-
Biology Open Dec 2020Mechanisms that enhance energy expenditure are attractive therapeutic targets for obesity. Previously we have demonstrated that mice lacking are leaner, exhibit...
Mechanisms that enhance energy expenditure are attractive therapeutic targets for obesity. Previously we have demonstrated that mice lacking are leaner, exhibit increased energy expenditure, and are protected against diet-induced obesity. In this study, we further defined the physiological role of deficiency in regulating mitochondrial function and energy expenditure in both white and brown adipose tissue. We observed that deficient mice (under normal chow diet) had comparable amount of white fat mass but reduced white adipocyte size as compared to wild-type mice. Subsequent and studies suggest enhanced lipolysis, and not impaired lipogenesis or energy utilization, contributes to this phenotype. In contrast to white adipose tissue, there were no obvious morphological differences in brown adipose tissue between wild-type and knockout mice. However, mitochondria isolated from brown fat of deficient mice had significantly higher rates of free fatty acid-mediated uncoupling. This suggests that enhanced fuel availability via white adipose tissue lipolysis may perpetuate elevated brown adipose tissue energy expenditure and contributes to the lean phenotype observed in deficient mice.
Topics: Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Biomarkers; CD47 Antigen; Energy Metabolism; Fatty Acids, Nonesterified; Gene Knockdown Techniques; Lipolysis; Male; Mice; Mice, Knockout; Mitochondria
PubMed: 33328190
DOI: 10.1242/bio.056747 -
Diabetes & Metabolism Journal Nov 2021Brown adipose tissue (BAT) is a specialized tissue for nonshivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in... (Review)
Review
Brown adipose tissue (BAT) is a specialized tissue for nonshivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. Moreover, several remarkable advancements have been made in brown fat biology over the past decade: The molecular and functional analyses of inducible thermogenic adipocytes (socalled beige adipocytes) arising from a developmentally different lineage from classical brown adipocytes have been accelerated. In addition to a well-established thermogenic activity of uncoupling protein 1 (UCP1), several alternative thermogenic mechanisms have been discovered, particularly in beige adipocytes. It has become clear that BAT influences other peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator, other than for thermogenesis. This notion is supported by discovering that various paracrine and endocrine factors are secreted from BAT. We review the current understanding of BAT pathophysiology, particularly focusing on its role as a metabolic regulator in small rodents and also in humans.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Energy Metabolism; Thermogenesis; Uncoupling Protein 1
PubMed: 34176254
DOI: 10.4093/dmj.2020.0291 -
Trends in Endocrinology and Metabolism:... May 2015Brown fat is highly active in fuel oxidation and dissipates chemical energy through uncoupling protein (UCP)1-mediated heat production. Activation of brown fat leads to... (Review)
Review
Brown fat is highly active in fuel oxidation and dissipates chemical energy through uncoupling protein (UCP)1-mediated heat production. Activation of brown fat leads to increased energy expenditure, reduced adiposity, and lower plasma glucose and lipid levels, thus contributing to better homeostasis. Uncoupled respiration and thermogenesis have been considered to be responsible for the metabolic benefits of brown adipose tissue. Recent studies have demonstrated that brown adipocytes also secrete factors that act locally and systemically to influence fuel and energy metabolism. This review discusses the evidence supporting a thermogenesis-independent role of brown fat, particularly through its release of secreted factors, and their implications in physiology and therapeutic development.
Topics: Adipocytes, Brown; Adiponectin; Adipose Tissue, Brown; Animals; Bone Morphogenetic Proteins; Energy Metabolism; Fibroblast Growth Factors; Homeostasis; Humans; Ion Channels; Mitochondrial Proteins; Nerve Growth Factor; Neuregulins; Obesity; Thermogenesis; Uncoupling Protein 1; Vascular Endothelial Growth Factor A
PubMed: 25843910
DOI: 10.1016/j.tem.2015.03.002 -
Frontiers in Endocrinology 2020Brown fat and beige fat are known as thermogenic fat due to their contribution to non-shivering thermogenesis in mammals following cold stimulation. Beige fat is unique... (Review)
Review
Brown fat and beige fat are known as thermogenic fat due to their contribution to non-shivering thermogenesis in mammals following cold stimulation. Beige fat is unique due to its origin and its development in white fat. Subsequently, both brown fat and beige fat have become viable targets to combat obesity. Over the last few decades, most therapeutic strategies have been focused on the canonical pathway of thermogenic fat activation via the β3-adrenergic receptor (AR). Notwithstanding, administering β3-AR agonists often leads to side effects including hypertension and particularly cardiovascular disease. It is thus imperative to search for alternative therapeutic approaches to combat obesity. In this review, we discuss the current challenges in the field with respect to stimulating brown/beige fat thermogenesis. Additionally, we include a summary of other newly discovered pathways, including non-AR signaling- and non-UCP1-dependent mechanisms, which could be potential targets for the treatment of obesity and its related metabolic diseases.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Animals; Anti-Obesity Agents; Humans; Obesity; Receptors, Adrenergic, beta-3; Signal Transduction; Thermogenesis
PubMed: 32351446
DOI: 10.3389/fendo.2020.00185 -
American Journal of Physiology. Cell... Jun 2022Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and... (Review)
Review
Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardiovascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ("yo-yo effect" or weight cycling). Strategies that increase REE are attractive treatment options. Brown fat tissue engages in nonshivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g., 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (chimeric antigen receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacological mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.
Topics: Adipose Tissue, Brown; Cell- and Tissue-Based Therapy; Energy Metabolism; Humans; Obesity; T-Lymphocytes; Thermogenesis; Uncoupling Protein 1
PubMed: 35476503
DOI: 10.1152/ajpcell.00034.2022 -
Biochimica Et Biophysica Acta.... Jan 2019White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic... (Review)
Review
White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic (beige/brite) adipocytes in WAT dissipate energy via Ucp1 to maintain body temperature. BAT and subcutaneous WAT develop perinatally while visceral WAT forms after birth from precursors expressing distinct markers, such as Myf5, Pref-1, Wt1, and Prx1, depending on the anatomical location. In addition to the embryonic adipose precursors, a pool of endothelial cells or mural cells expressing Pparγ, Pdgfrβ, Sma and Zfp423 may become adipocytes during WAT expansion in adults. Several markers, such as Cd29, Cd34, Sca1, Cd24, Pdgfrα and Pref-1 are detected in adult WAT SVF cells that can be differentiated into adipocytes. However, potential heterogeneity and differences in developmental stage of these cells are not clear. Beige cells form in a depot- and condition-specific manner by de novo differentiation of precursors or by transdifferentiation. Thermogenic gene activation in brown and beige adipocytes relies on common transcriptional machinery that includes Prdm16, Zfp516, Pgc1α and Ebf2. Moreover, through changing the chromatin landscape, histone methyltransferases, such as Mll3/4 and Ehmt1, as well as demethylases, such as Lsd1, play an important role in regulating the thermogenic gene program. With the presence of BAT and beige/brite cells in human adults, increasing thermogenic activity of BAT and BAT-like tissues may help promote energy expenditure to combat obesity.
Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Epigenesis, Genetic; Humans
PubMed: 29704660
DOI: 10.1016/j.bbalip.2018.04.016 -
International Journal of Molecular... Jul 2022Mammalian adipose tissue can be divided into white and brown adipose tissue based on its colour, location, and cellular structure. Certain conditions, such as... (Review)
Review
Mammalian adipose tissue can be divided into white and brown adipose tissue based on its colour, location, and cellular structure. Certain conditions, such as sympathetic nerve excitement, can induce the white adipose adipocytes into a new type of adipocytes, known as beige adipocytes. The process, leading to the conversion of white adipocytes into beige adipocytes, is called white fat browning. The dynamic balance between white and beige adipocytes is closely related to the body's metabolic homeostasis. Studying the signal transduction pathways of the white fat browning might provide novel ideas for the treatment of obesity and alleviation of obesity-related glucose and lipid metabolism disorders. This article aimed to provide an overview of recent advances in understanding white fat browning and the role of BAT in lipid metabolism.
Topics: Adipocytes, White; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Energy Metabolism; Humans; Lipid Metabolism; Mammals; Obesity; Thermogenesis
PubMed: 35886989
DOI: 10.3390/ijms23147641 -
The Journal of Pharmacology and... Jun 2018Indomethacin, a nonsteroidal anti-inflammatory drug, has been shown to induce white adipocyte differentiation; however, its roles in brown adipocyte differentiation and...
Indomethacin, a nonsteroidal anti-inflammatory drug, has been shown to induce white adipocyte differentiation; however, its roles in brown adipocyte differentiation and activation in brown adipose tissue (BAT) and obesity are unknown. To address this issue, we treated mouse brown preadipocytes with different doses of indomethacin, and delivered indomethacin to interscapular BAT (iBAT) of obese mice using implanted osmotic pumps. Indomethacin dose dependently increased brown preadipocyte differentiation and upregulated both mRNA and protein expression of uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor (PPAR) coactivator 1-alpha. The mechanistic study showed that indomethacin significantly activated the reporter driven by the PPAR response element, indicating that indomethacin may work as a PPAR agonist in this cell line. Consistently, indomethacin significantly decreased iBAT mass and fasting blood glucose levels in high-fat diet-induced obesity (DIO) mice. Histologic analysis showed that brown adipocytes of indomethacin-treated mice contained smaller lipid droplets compared with control mice, suggesting that indomethacin alleviated the whitening of BAT induced by the high-fat diet. Moreover, indomethacin significantly increased UCP1 mRNA expression in iBAT. Taken together, this study indicates that indomethacin can promote mouse brown adipocyte differentiation, and might increase brown fat and glucose oxidation capacity in DIO mice.
Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cell Differentiation; Cell Line; Indomethacin; Mice; Obesity
PubMed: 29567865
DOI: 10.1124/jpet.117.246256 -
Current Opinion in Endocrinology,... Apr 2010Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it... (Review)
Review
PURPOSE OF REVIEW
Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure. This review evaluates the recent discoveries regarding the identification of functional BAT in adult humans and its potential as a therapy for obesity and diabetes.
RECENT FINDINGS
Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry, and gene and protein expression assays to prove conclusively that adult humans have functional BAT. This has occurred against a backdrop of basic studies defining the origins of BAT, new components of its transcriptional regulation, and the role of hormones in stimulation of BAT growth and differentiation.
SUMMARY
Adult humans have functional BAT, a new target for antiobesity and antidiabetes therapies focusing on increasing energy expenditure. Future studies will refine the methodologies used to measure BAT mass and activity, expand our knowledge of critical-control points in BAT regulation, and focus on testing pharmacological agents that increase BAT thermogenesis and help achieve long-lasting weight loss and an improved metabolic profile.
Topics: Adipose Tissue, Brown; Animals; Anti-Obesity Agents; Body Fat Distribution; Cell Transdifferentiation; Cell- and Tissue-Based Therapy; Diabetes Mellitus; Humans; Models, Biological; Obesity; Thermogenesis
PubMed: 20160646
DOI: 10.1097/MED.0b013e328337a81f -
Cell Reports Dec 2022In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests...
In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)β/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARβ/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure.
Topics: Mice; Animals; Adipose Tissue, Brown; PPAR-beta; Lipoproteins, VLDL; Thermogenesis; Adipocytes, Brown; Mice, Knockout; Mammals
PubMed: 36516764
DOI: 10.1016/j.celrep.2022.111806