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Cell Reports. Medicine Oct 2021The Scandinavian winter-swimming culture combines brief dips in cold water with hot sauna sessions, with conceivable effects on body temperature. We study thermogenic...
The Scandinavian winter-swimming culture combines brief dips in cold water with hot sauna sessions, with conceivable effects on body temperature. We study thermogenic brown adipose tissue (BAT) in experienced winter-swimming men performing this activity 2-3 times per week. Our data suggest a lower thermal comfort state in the winter swimmers compared with controls, with a lower core temperature and absence of BAT activity. In response to cold, we observe greater increases in cold-induced thermogenesis and supraclavicular skin temperature in the winter swimmers, whereas BAT glucose uptake and muscle activity increase similarly to those of the controls. All subjects demonstrate nocturnal reduction in supraclavicular skin temperature, whereas a distinct peak occurs at 4:30-5:30 a.m. in the winter swimmers. Our data leverage understanding of BAT in adult human thermoregulation, suggest both heat and cold acclimation in winter swimmers, and propose winter swimming as a potential strategy for increasing energy expenditure.
Topics: Adipose Tissue, Brown; Adult; Circadian Rhythm; Cold Temperature; Hormones; Humans; Magnetic Resonance Imaging; Male; Perception; Positron-Emission Tomography; Seasons; Skin Temperature; Swimming; Thermogenesis; Thermography; Young Adult
PubMed: 34755128
DOI: 10.1016/j.xcrm.2021.100408 -
Endocrine Reviews Jan 2020Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central... (Review)
Review
Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).
Topics: Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adult; Animals; Cell Plasticity; Energy Metabolism; Humans; Infant; Muscle, Skeletal
PubMed: 31638161
DOI: 10.1210/endrev/bnz007 -
Nature Aug 2019Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of...
Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.
Topics: Adipose Tissue, Brown; Amino Acid Transport Systems; Amino Acids, Branched-Chain; Animals; Cold Temperature; Energy Metabolism; Glucose Intolerance; Homeostasis; Humans; Male; Mice; Mitochondria; Mitochondrial Proteins; Obesity; Solute Carrier Proteins; Thermogenesis
PubMed: 31435015
DOI: 10.1038/s41586-019-1503-x -
American Journal of Physiology.... Mar 2021Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy... (Review)
Review
Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy expenditure. Some interventions such as cold and β-adrenergic drugs are able to activate BAT thermogenesis as well as promote differentiation of white adipocytes into brown-like cells (browning), enhancing the thermogenic activity of these cells. In this mini-review, we discuss new mechanisms related to BAT and energy expenditure. In this regard, we will also discuss recent studies that have revealed the existence of important secretory molecules from BAT "batokines" that act in autocrine, paracrine, and endocrine mechanisms, which in turn may explain some of the beneficial roles of BAT on whole body glucose and fat metabolism. Finally, we will discuss new insights related to BAT thermogenesis with an additional focus on the distinct features of BAT metabolism between rodents and humans.
Topics: Adipocytes, White; Adipose Tissue, Brown; Animals; Energy Metabolism; Glucose; Humans; Thermogenesis
PubMed: 33459179
DOI: 10.1152/ajpendo.00310.2020 -
Cells Nov 2021Obesity-associated metabolic abnormalities comprise a cluster of conditions including dyslipidemia, insulin resistance, diabetes and cardiovascular diseases that has... (Review)
Review
Obesity-associated metabolic abnormalities comprise a cluster of conditions including dyslipidemia, insulin resistance, diabetes and cardiovascular diseases that has affected more than 650 million people all over the globe. Obesity results from the accumulation of white adipose tissues mainly due to the chronic imbalance of energy intake and energy expenditure. A variety of approaches to treat or prevent obesity, including lifestyle interventions, surgical weight loss procedures and pharmacological approaches to reduce energy intake and increase energy expenditure have failed to substantially decrease the prevalence of obesity. Brown adipose tissue (BAT), the primary source of thermogenesis in infants and small mammals may represent a promising therapeutic target to treat obesity by promoting energy expenditure through non-shivering thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1). Since the confirmation of functional BAT in adult humans by several groups, approximately a decade ago, and its association with a favorable metabolic phenotype, intense interest on the significance of BAT in adult human physiology and metabolic health has emerged within the scientific community to explore its therapeutic potential for the treatment of obesity and metabolic diseases. A substantially decreased BAT activity in individuals with obesity indicates a role for BAT in the setting of human obesity. On the other hand, BAT mass and its prevalence correlate with lower body mass index (BMI), decreased age and lower glucose levels, leading to a lower incidence of cardio-metabolic diseases. The increased cold exposure in adult humans with undetectable BAT was associated with decreased body fat mass and increased insulin sensitivity. A deeper understanding of the role of BAT in human metabolic health and its interrelationship with body fat distribution and deciphering proper strategies to increase energy expenditure, by either increasing functional BAT mass or inducing white adipose browning, holds the promise for possible therapeutic avenues for the treatment of obesity and associated metabolic disorders.
Topics: Adipose Tissue, Brown; Animals; Exercise; Female; Gene Expression Profiling; Health; Humans; Male; MicroRNAs; Obesity; Sex Characteristics
PubMed: 34831253
DOI: 10.3390/cells10113030 -
Nature Metabolism Apr 2021Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease....
Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. Here, we determine the identity of perivascular adipocyte progenitors in mice and humans. In mice, thoracic PVAT develops from a fibroblastic lineage, consisting of progenitor cells (Pdgfra, Ly6a and Pparg) and preadipocytes (Pdgfra, Ly6a and Pparg), which share transcriptional similarity with analogous cell types in white adipose tissue. Interestingly, the aortic adventitia of adult animals contains a population of adipogenic smooth muscle cells (Myh11, Pdgfra and Pparg) that contribute to perivascular adipocyte formation. Similarly, human PVAT contains presumptive fibroblastic and smooth muscle-like adipocyte progenitor cells, as revealed by single-nucleus RNA sequencing. Together, these studies define distinct populations of progenitor cells for thermogenic PVAT, providing a foundation for developing strategies to augment brown fat activity.
Topics: Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipose Tissue, Brown; Animals; Animals, Newborn; Aorta; Blood Vessels; Cell Lineage; Fibroblasts; Gene Expression Regulation; Humans; Infant, Newborn; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Stem Cells; Thermogenesis
PubMed: 33846639
DOI: 10.1038/s42255-021-00380-0 -
Nature Jan 2023Multilocular adipocytes are a hallmark of thermogenic adipose tissue, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an...
Multilocular adipocytes are a hallmark of thermogenic adipose tissue, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3β) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3β is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER-LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3β have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3β is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3β associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3β-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.
Topics: Animals; Female; Humans; Mice; Adipocytes; Adipose Tissue, Brown; Calcium-Binding Proteins; Membrane Proteins; Placenta; Triglycerides; Endoplasmic Reticulum; Lipid Metabolism; Lipid Droplets; Fatty Acids; Hypothermia; Thermogenesis
PubMed: 36477540
DOI: 10.1038/s41586-022-05507-1 -
Cell Reports Jun 2022In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This...
In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the β-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.
Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Hepatocytes; Ketone Bodies; Lipolysis; PPAR alpha
PubMed: 35675775
DOI: 10.1016/j.celrep.2022.110910 -
Frontiers in Endocrinology 2022Sarcopenic obesity is defined as a multifactorial disease in aging with decreased body muscle, decreased muscle strength, decreased independence, increased fat mass, due... (Review)
Review
Sarcopenic obesity is defined as a multifactorial disease in aging with decreased body muscle, decreased muscle strength, decreased independence, increased fat mass, due to decreased physical activity, changes in adipokines and myokines, and decreased satellite cells. People with sarcopenic obesity cause harmful changes in myokines and adipokines. These changes are due to a decrease interleukin-10 (IL-10), interleukin-15 (IL-15), insulin-like growth factor hormone (IGF-1), irisin, leukemia inhibitory factor (LIF), fibroblast growth factor-21 (FGF-21), adiponectin, and apelin. While factors such as myostatin, leptin, interleukin-6 (IL-6), interleukin-8 (IL-8), and resistin increase. The consequences of these changes are an increase in inflammatory factors, increased degradation of muscle proteins, increased fat mass, and decreased muscle tissue, which exacerbates sarcopenia obesity. In contrast, exercise, especially strength training, reverses this process, which includes increasing muscle protein synthesis, increasing myogenesis, increasing mitochondrial biogenesis, increasing brown fat, reducing white fat, reducing inflammatory factors, and reducing muscle atrophy. Since some people with chronic diseases are not able to do high-intensity strength training, exercises with blood flow restriction (BFR) are newly recommended. Numerous studies have shown that low-intensity BFR training produces the same increase in hypertrophy and muscle strength such as high-intensity strength training. Therefore, it seems that exercise interventions with BFR can be an effective way to prevent the exacerbation of sarcopenia obesity. However, due to limited studies on adipokines and exercises with BFR in people with sarcopenic obesity, more research is needed.
Topics: Adipokines; Adipose Tissue, Brown; Exercise Therapy; Humans; Interleukin-6; Obesity; Sarcopenia
PubMed: 35250869
DOI: 10.3389/fendo.2022.811751 -
Nature Cell Biology Jan 2024Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the...
Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.
Topics: Humans; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Cell Differentiation; Energy Metabolism; Obesity
PubMed: 38195707
DOI: 10.1038/s41556-023-01311-9