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Journal of Internal Medicine Oct 2014Obesity and related diseases are a major cause of human morbidity and mortality and constitute a substantial economic burden for society. Effective treatment regimens... (Review)
Review
Obesity and related diseases are a major cause of human morbidity and mortality and constitute a substantial economic burden for society. Effective treatment regimens are scarce, and new therapeutic targets are needed. Brown adipose tissue, an energy-expending tissue that produces heat, represents a potential therapeutic target. Its presence is associated with low body mass index, low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Knowledge about the development and function of thermogenic adipocytes in brown adipose tissue has increased substantially in the last decade. Important transcriptional regulators have been identified, and hormones able to modulate the thermogenic capacity of the tissue have been recognized. Intriguingly, it is now clear that humans, like rodents, possess two types of thermogenic adipocytes: the classical brown adipocytes found in the interscapular brown adipose organ and the so-called beige adipocytes primarily found in subcutaneous white adipose tissue after adrenergic stimulation. The presence of two distinct types of energy-expending adipocytes in humans is conceptually important because these cells might be stimulated and recruited by different signals, raising the possibility that they might be separate potential targets for therapeutic intervention. In this review, we will discuss important features of the energy-expending brown adipose tissue and highlight those that may serve as potential targets for pharmacological intervention aimed at expanding the tissue and/or enhancing its function to counteract obesity.
Topics: Adipocytes; Adipose Tissue, Brown; Animals; Energy Metabolism; Hormones; Humans; Obesity; Subcutaneous Fat; Thermogenesis
PubMed: 24717051
DOI: 10.1111/joim.12255 -
Protein & Cell Jun 2017Obesity, which underlies various metabolic and cardiovascular diseases, is a growing public health challenge for which established therapies are inadequate. Given the... (Review)
Review
Obesity, which underlies various metabolic and cardiovascular diseases, is a growing public health challenge for which established therapies are inadequate. Given the current obesity epidemic, there is a pressing need for more novel therapeutic strategies that will help adult individuals to manage their weight. One promising therapeutic intervention for reducing obesity is to enhance energy expenditure. Investigations into human brown fat and the recently discovered beige/brite fat have galvanized intense research efforts during the past decade because of their pivotal roles in energy dissipation. In this review, we summarize the evolution of human brown adipose tissue (hBAT) research and discuss new in vivo methodologies for evaluating energy expenditure in patients. We highlight the differences between human and mouse BAT by integrating and comparing their cellular morphology, function, and gene expression profiles. Although great advances in hBAT biology have been achieved in the past decade, more cellular models are needed to acquire a better understanding of adipose-specific processes and molecular mechanisms. Thus, this review also describes the development of a human brown fat cell line, which could provide promising mechanistic insights into hBAT function, signal transduction, and development. Finally, we focus on the therapeutic potential and current limitations of hBAT as an anti-glycemic, anti-lipidemic, and weight loss-inducing 'metabolic panacea'.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Cell Line; Energy Metabolism; Humans; Mice; Obesity
PubMed: 28220393
DOI: 10.1007/s13238-017-0378-6 -
Endocrine Journal 2014Brown adipose tissue (BAT) is the site of sympathetically activated adaptive thermognenesis during cold exposure and after hyperphagia, thereby controlling whole-body... (Review)
Review
Brown adipose tissue (BAT) is the site of sympathetically activated adaptive thermognenesis during cold exposure and after hyperphagia, thereby controlling whole-body energy expenditure (EE) and body fat. Radionuclide imaging studies have demonstrated that adult humans have metabolically active BAT composed of mainly beige/brite adipocytes, recently identified brown-like adipocytes. The inverse relationship between the BAT activity and body fatness suggests that BAT is, because of its energy dissipating activity, protective against body fat accumulation in humans as it is in small rodents. In fact, either repeated cold exposure or daily ingestion of some food ingredients acting on transient receptor potential channels recruits BAT in parallel with increased EE and decreased body fat. In addition to the sympathetic nervous system, several endocrine factors are also shown to recruit BAT. Thus, BAT is a promising therapeutic target for combating human obesity and related metabolic disorders.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Adult; Animals; Body Weight; Energy Metabolism; Humans; Obesity; Sympathetic Nervous System; Thermogenesis
PubMed: 24401694
DOI: 10.1507/endocrj.ej13-0527 -
The Biochemical Journal Jul 2013Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non-alcoholic... (Review)
Review
Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non-alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function.
Topics: Adipose Tissue, Brown; Animals; Humans; Metabolic Diseases; Obesity; Stem Cells; Thermogenesis
PubMed: 23805974
DOI: 10.1042/BJ20130457 -
Frontiers in Endocrinology 2020Non-shivering thermogenesis in mammalian brown adipose tissue is a powerful mechanism to defend normothermia in cold climates. To minimize the loss of chemical energy,... (Review)
Review
Non-shivering thermogenesis in mammalian brown adipose tissue is a powerful mechanism to defend normothermia in cold climates. To minimize the loss of chemical energy, the central functional component, mitochondrial uncoupling protein 1, UCP1, must be tightly regulated. The canonical pathway of UCP1 activation includes lipolytic release of free fatty acids in response to an adrenergic signal. Activating fatty acids overcome constitutive inhibition of UCP1 by the di- and triphosphate forms of purine nucleotides, i.e., ATP, ADP, GTP, and GDP. Cellular concentrations of inhibitory, free nucleotides are subject to significant, adrenergically induced alterations. The regulatory components involved may constitute novel drug targets to manipulate brown fat thermogenesis and thereby organismic energy balance. We here review evidence for and against a dominant role of nucleotides in thermogenic control, describe conceptual routes to endogenously and pharmacologically alter free nucleotide pool size, speculate on a signaling role of degradation products released from active brown fat, and highlight gaps in our understanding of signaling and metabolic pathways involved.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Animals; Energy Metabolism; Humans; Mammals; Oxygen Consumption; Purine Nucleotides; Thermogenesis
PubMed: 32210919
DOI: 10.3389/fendo.2020.00118 -
Clinical and Translational Medicine Feb 2022Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl-CoA...
Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl-CoA synthetase short-chain family member 3 (ACSS3), located on the mitochondrial inner membrane in brown adipocytes. Knockout of Acss3 gene (Acss3 ) in mice reduces brown adipose tissue (BAT) mass but increases white adipose tissue (WAT) mass, leading to glucose intolerance and insulin resistance that are exacerbated by high-fat diet (HFD). Intriguingly, Acss3 or HFD feeding significantly elevates propionate levels in BAT and serum, and propionate supplementation induces autophagy in cultured brown and white adipocytes. The elevated levels of propionate in Acss3 mice similarly drive adipocyte autophagy, and pharmacological inhibition of autophagy using hydroxychloroquine ameliorates obesity, hepatic steatosis and insulin resistance of the Acss3 mice. These results establish ACSS3 as the key enzyme for propionate metabolism and demonstrate that accumulation of propionate promotes obesity and Type 2 diabetes through triggering adipocyte autophagy.
Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue, Brown; Animals; Coenzyme A Ligases; Disease Models, Animal; Mice; Mice, Knockout; Propionates
PubMed: 35184387
DOI: 10.1002/ctm2.665 -
Biotechnology Advances Nov 2015The formation of brown adipose tissue (BAT) via brown adipogenesis has become a notable process due to its ability to expend energy as heat with implications in the... (Review)
Review
The formation of brown adipose tissue (BAT) via brown adipogenesis has become a notable process due to its ability to expend energy as heat with implications in the treatment of metabolic disorders and obesity. With the advent of complexity within white adipose tissue (WAT) along with inducible brown adipocytes (also known as brite and beige), there has been a surge in deciphering adipocyte biology as well as in vivo adipogenic microenvironments. A therapeutic outcome would benefit from understanding early events in brown adipogenesis, which can be accomplished by studying cellular differentiation. Pluripotent stem cells are an efficient model for differentiation and have been directed towards both white adipogenic and brown adipogenic lineages. The stem cell microenvironment greatly contributes to terminal cell fate and as such, has been mimicked extensively by various polymers including those that can form 3D hydrogel constructs capable of biochemical and/or mechanical modifications and modulations. Using bioengineering approaches towards the creation of 3D cell culture arrangements is more beneficial than traditional 2D culture in that it better recapitulates the native tissue biochemically and biomechanically. In addition, such an approach could potentially protect the tissue formed from necrosis and allow for more efficient implantation. In this review, we highlight the promise of brown adipocytes with a focus on brown adipogenic differentiation of stem cells using bioengineering approaches, along with potential challenges and opportunities that arise when considering the energy expenditure of BAT for prospective therapeutics.
Topics: Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Animals; Cell Culture Techniques; Cell Differentiation; Humans; Mice; Stem Cells; Tissue Engineering
PubMed: 26231586
DOI: 10.1016/j.biotechadv.2015.07.005 -
Adipocyte 2018Numerous studies have shown that feeding rodents n-3 polyunsaturated fatty acids attenuates adiposity. Moreover, meta-analyses of human dietary intervention studies... (Review)
Review
Numerous studies have shown that feeding rodents n-3 polyunsaturated fatty acids attenuates adiposity. Moreover, meta-analyses of human dietary intervention studies indicate that fish oil (eicosapentaenoic and docosahexaenoic acid) supplementation might reduce waist circumference. A recent line of research suggests that browning of white adipose depots and activation of uncoupled respiration in brown fat contributes to these effects. This mini-review summarizes the observations in rodents, highlights several mechanisms that might explain these observations and discusses the translational potential. Given the available in vivo evidence and the ability of human adipocytes to aquire a beige phenotype in response to eicosapentaenoic acid incubation, future studies should test the hypothesis that fish oil activates thermogenic brown and beige adipose tissue in humans.
Topics: Adipocytes; Adipose Tissue, Beige; Adipose Tissue, Brown; Fish Oils; Humans; Thermogenesis
PubMed: 29521565
DOI: 10.1080/21623945.2018.1442980 -
Cell Reports. Medicine Jul 2021The association of brown adipose tissue (BAT) and body fat distribution and their combined effects on metabolic health in humans remains unknown. Here, we...
The association of brown adipose tissue (BAT) and body fat distribution and their combined effects on metabolic health in humans remains unknown. Here, we retrospectively identify individuals with and without BAT on F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/computed tomography (CT) and assemble a propensity score-matched study cohort to compare body fat distribution and determine its role in mediating the benefits of brown fat. We find that BAT is associated with lower amounts of visceral adipose tissue and higher amounts of subcutaneous adipose tissue, resulting in less central obesity. In addition, BAT is independently associated with lower blood glucose and white blood cell count, improved lipids, lower prevalence of type 2 diabetes mellitus, and decreased liver fat accumulation. These observations are most prominent in individuals with central obesity. Our results support a role of BAT in protection from visceral adiposity and improved metabolic health.
Topics: Adipose Tissue, Brown; Adiposity; Body Fat Distribution; Cohort Studies; Diabetes Mellitus, Type 2; Fatty Liver; Female; Fluorodeoxyglucose F18; Humans; Liver; Male; Metabolome; Middle Aged; Multivariate Analysis; Positron Emission Tomography Computed Tomography
PubMed: 34337558
DOI: 10.1016/j.xcrm.2021.100332 -
Journal of Lipid Research Jul 1993Five adrenoceptor subtypes are involved in the adrenergic regulation of white and brown fat cell function. The effects on cAMP production and cAMP-related cellular... (Review)
Review
Five adrenoceptor subtypes are involved in the adrenergic regulation of white and brown fat cell function. The effects on cAMP production and cAMP-related cellular responses are mediated through the control of adenylyl cyclase activity by the stimulatory beta 1-, beta 2-, and beta 3-adrenergic receptors and the inhibitory alpha 2-adrenoceptors. Activation of alpha 1-adrenoceptors stimulates phosphoinositidase C activity leading to inositol 1,4,5-triphosphate and diacylglycerol formation with a consequent mobilization of intracellular Ca2+ stores and protein kinase C activation which trigger cell responsiveness. The balance between the various adrenoceptor subtypes is the point of regulation that determines the final effect of physiological amines on adipocytes in vitro and in vivo. Large species-specific differences exist in brown and white fat cell adrenoceptor distribution and in their relative importance in the control of the fat cell. Functional beta 3-adrenoceptors coexist with beta 1- and beta 2-adrenoceptors in a number of fat cells; they are weakly active in guinea pig, primate, and human fat cells. Physiological hormones and transmitters operate, in fact, through differential recruitment of all these multiple alpha- and beta-adrenoceptors on the basis of their relative affinity for the different subtypes. The affinity of the beta 3-adrenoceptor for catecholamines is less than that of the classical beta 1- and beta 2-adrenoceptors. Conversely, epinephrine and norepinephrine have a higher affinity for the alpha 2-adrenoceptors than for beta 1-, 2-, or 3-adrenoceptors. Antagonistic actions exist between alpha 2- and beta-adrenoceptor-mediated effects in white fat cells while positive cooperation has been revealed between alpha 1- and beta-adrenoceptors in brown fat cells. Homologous down-regulation of beta 1- and beta 2-adrenoceptors is observed after administration of physiological amines and beta-agonists. Conversely, beta 3- and alpha 2-adrenoceptors are much more resistant to agonist-induced desensitization and down-regulation. Heterologous regulation of beta-adrenoceptors was reported with glucocorticoids while sex-steroid hormones were shown to regulate alpha 2-adrenoceptor expression (androgens) and to alter adenylyl cyclase activity (estrogens).
Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Catecholamines; Hormones; Humans; Receptors, Adrenergic
PubMed: 8371057
DOI: No ID Found