Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

Metabolic regulation and the anti-obesity perspectives of human brown fat

Activation of brown adipose tissue (BAT) in adult humans increase glucose and fatty acid clearance as well as resting metabolic rate, whereas a prolonged elevation of BAT activity improves insulin sensitivity. However, substantial reductions in body weight following BAT activation has not yet been shown in humans. This observation raise the possibility for feedback mechanisms in adult humans in terms of a brown fat-brain crosstalk, possibly mediated by batokines, factors produced by and secreted from brown fat. Batokines also seems to be involved in BAT recruitment by stimulating proliferation and differentiation of brown fat progenitors. Increasing human BAT capacity could thus include inducing brown fat biogenesis as well as identifying novel batokines. Another attractive approach would be to induce a brown fat phenotype, the so-called brite or beige fat, within the white fat depots. In adult humans, white fat tissue transformation into beige has been observed in patients with pheochromocytoma, a norepinephrine-producing tumor. Interestingly, human beige fat is predominantly induced in regions that were BAT during early childhood, possibly reflecting that a presence of human beige progenitors is depot specific and originating from BAT. In conclusion, to utilize the anti-obesity potential of human BAT focus should be directed towards identifying novel regulators of brown and beige fat progenitor cells, as well as feedback mechanisms of BAT activation. This would allow for identification of novel anti-obesity targets

Novel approaches to white adipose browning and beige adipose activation for the treatment of obesity

Brown and beige fat are specialized adipose tissues found in almost all mammals that can increase energy expenditure and produce heat. Cold exposure and b3-adrenergic stimulation has been extensively shown to activate brown adipose tissue (BAT) in rodents, which promotes uncoupled respiration of glucose and lipid substrates via uncoupling protein 1 (UCP1). Prolonged stimulation can induce white adipose browning, which leads to the emergence of thermogenic cells within white fat depots, called beige adipocytes. The beige adipocyte possesses a unique molecular signature, yet shares several characteristics of brown adipocytes, including high mitochondrial content. When activated, beige fat can be induced to initiate a thermogenic transcriptional program similar to that of BAT. Recent human studies have identified brown and/or beige fat in the supraclavicular region using various radiation imaging modalities. This remarkable discovery has reinvigorated scientific interest in adipose browning and brown/beige fat activation as possible therapeutic targets for obesity. Like in rodents, several groups have previously tested the potential impact of cold exposure and b3-adrenergic agonism on BAT-mediated thermogenesis in humans. However, even though these approaches were shown to significantly increase energy expenditure and promote weight loss in obese individuals, they are not ideal clinical interventions. Cold exposure is uncomfortable and requires prolonged treatment, while b3-adrenergic agonists may lead to many adverse effects like cardiovascular problems. This thesis will evaluate the therapeutic potential and clinical relevance of alternative anti-obesity approaches that target adipose browning and beige adipose activation

Brown and Beige Fat: Therapeutic Potential in Obesity

BACKGROUND: The epidemic of obesity and type 2 diabetes presents a serious challenge to scientific and biomedical communities worldwide. There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function.CONTENT: Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible ‘brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.SUMMARY: The complexity of adipose tissue presents numerous challenges but also several opportunities for therapeutic intervention. There is persuasive evidence from animal models that enhancement of the function of brown adipocytes, beige adipocytes or both in humans could be very effective for treating type 2 diabetes and obesity. Moreover, there are now an extensive variety of factors and pathways that could potentially be targeted for therapeutic effects. In particular, the discoveries of circulating factors, such as irisin, fibroblast growth factor (FGF)21 and natriuretic peptides, that enhance brown and beige fat function in mice have garnered tremendous interest. Certainly, the next decade will see massive efforts to use beige and brown fat to ameliorate human metabolic disease

Unraveling the Interaction Between Beige Adipocytes and the Sympathetic Nervous System

Obesity affects more than one in three adults in the United States and is a significant risk factor for a constellation of chronic diseases. The crucial role of adipose tissue in energy balance has driven great interest in investigating this tissue as a target for treatment of obesity and its sequelae. While white adipocytes store excess energy, thermogenic brown and beige adipocytes convert lipids and glucose into heat, thereby increasing energy expenditure. Unlike classical brown adipocytes which are thermogenic under basal conditions, inducible brown adipocytes, commonly known as beige adipocytes, reside in white adipose depots and need to be activated by external stimuli such as the sympathetic nervous system to drive thermogenesis. Recent studies have shown that active beige adipocytes can increase energy expenditure and are associated with anti-obesity and anti-diabetes effects in mice and humans. However, the origin of beige adipocytes and how they interact with other adipose cell types remains unclear, creating critical hurdles to manipulating these cells for therapeutic ends. To seek a comprehensive understanding of beige adipocyte formation, we developed a novel technique that enables whole-tissue immunostaining, clearing, and imaging in adipose tissue. Using this new method, we profiled various murine white adipose depots and observed pronounced depot to depot variability in tissue organization. Analysis of cold-induced beige adipocyte formation in whole adipose depots uncovered prominent regional variation in beige adipocyte distribution in subcutaneous fat. Through morphological characterization of the sympathetic nerve projections in subcutaneous fat, we found a dense network of sympathetic parenchymal neurites localizing to the same region where beige adipocytes readily arise. To understand how the dense sympathetic network is established, we used an adipocyte-specific Prdm16 knockout mouse model to ablate beige adipocyte function and demonstrated that the density of sympathetic parenchymal innervation depends on the presence of functional beige adipocytes. These results suggest that communication between beige adipocytes and the sympathetic neurites is important for the establishment of sympathetic innervation. To address whether the regulation by beige adipocytes occurs during early tissue morphogenesis, we applied whole-tissue imaging to examine the development of sympathetic innervation in subcutaneous fat. We found that parenchymal neurites actively grow between postnatal day 6 (P6) and P28, overlapping with early postnatal beige adipogenesis. Constitutive deletion of Prdm16 in adipocytes led to a significant reduction in early postnatal beige adipocytes and sympathetic density within this window. Using an inducible, adipocyte-specific Prdm16 knockout model, we ablated the function of early postnatal beige adipocytes and found strongly impaired sympathetic growth. These data suggest that sympathetic growth in subcutaneous fat depend on a PRDM16- mediated mechanism. However, deleting Prdm16 in adult animals, did not affect sympathetic structure. Together, these findings highlight that beige adipocyte-sympathetic neurite communication is crucial to establish sympathetic structure during the early postnatal period, but may be dispensable for its maintenance in mature animals. These studies unravel the complex interaction between beige adipocytes and the sympathetic nervous system, providing a framework for further investigation of the molecular mechanisms underlying this interaction. Lastly, investigation of the early postnatal beige adipocytes allowed us to appreciate an unprecedented link between early postnatal and adult beige adipocytes. By fate mapping beige adipocytes through development, we found that the majority of cold-induced beige adipocytes in adult subcutaneous fat arise from existing mature adipocytes that were once early postnatal beige adipocytes. These studies provide fundamental insights into beige adipocyte formation and will guide future investigation of the origin and fate of beige adipocytes

Analysis of anti-diabetic exosomes secreted from beige adipocytes

Accumulation of excess fat in white adipose tissue is associated with an increase in risk for type 2 diabetes. Within white fat tissue resides a population of “beige” adipocytes that are activated by cold exposure and expend energy contained in fats, which is released as heat. Increasing energy expenditure through beige adipocyte activation has been shown to reduce diabetic symptoms in rodent models of obesity. However, activation of beige adipocytes through exposure of humans to cold temperatures is uncomfortable and likely not a realistic strategy to control body weight. In addition to its fat burning potential, secreted factors derived from activated beige adipocytes may enter the circulation and reduce diabetic symptoms such as insulin resistance in other tissues. The mechanisms by which these secreted factors act on distant tissues may in part be due to their transport inside extracellular vesicles, known as exosomes. Exosomes carry a diverse array of signaling molecules, including microRNAs that are transported and released into recipient cells and tissues. The goal of this project was to determine if beige adipocytes grown in cell culture secrete exosomes that contain microRNAs that may harbor anti-diabetic properties. Unexpectedly, we found that during the activation of beige adipocytes, secreted exosomes contain elevated expression of a number of microRNAs known to be negative regulators of beige adipocyte activation, including mir27. This suggests that exosome secretion may be a way to increase beige adipocyte activation by decreasing the expression of specific microRNAs. Future testing of these microRNA candidates may translate to improved therapies for obese patients that develop diabetes

Intra-abdominal adipose tissue of laboratory mice adapted to different temperature regimes

For the first time the presence of beige adipocytes, cellularity, basic metabolic parameters of perigonadal abdominal fat have studied in autbred laboratory mice kept at different temperature regimes: 1) 30°С (thermoneutral zone) and 2) regular daily 8-hour cold exposures. Unlike brown fat in the abdominal depot, temperature-dependent changes of these parameters were not detected. The functions of the beige adipocytes of the abdominal depot were discussed

Intra-abdominal adipose tissue of laboratory mice adapted to different temperature regimes

For the first time the presence of beige adipocytes, cellularity, basic metabolic parameters of perigonadal abdominal fat have studied in autbred laboratory mice kept at different temperature regimes: 1) 30°С (thermoneutral zone) and 2) regular daily 8-hour cold exposures. Unlike brown fat in the abdominal depot, temperature-dependent changes of these parameters were not detected. The functions of the beige adipocytes of the abdominal depot were discussed

PON2 Deficiency Leads to Increased Susceptibility to Diet-Induced Obesity.

(1) Background: Paraoxonase 2 (PON2) is a ubiquitously expressed protein localized to endoplasmic reticulum and mitochondria. Previous studies have shown that PON2 exhibits anti-oxidant and anti-inflammatory functions, and PON2-deficient (PON2-def) mice are more susceptible to atherosclerosis. Furthermore, PON2 deficiency leads to impaired mitochondrial function. (2) Methods: In this study, we examined the susceptibility of PON2-def mice to diet-induced obesity. (3) Results: After feeding of an obesifying diet, the PON2-def mice exhibited significantly increased body weight due to increased fat mass weight as compared to the wild-type (WT) mice. The increased adiposity was due, in part, to increased adipocyte hypertrophy. PON2-def mice had increased fasting insulin levels and impaired glucose tolerance after diet-induced obesity. PON2-def mice had decreased oxygen consumption and energy expenditure. Furthermore, the oxygen consumption rate of subcutaneous fat pads from PON2-def mice was lower compared to WT mice. Gene expression analysis of the subcutaneous fat pads revealed decreased expression levels of markers for beige adipocytes in PON2-def mice. (4) Conclusions: We concluded that altered systemic energy balance, perhaps due to decreased beige adipocytes and mitochondrial dysfunction in white adipose tissue of PON2-def mice, leads to increased obesity in these mice

Brown adipose tissue and glucose homeostasis – the link between climate change and the global rise in obesity and diabetes

There is increasing evidence that the global rise in temperature is contributing to the onset of diabetes, which could be mediated by a concomitant reduction in brown fat activity. Brown (and beige) fat are characterised as possessing a unique mitochondrial protein uncoupling protein (UCP)1 that when activated can rapidly generate large amounts of heat. Primary environmental stimuli of UCP1 include cold-exposure and diet, leading to increased activity of the sympathetic nervous system and large amounts of lipid and glucose being oxidised by brown fat. The exact contribution remains controversial, although recent studies indicate that the amount of brown and beige fat in adult humans has been greatly underestimated. We therefore review the potential mechanisms by which glucose could be utilised within brown and beige fat in adult humans and the extent to which these are sensitive to temperature and diet. This includes the potential contribution from the peridroplet and cytoplasmic mitochondrial sub-fractions recently identified in brown fat, and whether a proportion of glucose oxidation could be UCP1-independent. It is thus predicted that as new methods are developed to assess glucose metabolism by brown fat, a more accurate determination of the thermogenic and non-thermogenic functions could be feasible in humans