Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better ...understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
Kajimura and colleagues propose the new idea that BAT is not simply a heat-generating organ. In addition to recent findings regarding the developmental lineages and molecular regulation of brown and beige adipocytes, they discuss the adipocytes’ roles in glucose and lipid homeostasis that may go beyond heat production through UCP1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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. The past few years, in particular, have seen significant changes in the way that we classify adipocytes and how we view adipose development and differentiation. We have new perspective on the roles played by adipocytes in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues. Finally, there has been significant progress in understanding how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Brown and beige adipocytes can catabolize stored energy to generate heat, and this distinct capacity for thermogenesis could be leveraged as a therapy for metabolic diseases like obesity and type 2 ...diabetes. Thermogenic adipocytes drive heat production through close coordination of substrate supply with the mitochondrial oxidative machinery and effectors that control the rate of substrate oxidation. Together, this apparatus affords these adipocytes with tremendous capacity to drive thermogenesis. The best characterized thermogenic effector is uncoupling protein 1 (UCP1). Importantly, additional mechanisms for activating thermogenesis beyond UCP1 have been identified and characterized to varying extents. Acute regulation of these thermogenic pathways has been an active area of study, and numerous regulatory factors have been uncovered in recent years. Here we will review the evidence for regulators of heat production in thermogenic adipocytes in the context of the thermodynamic and kinetic principles that govern their therapeutic utility.
Brown and beige adipocytes can catabolize stored energy to generate heat, and this distinct capacity for thermogenesis could be leveraged as a therapy for metabolic disease. Here we discuss regulators of heat production in thermogenic adipocytes in the context of the thermodynamic and kinetic principles that govern their therapeutic utility.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity. PPARγ ligands have been shown to induce the browning of white adipocytes; however, the ...underlying mechanisms remain unclear. Here, we show that PPARγ ligands require full agonism to induce a brown fat gene program preferentially in subcutaneous white adipose. These effects require expression of PRDM16, a factor that controls the development of classical brown fat. Depletion of PRDM16 blunts the effects of the PPARγ agonist rosiglitazone on the induced brown fat gene program. Conversely, PRDM16 and rosiglitazone synergistically activate the brown fat gene program in vivo. This synergy is tightly associated with an increased accumulation of PRDM16 protein, due in large measure to an increase in the half-life of the protein in agonist treated cells. Identifying compounds that stabilize PRDM16 protein may represent a plausible therapeutic pathway for the treatment of obesity and diabetes.
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► PPARγ full agonists induce a brown fat phenotype in subcutaneous WAT ► PRDM16 is required for the development of PPARγ agonist-inducible brow adipocytes ► PRDM16 and PPARγ agonists synergistically activate the brown fat gene program ► Browning effect is mediated through the enhanced stability of the PRDM16 protein
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can increase energy expenditure ...through the dissipation of chemical energy in the form of heat, using mitochondrial uncoupling and perhaps other pathways. We discuss here some of the thermodynamic and cellular aspects of recent progress in brown fat research. This includes studies of developmental lineages of UCP1(+) adipocytes, including the discovery of beige fat cells, a new thermogenic cell type. We also discuss the physiology and transcriptional control of brown and beige cells in rodents and the state of current knowledge about human brown fat.
One of the most promising areas in the therapeutics for metabolic diseases centers around activation of the pathways of energy expenditure. Brown adipose tissue is a particularly appealing target for ...increasing energy expenditure, given its amazing capacity to transform chemical energy into heat. In addition to classical brown adipose tissue, the last few years have seen great advances in our understanding of inducible thermogenic adipose tissue, also referred to as beige fat. A deeper understanding of the molecular processes involved in the development and function of these cell types may lead to new therapeutics for obesity, diabetes, and other metabolic diseases.
Cell biology of fat storage Cohen, Paul; Spiegelman, Bruce M
Molecular biology of the cell,
08/2016, Volume:
27, Issue:
16
Journal Article
Peer reviewed
Open access
The worldwide epidemic of obesity and type 2 diabetes has greatly increased interest in the biology and physiology of adipose tissues. Adipose (fat) cells are specialized for the storage of energy in ...the form of triglycerides, but research in the last few decades has shown that fat cells also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete important hormone-like molecules such as leptin, adiponectin, and adipsin to influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown fat, on the other hand, dissipates chemical energy in the form of heat, thereby defending against hypothermia, obesity, and diabetes. It is now appreciated that there are two distinct types of thermogenic fat cells, termed brown and beige adipocytes. In addition to these distinct properties of fat cells, adipocytes exist within adipose tissue, where they are in dynamic communication with immune cells and closely influenced by innervation and blood supply. This review is intended to serve as an introduction to adipose cell biology and to familiarize the reader with how these cell types play a role in metabolic disease and, perhaps, as targets for therapeutic development.
Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown ...fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of “beige” cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential.
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► A subset of precursor cells from white fat gives rise to beige adipocytes ► Beige adipocytes have a highly inducible thermogenic capacity upon stimulation ► Beige adipocytes express distinct genes and are sensitive to irisin ► “Brown” fat in human adults is composed primarily of beige adipocytes
A subset of adipocytes in adult human fat depots shows a distinctive gene expression pattern and deploys a thermogenic program in response to the hormone irisin. These so-called beige cells may therefore represent a therapeutic target for treating obesity and associated metabolic disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and ...beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a β3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis.
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•Quantitative proteomics identifies a creatine enzyme signature in beige fat•Creatine-driven substrate cycling enhances beige-fat mitochondrial respiration•Genes and proteins of creatine metabolism exhibit a reciprocal relationship with Ucp1•Creatine reduction decreases energy expenditure in mice and human brown adipocytes
Beige fat uses creatine to dissipate energy and stimulate mitochondrial ATP demand, thereby promoting cold adaptation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The increasing incidence of obesity and its co-morbid conditions poses a great challenge to global health. In addition to cardiovascular disease and diabetes, epidemiological data demonstrate a link ...between obesity and multiple types of cancer. The molecular mechanisms underlying how obesity causes an increased risk of cancer are poorly understood. Obesity disrupts the dynamic role of the adipocyte in energy homeostasis, resulting in inflammation and alteration of adipokine (for example, leptin and adiponectin) signalling. Additionally, obesity causes secondary changes that are related to insulin signalling and lipid deregulation that may also foster cancer development. Understanding these molecular links may provide an avenue for preventive and therapeutic strategies to reduce cancer risk and mortality in an increasingly obese population.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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