Brown Adipose Tissue Transplantation Research Articles

Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

Obesity results in the chronic activation of innate immune system and subsequently sets in diabetes. Aim of the study was to investigate the immunometabolic role of brown adipose tissue (BAT) in the obesity. We performed both BAT transplantation as well as extirpation experiments in the mouse model of high-fat diet (HFD)-induced obesity. We carried out immune cell profiling in the stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). BAT transplantation reversed HFD-induced increase in body weight gain and insulin resistance without altering diet intake. Importantly, BAT transplantation attenuated the obesity-associated adipose tissue inflammation in terms of decreased pro-inflammatory M1-macrophages, cytotoxic CD8a T-cells and restored anti-inflammatory regulatory T-cells (Tregs) in the eWAT. BAT transplantation also improved endogenous BAT activity by elevating protein expression of browning markers (UCP-1, PRDM16 and PGC1α) in it. In addition, BAT transplantation promoted the eWAT expression of various genes involved in fatty acid oxidation (such as Elvol3 and Tfam,). In contrast, extirpation of the interscapular BAT exacerbated HFD-induced obesity, insulin resistance and adipose tissue inflammation (by increasing M1 macrophages, CD8a T-cell and decreasing Tregs in eWAT). Taken together, our results suggested an important role of BAT in combating obesity-associated metabolic complications. These results open a novel therapeutic option to target obesity and related metabolic disorders like type 2 diabetes.

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14.

SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

Transplantation of interscapular brown adipose tissue in rats

Background: the activity of brown adipose tissue (BAT) – a highly metabolic tissue – has a magnificent role in the management of metabolic diseases such as obesity and diabetes and numerous researchers have attempted to increase BAT via different methods including transplantation of BAT in animal models. Aims: to describe the protocol of the BAT transplantation in rats, as an animal model for studies about elevated BAT. Methods: twenty female Wistar rats were randomly divided in two groups (donor and recipient). Interscapular BAT (iBAT) were carefully removed from donors and transplanted into the interscapular region of the recipient rats, subcutaneously. To approve the successfulness of the operation, expression of the UCP1 mRNA and histological changes were evaluated in the grafts two months after surgery. Results: all operated rats have survived and fifty percent of the operations were successful. Conclusion: transplantation of BAT following this procedure in rats could be used as an acceptable animal model to investigate multiple aspects of elevated BAT.

Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE−/− mice

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE−/− mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the β3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE−/− mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.

Stem Cell and Obesity: Current State and Future Perspective.

Obesity as a worldwide growing challenge is determined by abnormal fat deposition, which may damage general health. Weight loss and control of related risk factors like type2 diabetes, dyslipidemia, hypertension, cardiovascular diseases, and metabolic syndrome is an important concern in obesity management. Different therapeutic approaches such as lifestyle change, medications, and surgery are introduced for obesity treatment. Despite of gaining partially desirable results, the problem is remained unsolved. Therefore, finding a new approach that can overcome previous limitations is very attractive for both researchers and clinicians. Cell-based therapy using adipose-derived stromal cells seems to be a promising strategy to control obesity and related syndromes. To attain this aim, understanding of different type of adipose tissues, main signaling pathways, and different factors involved in development of adipocyte is essential. Recently, several cell-based methods like stem cell administration, brown adipose tissue transplantation, cell lysates and exosomes have been examined on obese mouse models to manage obesity and related disorders. Successful outcome of such preclinical studies can encourage the cell-based clinical trials in the near future.

Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia.

Brown adipose tissue (BAT) plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue (WAT), have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BATactivation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.

Retracted: Transplantation of brown adipose tissue inhibits atherosclerosis in apoE-/- mice: contribution of the activated FGF-21-adiponectin axis.

Retracted: Transplantation of brown adipose tissue inhibits atherosclerosis in apoE-/- mice: contribution of the activated FGF-21-adiponectin axis.

YIA-BS5 - Brown Adipose Tissue Function Plays a Critical Role in the Development of Heart Failure during Pressure Overload

Heart failure (HF) is one of the main causes of mortality worldwide. It has been reported that low body temperature is linked to cardiac systolic dysfunction as well as to poor clinical outcome in patients with HF; however the underlying mechanisms and pathological implications are largely unknown. Brown adipose tissue (BAT) was initially characterized as an organ involved in thermogenic response, and studies suggest that BAT has crucial roles for the maintenance of systemic metabolism in obesity. Here we show that BAT dysfunction develops with heart failure and promotes cardiac remodeling by inducing systemic metabolic dysfunction. We generated a left ventricular (LV) pressure-overload model in mice with a thoracic aortic constriction (TAC). Cardiac systolic dysfunction developed in four weeks after operation, together with a reduction of the thermogenic response to acute cold exposure and an increase of TUNEL-positive cells in BAT. In-vitro studies with differentiated brown adipocytes suggested that the chronic activation of adrenergic signaling reduced mitochondrial membrane potential and increased apoptotic cells. The transplantation of healthy BAT into mice undergoing TAC improved thermogenic response and ameliorated cardiac dysfunction. Studies with metabolome analyses indicated that BAT dysfunction has a causal role for accumulation of one metabolite which contributes to the progression of cardiac metabolic remodeling and dysfunction. Maintenance of BAT homeostasis would become a novel therapeutic target for heart failure.

Research progress on the relationship of brown adipose tissue with polycystic ovary syndrome

Brown adipose tissue (BAT) holds great promise for the prevention and treatment of metabolism diseases through thermoregulation. Polycystic ovary syndrome (PCOS) is a complex condition with anovulation, hyperandrogenism, and polycystic ovaries, and also manifests glucolipid metabolic disorders. Recent researches have shown that transplantation of BAT into a PCOS rat could significantly alleviate the phenotypes. This article reviews the role of BAT in pathogenesis of PCOS, which may provide information for prevention and treatment of PCOS.

Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism.

Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.

Brown adipose tissue activation by rutin ameliorates polycystic ovary syndrome in rat

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy that is characterized by anovulation, hyperandrogenism and polycystic ovary. However, there is a lack of effective treatment for PCOS at present because the pathologic cause of PCOS has not been elucidated. Although it has been known that brown adipose tissue transplantation ameliorates PCOS by activating endogenous BAT, BAT transplantation is not applicable in clinic. Therefore, BAT activation with natural compound could be an effective treatment strategy for PCOS patients. Here, we found that 3 weeks of rutin (a novel compound for BAT activation) treatment increased BAT activation, thereby it improved thermogenesis and systemic insulin sensitivity in dehydroepiandrosterone (DHEA)-induced PCOS rat. In addition, the expression levels of ovarian steroidogenic enzymes such as P450C17, aromatase, 3β-HSD, 17β-HSD and STAR were up-regulated in rutin-treated PCOS rat. Furthermore, acyclicity and the serum level of luteinizing hormone were normalized, and a large number of mature ovulated follicle with a reduction of cystic formation were observed in PCOS rat after rutin treatment. Finally, rutin treatment surprisingly improved fertility and birth defect in PCOS rat. Collectively, our results indicate that rutin treatment significantly improves systemic insulin resistance and ovarian malfunction in PCOS, and our findings in this study provide a novel therapeutic option for the treatment of PCOS by activating BAT with rutin.

DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue

DJ-1 protein is involved in multiple physiological processes, including Parkinson’s disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasis via regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders.

Brown adipose tissue as a secretory organ.

Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and experimental studies have associated BAT activity with protection against obesity and metabolic diseases, such as type 2 diabetes mellitus and dyslipidaemia. Active BAT is present in adult humans and its activity is impaired in patients with obesity. The ability of BAT to protect against chronic metabolic disease has traditionally been attributed to its capacity to utilize glucose and lipids for thermogenesis. However, BAT might also have a secretory role, which could contribute to the systemic consequences of BAT activity. Several BAT-derived molecules that act in a paracrine or autocrine manner have been identified. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced. Additionally, BAT can release regulatory molecules that act on other tissues and organs. This secretory capacity of BAT is thought to be involved in the beneficial effects of BAT transplantation in rodents. Fibroblast growth factor 21, IL-6 and neuregulin 4 are among the first BAT-derived endocrine factors to be identified. In this Review, we discuss the current understanding of the regulatory molecules (the so-called brown adipokines or batokines) that are released by BAT that influence systemic metabolism and convey the beneficial metabolic effects of BAT activation. The identification of such adipokines might also direct drug discovery approaches for managing obesity and its associated chronic metabolic diseases.

The Role Of Adipose Tissue In Glucose Homeostasis

It is today established that adipose tissue subserves not only in the storage of excess energy but it is also an organ that regulates immune response, metabolic and endocrine functions as well. Broadly, there are three types of adipose tissue - the white adipose tissue (WAT) the brown adipose tissue (BAT) and the brite adipose tissue. Brown adipose tissue expends energy and generates heat. It is however the WAT that truely relates to the traditional belief that adipose tissue stores excess energy. This review takes a step further in revealing that healthy WAT secretes adipokines which are molecular proteins that regulates glucose homeostasis. However, when healthy WAT is transformed into an inflamed WAT as in obesity, there is perturbation in the glucose homeostasis which further leads to the development of metabolic disease. This review also explores the trend that is now followed in reversing the inflammation of WAT by administration of drugs like thiazolidinediones, statins and aspirin. The replenishment of WAT by transplantation of embryonic BAT is also highlighted as one of the promising methods to reverse inflammation in WAT and correct perturbation of glucose homeostasis.

Brown adipose tissue transplantation ameliorates male fertility impairment caused by diet-induced obesity

Populations with obesity or overweight have a high incidence of infertility. We hypothesised that brown adipose tissue (BAT) transplantation can attenuate the impairment of male fertility caused by diet-induced obesity. BATs were transplanted from male donor mice into age and sex matched recipient mice fed high-fat diets (HFD). Sperm motility experiment was conducted after surgical procedure. X-ray computed tomography scanning, biochemical assay, real-time PCR and western blot analysis were performed. BAT transplantation reduced body fat and epididymal fat mass, as well as triglycerides (TG) content in testis and epididymis and total cholesterol (TCHO) contents in epididymis compared with the HFD group. Sperm motility and progressiveness were recovered and mRNA and protein levels of genes related to sperm motility such as cullin 3 (Cul3), peroxisome proliferator activated receptor alpha (PPARα) and its down-stream genes were significantly down-regulated post BAT transplantation. BAT transplantation partially ameliorated impairment of male fertility caused by diet-induced obesity.

PCOS: Benefits of brown adipose tissue transplantation.

PCOS: Benefits of brown adipose tissue transplantation.

Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS.

Abstract 13907: Transplantation of Brown Adipose Tissue Inhibits Atherosclerosis in Apoe Deficient Mice via Activation of Fgf-21/adiponectin Axis

[Background] Brown adipose tissue (BAT), a key nonshivering thermogenic tissue, has been recently identified as an endocrine organ to regulate metabolic homeostasis. Experimental BAT transplantation has been reported to improve glucose tolerance and insulin sensitivity; however, the beneficial effect of BAT transplantation on atherogenesis remains undefined. [Method and Result] Interscapular BAT was harvested from 12-week-old mice (C57BL/6) and transplanted into the visceral cavity in 12-week-old recipient apoE-/- mice. After 3 months of high-cholesterol diet, atherosclerosis development was evaluated. BAT transplanted mice showed a modest, but significant, decrease in body weight and increase in mean blood pressure compared with sham control mice (4.7%, 12%, respectively, P<0.05). Food intake and lipid profile except for triglyceride level did not differ between the 2 groups. Oil-red-O staining of entire aorta showed a significant decrease in atherosclerotic lesion area in BAT transplanted mice by 19.7 % compared with sham control mice (P<0.05). Histomorphological analysis of transplanted BAT graft showed a similar appearance as white adipose tissue rather than brown adipose tissue. Consistently, mRNA expression levels of brown adipose tissue-related genes such as UCP-1 and PGC-1α were markedly decreased compared with those in endogenous BAT. Interestingly, transplanted BAT graft showed a significantly increased mRNA expression level of fibroblast growth factor-21 (FGF-21), while its expression level in liver was comparable between the 2 groups. The serum concentration of FGF-21 was also increased in BAT transplanted mice (49%, P<0.05), accompanied by the higher concentration of circulating adiponectin (36%, P<0.05). Serum concentration of adiponectin was negatively correlated with the percentage of plaque area (r=-0.44, P<0.05), suggesting that transplanted BAT graft exerts atheroprotective effect via activation of FGF-21/adiponectin axis. [Conclusion] Our findings demonstrated for the first time that BAT transplantation reduces atherosclerosis development, and phenotypic modulation of BAT graft could be a potential therapeutic strategy for preventing atherosclerotic diseases.

The Beneficial Effects of Brown Fat Transplantation: Further Evidence of an Endocrine Role of Brown Adipose Tissue.

Transplantation procedures have been traditionally used in endocrinology research to assess the ability of factors secreted by transplanted tissues and organs to signal at distance to other tissues and organs. This strategy contributed to reveal the role of white adipose tissue (WAT) as an endocrine organ. For example, studies showing that white fat transplantation caused the systemic amelioration of metabolism in lipoatrophic mice contributed significantly to current awareness that white fat, in addition to its role as a site of storage of metabolic energy, is an active site of release of bioactive molecules with hormonal action, known as adipokines (1). Brown adipose tissue (BAT) is a form of adipose tissue completely distinct from WAT. Rather than being a site of lipid storage, BAT is the main site of nonshivering thermogenesis. The uncoupled oxidation occurring in mitochondria of BAT results in the consumption of metabolic substrates and the production of heat. Studies in rodents have shown that activation of BAT has healthy metabolic consequences in regard to obesity and type 2 diabetes. Promotion of energy expenditure by brown fat protects against obesity by preventing a potentially positive energy balance (2). Moreover, the ability of brown fat to actively drain circulating glucose and triglycerides, oxidizing them to produce heat, can prevent hyperglycemia and hypertriglyceridemia (3). In humans, BAT was previously thought to play a relevant role only in neonatal thermogenesis. However, the recent findings that adult humans have higher amounts of active brown fat than expected has renewed interest in the role of brown fat activation in promoting metabolic health (4). In the last years, several reports using rodent models have indicated that transplantation of BAT has beneficial effects on metabolic health. For example, transplantation of embryonic BAT into rodent models of type1 diabetes, induced by streptozotocin or associated with autoimmune processes (5, 6), was found to normalize glycemia. These effects were independent of insulin, which remained abnormally low after transplantation, and were accompanied by increased amounts of sc white fat and reduced signs of WAT inflammation. The beneficial effects of BAT transplantation were proposed to be due to significant increases of adipokines, such as adiponectin and leptin, originating from the newly replenished sc WAT. IGF-1, released by transplanted BAT, has been proposed to play a major role in improving type 1 diabetes in this experimental model. In 2013, 2 independent laboratories (7, 8) reported that adult BAT transplantation could reverse metabolic abnormalities in high-fat diet-induced obese, insulin-resistant, mice. In one study, BAT transplantation improved glucose tolerance, increased insulin sensitivity, reduced body weight, and completely reversed high-fat diet-induced insulin resistance (7). The other study found that BAT transplantation could prevent and even reverse high-fat dietinduced obesity in mice (8). Although one study has found that the main targets of BAT transplantation were the WAT and BAT of transplant recipients, the other study reported that transplanted BAT primarily activated BAT and muscle. However, despite some discrepancies in the processes underlying the effects of transplanted BAT and several technical differences (eg, the site of transplantation

Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy

Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1−/−) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1−/− mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1−/− mice. UCP1−/− mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1−/− mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1−/− BAT transplanted to either UCP1−/− or WT mice had no effect on cTnI release. After 3days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1−/− mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1−/− mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy.