Brown Fat Activity Research Articles

Brown adipose tissue: a potential target in the fight against obesity and the metabolic syndrome.

BAT (brown adipose tissue) is the main site of thermogenesis in mammals. It is essential to ensure thermoregulation in newborns. It is also found in (some) adult humans. Its capacity to oxidize fatty acids and glucose without ATP production contributes to energy expenditure and glucose homoeostasis. Brown fat activation has thus emerged as an attractive therapeutic target for the treatment of obesity and the metabolic syndrome. In the present review, we integrate the recent advances on the metabolic role of BAT and its relation with other tissues as well as its potential contribution to fighting obesity and the metabolic syndrome.

Renaissance of brown adipose tissue research: integrating the old and new.

The recent demonstration of active brown adipose tissue (BAT) in adult humans, along with the discovery of vast cellular and metabolic plasticity of adipocyte phenotypes, has given new hope of targeting adipose tissue for therapeutic benefit. Application of principles learned from the first wave of obesity-related BAT research, conducted 30 years earlier, suggests that the activity and/or mass of brown fat will need to be greatly expanded for it to significantly contribute to total energy expenditure. Although the thermogenic capacity of human brown fat is very modest, its presence often correlates with improved metabolic status, suggesting possible beneficial endocrine functions. Recent advances in our understanding of the nature of progenitors and the transcriptional programs that guide phenotypic diversity have demonstrated the possibility of expanding the population of brown adipocytes in rodent models. Expanded populations of brown and beige adipocytes will require tight control of their metabolic activity, which might be achieved by selective neural activation, tissue-selective signaling or direct activation of lipolysis, which supplies the central fuel of thermogenesis.

Of mice and men: novel insights regarding constitutive and recruitable brown adipocytes.

Recently, there has been great attention given to the possibility of combating obesity by targeting brown fat activity or increasing differentiation of brown adipocytes in white fat depots through a process termed 'browning'. Sympathetic innervation of brown and white adipose tissues provides adrenergic input that drives thermogenesis and regulates fatty acid metabolism, as well as stimulating adipogenesis of recruitable brown adipocyte tissue (rBAT, also known as beige or brite) in white fat. Other factors acting in an endocrine or autocrine/paracrine manner in adipose tissue may also stimulate browning. There have been significant recent advances in understanding the mechanisms of increasing adipose tissue energy expenditure, as well as how brown adipocytes appear in white fat depots, including via de novo adipogenesis from tissue precursor cells. In this article, we integrate this new knowledge with a historical perspective on the discovery of 'browning'. We also provide an overview of constitutive BAT vs rBAT in mouse and human.

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

FGF21, energy expenditure and weight loss - How much brown fat do you need?

BackgroundFibroblast growth factor 21 (FGF21) belongs to the large family of fibroblast growth factors (FGFs). Even though FGF signaling has been mainly implicated in developmental processes, recent studies have demonstrated that FGF21 is an important regulator of whole body energy expenditure and metabolism, in obesity.Scope of reviewGiven the fact that obesity has developed epidemic proportions, not just in industrialized countries, FGF21 has emerged as a novel therapeutic avenue to treat obesity as well as associated metabolic disorders. While the metabolic effects of FGF21 are undisputed, the mechanisms by which FGF21 regulate weight loss have not yet been fully resolved. Until recently it was believed that FGF21 induces brown fat activity, thereby enhancing energy expenditure, which concomitantly leads to weight loss. Novel studies have challenged this concept as they could demonstrate that a part of the FGF21 mediated effects are retained in a mouse model of impaired brown adipose tissue function.Major conclusionsThe review illustrates the recent advances in FGF21 research and discusses the role of FGF21 in the regulation of energy expenditure linked to brown fat activity.

Transcriptional Regulatory Circuits Controlling Brown Fat Development and Activation.

Brown and beige adipose tissue is specialized for heat production and can be activated to reduce obesity and metabolic dysfunction in animals. Recent studies also have indicated that human brown fat activity levels correlate with leanness. This has revitalized interest in brown fat biology and has driven the discovery of many new regulators of brown fat development and function. This review summarizes recent advances in our understanding of the transcriptional mechanisms that control brown and beige fat cell development.

“Fight fat with fat”: The impact of brown adipose tissue (BAT) on breast cancer prognosis–A retrospective analysis.

1585 Background: Two types of adipose tissue exist: white adipose tissue (WAT) and BAT. WAT is the main energy store in humans and is associated with obesity and inflammation. BAT is thought to be protective against obesity and acts as an energy dissipating organ, which may fight obesity by reducing adipokines, inflammatory cytokines, and insulin resistance. The relationship of brown fat activation and cancer prognosis is unknown. We hypothesize that BAT may be protective to breast cancer patients by shifting glucose pool away from tumors and reducing tumor activity. Methods: Through a retrospective chart review of over 900 patients treated by the Breast Cancer Group at our institution, we identified 98 patients with BAT on PET CT scans. We collected information on patient demographics, lifestyle, staging and treatments received and response, progression of disease, overall survival, labs (lipids, hemoglobin A1C, Vitamin D, CRP), metabolic syndrome, metformin use, and antidepressants. Results: Of the 98 c...

Abstract 691: Arv1 Deletion Alters Fat Storage via Adipose-Extrinsic Mechanisms

ARE2 Required for Viability 1 (ARV1) is a transmembrane protein of the endoplasmic reticulum (ER) that is believed to promote intracellular sterol transport in yeast. Deletion of ARV1 in yeast causes lipid accumulation in the ER, altered membrane structure, and constitutive activation of the unfolded protein response. This protein is conserved in mammals, and human ARV1 is known to rescue the growth and viability defects in ARV1 deficient yeast. In previous work, we found that germline deletion of Arv1 in mice results in a 25% reduction in body weight, greatly reduced fat mass, increased energy expenditure, andimproved glucose tolerance. In the present work, we sought to test the hypothesis that loss of ARV1 activity in white and brown fat is responsible for the metabolic changes we observed. To test this, we utilized two different adipose-selective Cre drivers: Adiponectin-Cre and Ap2-Cre . Adiponectin-Cre mediated deletion was robust and highly specific to the white and brown fat, and had no impact on fat storage or blood glucose. In contrast, Ap2-Cre resulted in a substantial 53% decrease in Arv1 mRNA in the brain (p < 0.05), accompanied by reduced fat mass and markedly improved glucose tolerance. The data suggest that mammalian ARV1 controls metabolic rate and fat storage through non-adipocyte tissues, most likely involving the central nervous system.

De Novo Reconstruction of Adipose Tissue Transcriptomes Reveals Long Non-coding RNA Regulators of Brown Adipocyte Development

Brown adipose tissue (BAT) protects against obesity by promoting energy expenditure via uncoupled respiration. To uncover BAT-specific long non-coding RNAs (lncRNAs), we used RNA-seq to reconstruct de novo transcriptomes of mouse brown, inguinal white, and epididymal white fat and identified ∼1,500 lncRNAs, including 127 BAT-restricted loci induced during differentiation and often targeted by key regulators PPARγ, C/EBPα, and C/EBPβ. One of them, lnc-BATE1, is required for establishment and maintenance of BAT identity and thermogenic capacity. lnc-BATE1 inhibition impairs concurrent activation of brown fat and repression of white fatgenes and is partially rescued by exogenous lnc-BATE1 with mutated siRNA-targeting sites, demonstrating a function in trans. We show that lnc-BATE1 binds heterogeneous nuclear ribonucleoprotein U and that both are required for brown adipogenesis. Our work provides an annotated catalog for the study of fat depot-selective lncRNAs and establishes lnc-BATE1 as a regulator of BAT development and physiology.

Central and peripheral irisin differentially regulate blood pressure.

Irisin is a newly identified 112 amino acid hormone, derived as a product of fibronectin type III domain containing 5 (FNDC5), which is highly related to metabolic activity in skeletal muscle and brown fat. The effects of irisin on cardiovascular functions are unknown. To explore the effects of central and peripheral irisin on cardiovascular functions. Irisin was either administrated into 3rd ventricle of rats or intravenously, and its effects on blood pressure and cardiac contractibility measured. Administration of recombinant human irisin into the 3rd brain ventricle of rats activated neurons in the paraventricular nuclei of the hypothalamus. Central administration of irisin increased blood pressure and cardiac contractibility. Exogenous irisin reversed atenolol-induced inhibition of cardiac contractibility. In contrast, peripheral administration of irisin reduced blood pressure in both control and spontaneously hypertensive rats. Irisin dilated mesenteric artery rings through ATP-sensitive potassium channels. Our studies indicate that central and peripheral irisin may differentially regulate cardiovascular activities.

Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development.

Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by β3-adrenergic receptor stimulation protects from atherosclerosis in hyperlipidemic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism that unlike hyperlipidemic Apoe−/− and Ldlr−/− mice expresses functional apoE and LDLR. BAT activation increases energy expenditure and decreases plasma triglyceride and cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT, subsequently accelerating the hepatic clearance of the cholesterol-enriched remnants. These effects depend on a functional hepatic apoE-LDLR clearance pathway as BAT activation in Apoe−/− and Ldlr−/− mice does not attenuate hypercholesterolaemia and atherosclerosis. We conclude that activation of BAT is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis.

Modulação da Dor na Síndrome Fibromiálgica: Um Distúrbio Termorregulatório?

Several characteristics from Fibromyalgia Syndrome (FMS) suggest alterations in the thermoregulatory activity. There is an overl ap between thermoregulation and nociceptive modulation, consistent with the symptoms of the syndrome. Several studies, addressed in this review , describe common aspects between the regulation of pain and temperature, what may contribute to the generalized and persistent pain of FMS. Several findings, evidenced in the literature, support this idea: the distribution of Brown Fat (BAT) resembles the tender points; stress and cold cause sympathetic hyperactivity stimulating afferent fibers C, innervating BAT and adjacent tissues. They stimulate thermogenesis of BAT, which exacerbates hyperalgesia of FMS in regions corresponding to the tender points; physical activi ty acts in an antagonistic way, avoiding the BAT recruitment and alleviating the symptoms; women may be more susceptible to FMS, because they are less capable of initiating adaptive thermogenesis than men. The activation of the BAT has a peripheral vasoconstriction action, but it increase s the supraclavicular temperature. Infrared thermography may record the activation of BAT in the FMS through the mantle signal. Hands or feet immersion in water at 20oC test evaluates the aforementioned activation. Although not a definitive diagnosis, the phenomenon of the mantle and peripheral vasoconstriction may support the clinical diagnosis, having an important role in monitoring patients with FMS, as markers of autonomic dysfunction, present in this disease.

Adenosine activates thermogenic adipocytes.

Brown or beige fat activation can cause potent anti-obesity and anti-diabetic effects. In a study recently published in Nature, Gnad et al. show that adenosine is a novel activator of brown and beige fat that acts through the A2A receptor.

Is the heat surrounding adipose tissue mitochondria warranted?

Mitochondrial uncoupling proteins uncouple oxidative phosphorylation. The physiological role ascribed to this process is thermoregulation. The metabolic consequence of mitochondrial respiration uncoupled from ATP production is increased substrate oxidation and metabolic rate. The recent discovery of uncoupling protein 1 (UCP1) positive mitochondria in human adipose tissue has rekindled interest in the role of UCP1 in energy balance and metabolic health. Recently, there have been numerous reports of functional brown adipose tissue in humans. Further, data from cell and murine studies suggest that beige adipocytes can be induced within white adipose tissue. The presence of brown/beige adipocytes with mitochondria expressing UCP1 negatively correlates with adiposity. Further, activation of these adipocytes alters energy balance and substrate metabolism. However, in humans, brown fat content varies significantly. Further, although beige adipocytes can be induced in white adipose tissue of rodents, whether this is also true in humans remains unclear. The presence of UCP1-positive mitochondria in human adipose tissue represents an exciting therapeutic target for treating obesity and its metabolic complications. Understanding the mechanisms governing brown fat activation will be crucial if the therapeutic potential of UCP1 is to be realized.

Shc depletion stimulates brown fat activity in vivo and in vitro.

Adipose tissue is an important metabolic organ that integrates a wide array of homeostatic processes and is crucial for whole-body insulin sensitivity and energy metabolism. Brown adipose tissue (BAT) is a key thermogenic tissue with a well-established role in energy expenditure. BAT dissipates energy and protects against both hypothermia and obesity. Thus, BAT stimulation therapy is a rational strategy for the looming pandemic of obesity, whose consequences and comorbidities have a huge impact on the aged. Shc-deficient mice (ShcKO) were previously shown to be lean, insulin sensitive, and resistant to high-fat diet and obesity. We investigated the contribution of BAT to this phenotype. Insulin-dependent BAT glucose uptake was higher in ShcKO mice. Primary ShcKO BAT cells exhibited increased mitochondrial respiration; increased expression of several mitochondrial and lipid-oxidative enzymes was observed in ShcKO BAT. Levels of brown fat-specific markers of differentiation, UCP1, PRDM16, ELOVL3, and Cox8b, were higher in ShcKO BAT. In vitro, Shc knockdown in BAT cell line increased insulin sensitivity and metabolic activity. In vivo, pharmacological stimulation of ShcKO BAT resulted in higher energy expenditure. Conversely, pharmacological inhibition of BAT abolished the improved metabolic parameters, that is the increased insulin sensitivity and glucose tolerance of ShcKO mice. Similarly, in vitro Shc knockdown in BAT cell lines increased their expression of UCP1 and metabolic activity. These data suggest increased BAT activity significantly contributes to the improved metabolic phenotype of ShcKO mice.

Role of forkhead box protein A3 in age-associated metabolic decline.

Aging is associated with increased adiposity and diminished thermogenesis, but the critical transcription factors influencing these metabolic changes late in life are poorly understood. We recently demonstrated that the winged helix factor forkhead box protein A3 (Foxa3) regulates the expansion of visceral adipose tissue in high-fat diet regimens; however, whether Foxa3 also contributes to the increase in adiposity and the decrease in brown fat activity observed during the normal aging process is currently unknown. Here we report that during aging, levels of Foxa3 are significantly and selectively up-regulated in brown and inguinal white fat depots, and that midage Foxa3-null mice have increased white fat browning and thermogenic capacity, decreased adipose tissue expansion, improved insulin sensitivity, and increased longevity. Foxa3 gain-of-function and loss-of-function studies in inguinal adipose depots demonstrated a cell-autonomous function for Foxa3 in white fat tissue browning. Furthermore, our analysis revealed that the mechanisms of Foxa3 modulation of brown fat gene programs involve the suppression of peroxisome proliferator activated receptor γ coactivtor 1 α (PGC1α) levels through interference with cAMP responsive element binding protein 1-mediated transcriptional regulation of the PGC1α promoter. Overall, our data demonstrate a role for Foxa3 in energy expenditure and in age-associated metabolic disorders.

New Physiological Aspects of Brown Adipose Tissue.

Brown adipose tissue is specialised for the generation of heat by non-shivering mechanisms. In rodents, the tissue plays a role in energy balance and the development of obesity, as well as in thermoregulation. Studies using fluorodeoxyglucose positron emission tomography (FDG-PET), together with the identification of uncoupling protein-1, have provided definitive evidence that brown adipose tissue is present in adult humans. Brown fat activity is stimulated by cold exposure, declines with age and is inversely proportional to BMI. This has led to renewed interest in the tissue as a therapeutic target for the treatment of obesity. Brown adipose tissue also plays a role in glucose disposal and triglyceride clearance, implicating it in the metabolic syndrome. A potential mechanism for increasing thermogenesis is by the 'browning' of white adipose depots through the recruitment of the recently identified third type of adipocyte - the brite (or beige) fat cell.

Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia.

Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

Hypothalamus-adipose tissue crosstalk: neuropeptide Y and the regulation of energy metabolism.

Neuropeptide Y (NPY) is an orexigenic neuropeptide that plays a role in regulating adiposity by promoting energy storage in white adipose tissue and inhibiting brown adipose tissue activation in mammals. This review describes mechanisms underlying NPY’s effects on adipose tissue energy metabolism, with an emphasis on cellular proliferation, adipogenesis, lipid deposition, and lipolysis in white adipose tissue, and brown fat activation and thermogenesis. In general, NPY promotes adipocyte differentiation and lipid accumulation, leading to energy storage in adipose tissue, with effects mediated mainly through NPY receptor sub-types 1 and 2. This review highlights hypothalamus-sympathetic nervous system-adipose tissue innervation and adipose tissue-hypothalamus feedback loops as pathways underlying these effects. Potential sources of NPY that mediate adipose effects include the bloodstream, sympathetic nerve terminals that innervate the adipose tissue, as well as adipose tissue-derived cells. Understanding the role of central vs. peripherally-derived NPY in whole-body energy balance could shed light on mechanisms underlying the pathogenesis of obesity. This information may provide some insight into searching for alternative therapeutic strategies for the treatment of obesity and associated diseases.

Effect of Intermittent Cold Exposure on Brown Fat Activation, Obesity, and Energy Homeostasis in Mice

Homeotherms have specific mechanisms to maintain a constant core body temperature despite changes in thermal environment, food supply, and metabolic demand. Brown adipose tissue, the principal thermogenic organ, quickly and efficiently increases heat production by dissipating the mitochondrial proton motive force. It has been suggested that activation of brown fat, via either environmental (i.e. cold exposure) or pharmacologic means, could be used to increase metabolic rate and thus reduce body weight. Here we assess the effects of intermittent cold exposure (4°C for one to eight hours three times a week) on C57BL/6J mice fed a high fat diet. Cold exposure increased metabolic rate approximately two-fold during the challenge and activated brown fat. In response, food intake increased to compensate fully for the increased energy expenditure; thus, the mice showed no reduction in body weight or adiposity. Despite the unchanged adiposity, the cold-treated mice showed transient improvements in glucose homeostasis. Administration of the cannabinoid receptor-1 inverse agonist AM251 caused weight loss and improvements in glucose homeostasis, but showed no further improvements when combined with cold exposure. These data suggest that intermittent cold exposure causes transient, meaningful improvements in glucose homeostasis, but without synergy when combined with AM251. Since energy expenditure is significantly increased during cold exposure, a drug that dissociates food intake from metabolic demand during cold exposure may achieve weight loss and further metabolic improvements.