid oxidation, and increased inflammatory gene expression. The BMP-derived adipocytes accumulate with age, occur in higher numbers in visceral than in subcutaneous fat, and in female versus male mice. BMP-derived adipocytes may, therefore, account in part for adipose depot heterogeneity and detrimental changes in adipose metabolism and inflammation with aging and adiposity.     

Conversion from white to brown adipocytes: a strategy for the control of fat mass?

Understanding the mechanisms governing the acquisition of white and brown adipocyte phenotypes might have implications for the physiopathology of, and therapeutic strategies for obesity. Peroxisome proliferator-activated recetor γ (PPARγ) and its coactivators, PGC-1 and SRC-1, influence brown adipocyte metabolism and development. Ectopic expression of PGC-1 induces the expression of brown adipocyte genes in human white adipocytes. The changes in gene expression promote stimulation of fatty acid oxidation. There is now evidence to support the concept of an alteration in energy balance through a conversion of white to brown adipose tissue.