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Theranostics 2022Brown and beige fat protect against cold environments and obesity by catabolizing stored energy to generate heat. This process is achieved by controlling...
Brown and beige fat protect against cold environments and obesity by catabolizing stored energy to generate heat. This process is achieved by controlling thermogenesis-related gene expression and the development of brown/beige fat through the induction of transcription factors, most notably PPARγ. However, the cofactors that induce the expression of thermogenic genes with PPARγ are still not well understood. In this study, we explored the role of SOX4 in adaptive thermogenesis and its relationship with PPARγ. Whole transcriptome deep sequencing (RNA-seq) analysis of inguinal subcutaneous white adipose tissue (iWAT) after cold stimulation was performed to identify genes with differential expression in mice. Indirect calorimetry detected oxygen consumption rate and heat generation. mRNA levels were analyzed by qPCR assays. Proteins were detected by immunoblotting and immunofluorescence. Interaction of proteins was detected by endogenous and exogenous Co-IP. ChIP-qPCR, FAIRE assay and luciferase reporter assays were used to investigate transcriptional regulation. SOX4 was identified as the main transcriptional effector of thermogenesis. Mice with either adipocyte-specific or UCP1 cells deletion of SOX4 exhibited significant cold intolerance, decreased energy expenditure, and beige adipocyte formation, which was attributed to decreased thermogenic gene expression. In addition, these mice developed obesity on a high-fat diet, with severe hepatic steatosis, insulin resistance, and inflammation. At the cell level, loss of SOX4 from preadipocytes inhibited the development of beige adipocytes, and loss of SOX4 from mature beige adipocytes reduced the expression of thermogenesis-related genes and energy metabolism. Mechanistically, SOX4 stimulated the transcriptional activity of by binding to PPARγ and activating its transcriptional function. These actions of SOX4 were, at least partly, mediated by recruiting PRDM16 to PPARγ, thus forming a transcriptional complex to elevate the expression of thermogenic genes. SOX4, as a coactivator of PPARγ, drives the thermogenic gene expression program and thermogenesis of beige fat, promoting energy expenditure. It has important physiological significance in resisting cold and obesity.
Topics: Animals; Mice; Adipocytes, Beige; DNA-Binding Proteins; Obesity; PPAR gamma; Thermogenesis; Transcription Factors
PubMed: 36451857
DOI: 10.7150/thno.77102 -
Annual Review of Physiology Feb 2022Mitochondria of all tissues convert various metabolic substrates into two forms of energy: ATP and heat. Historically, the primary focus of research in mitochondrial... (Review)
Review
Mitochondria of all tissues convert various metabolic substrates into two forms of energy: ATP and heat. Historically, the primary focus of research in mitochondrial bioenergetics was on the mechanisms of ATP production, while mitochondrial thermogenesis received significantly less attention. Nevertheless, mitochondrial heat production is crucial for the maintenance of body temperature, regulation of the pace of metabolism, and prevention of oxidative damage to mitochondria and the cell. In addition, mitochondrial thermogenesis has gained significance as a pharmacological target for treating metabolic disorders. Mitochondria produce heat as the result of H leak across their inner membrane. This review provides a critical assessment of the current field of mitochondrial H leak and thermogenesis, with a focus on the molecular mechanisms involved in the function and regulation of uncoupling protein 1 and the ADP/ATP carrier, the two proteins that mediate mitochondrial H leak.
Topics: Energy Metabolism; Humans; Mitochondria; Mitochondrial Proteins; Thermogenesis; Uncoupling Protein 1
PubMed: 34758268
DOI: 10.1146/annurev-physiol-021119-034405 -
Cell Metabolism Jun 2022Homeostatic thermogenesis is an essential protective feature of endotherms. However, the specific neuronal types involved in cold-induced thermogenesis remain largely...
Homeostatic thermogenesis is an essential protective feature of endotherms. However, the specific neuronal types involved in cold-induced thermogenesis remain largely unknown. Using functional magnetic resonance imaging and in situ hybridization, we screened for cold-sensitive neurons and found preprodynorphin (PDYN)-expressing cells in the dorsal medial region of the ventromedial hypothalamus (dmVMH) to be a candidate. Subsequent in vivo calcium recording showed that cold temperature activates dmVMH neurons, whereas hot temperature suppresses them. In addition, optogenetic activation of dmVMH neurons increases the brown adipose tissue and core body temperature, heart rate, and blood pressure, whereas optogenetic inhibition shows opposite effects, supporting their role in homeostatic thermogenesis. Furthermore, we found that dmVMH neurons are linked to known thermoregulatory circuits. Importantly, dmVMH neurons also show activation during mouse social interaction, and optogenetic inhibition suppresses social interaction and associated hyperthermia. Together, our study describes dual functions of dmVMH neurons that allow coordinated regulation of body temperature and social behaviors.
Topics: Adipose Tissue, Brown; Animals; Cold Temperature; Hyperthermia, Induced; Hypothalamus; Mice; Neurons; Social Interaction; Thermogenesis
PubMed: 35675799
DOI: 10.1016/j.cmet.2022.05.002 -
Biological Chemistry Aug 2020The proper production, degradation, folding and activity of proteins, proteostasis, is essential for any cellular function. From single cell organisms to humans,... (Review)
Review
The proper production, degradation, folding and activity of proteins, proteostasis, is essential for any cellular function. From single cell organisms to humans, selective pressures have led to the evolution of adaptive programs that ensure proteins are properly produced and disposed of when necessary. Environmental factors such as temperature, nutrient availability, pathogens as well as predators have greatly influenced the development of mechanisms such as the unfolded protein response, endoplasmic reticulum-associated protein degradation and autophagy, working together in concert to secure cellular proteostasis. In our modern society, the metabolic systems of the human body face the distinct challenge of changed diets, chronic overnutrition and sedentary lifestyles. Obesity and excess white adipose tissue accumulation are linked to a cluster of metabolic diseases and disturbed proteostasis is a common feature. Conversely, processes that promote energy expenditure such as exercise, shivering as well as non-shivering thermogenesis by brown adipose tissue (BAT) and beige adipocytes counteract metabolic dysfunction. Here we review the basic concepts of proteostasis in obesity-linked metabolic diseases and focus on adipocytes, which are critical regulators of mammalian energy metabolism.
Topics: Humans; Obesity; Proteostasis; Thermogenesis
PubMed: 32061163
DOI: 10.1515/hsz-2019-0427 -
Adipocyte Dec 2023Brown adipocytes were proposed to reverse metabolic conditions such as obesity and diabetes, which make them potential for therapeutic applications. Brown adipocytes and... (Review)
Review
Brown adipocytes were proposed to reverse metabolic conditions such as obesity and diabetes, which make them potential for therapeutic applications. Brown adipocytes and browning process are capable of thermogenesis, the uncoupling metabolism which allows them to promote balanced energy expenditure, a fundamental mechanism for improving metabolic disorders. Thermogenesis process is not only performed by the thermogenin UCPs within the mitochondria, but instead, is globally regulated within brown and browning adipose tissues, which induces signalling molecules that can be sent to nearby and distant tissues to generate systemic effects on metabolism. This review highlights thermogenesis and describes the crosstalk between different organelles within browning and brown adipocytes, as well as their interorgan axes to regulate whole body metabolism. Finally, browning and thermogenesis activation will also be discussed in terms of physiological conditions, in which, we propose that thermogenesis and functional activities of brown adipocytes should be considered individually in future clinical application.
Topics: Adipocytes, Brown; Mitochondria; Energy Metabolism; Adipose Tissue; Thermogenesis
PubMed: 37488770
DOI: 10.1080/21623945.2023.2237164 -
Ageing Research Reviews Jun 2023Adipose tissue undergoes significant changes in structure, composition, and function with age including altered adipokine secretion, decreased adipogenesis, altered... (Review)
Review
Adipose tissue undergoes significant changes in structure, composition, and function with age including altered adipokine secretion, decreased adipogenesis, altered immune cell profile and increased inflammation. Considering the role of adipose tissue in whole-body energy homeostasis, age-related dysfunction in adipose metabolism could potentially contribute to an increased risk for metabolic diseases and accelerate the onset of other age-related diseases. Increasing cellular energy expenditure in adipose tissue, also referred to as thermogenesis, has emerged as a promising strategy to improve adipose metabolism and treat obesity-related metabolic disorders. However, translating this strategy to the aged population comes with several challenges such as decreased thermogenic response and the paucity of safe pharmacological agents to activate thermogenesis. This mini-review aims to discuss the current body of knowledge on aging and thermogenesis and highlight the unexplored opportunities (cellular mechanisms and secreted factors) to target thermogenic mechanisms for delaying aging and age-related diseases. Finally, we also discuss the emerging role of thermogenic adipocytes in healthspan and lifespan extension.
Topics: Humans; Aged; Adipose Tissue, Brown; Obesity; Energy Metabolism; Aging; Thermogenesis
PubMed: 36924940
DOI: 10.1016/j.arr.2023.101912 -
Cell Mar 2022Maintenance of body temperature is intimately tied to energy expenditure and body weight regulation. In this issue of Cell, Li, Wang, et al. discovered that localized...
Maintenance of body temperature is intimately tied to energy expenditure and body weight regulation. In this issue of Cell, Li, Wang, et al. discovered that localized hyperthermia induces the thermogenic program to increase energy expenditure and decrease body weight in mice and humans.
Topics: Adipocytes; Animals; Body Weight; Energy Metabolism; Mice; Thermogenesis
PubMed: 35303425
DOI: 10.1016/j.cell.2022.02.024 -
Frontiers in Endocrinology 2023Brown and beige adipose tissues regulate body energy expenditure through adaptive thermogenesis, which converts energy into heat by oxidative phosphorylation uncoupling.... (Review)
Review
Brown and beige adipose tissues regulate body energy expenditure through adaptive thermogenesis, which converts energy into heat by oxidative phosphorylation uncoupling. Although promoting adaptive thermogenesis has been demonstrated to be a prospective strategy for obesity control, there are few methods for increasing adipose tissue thermogenesis in a safe and effective way. Histone deacetylase (HDAC) is a category of epigenetic modifying enzymes that catalyzes deacetylation on both histone and non-histone proteins. Recent studies illustrated that HDACs play an important role in adipose tissue thermogenesis through modulating gene transcription and chromatin structure as well as cellular signals transduction in both deacetylation dependent or independent manners. Given that different classes and subtypes of HDACs show diversity in the mechanisms of adaptive thermogenesis regulation, we systematically summarized the effects of different HDACs on adaptive thermogenesis and their underlying mechanisms in this review. We also emphasized the differences among HDACs in thermogenesis regulation, which will help to find new efficient anti-obesity drugs targeting specific HDAC subtypes.
Topics: Adipose Tissue; Adipose Tissue, Beige; Anti-Obesity Agents; Histone Deacetylases; Thermogenesis
PubMed: 36875455
DOI: 10.3389/fendo.2023.1124408 -
Nature Metabolism Jul 2023Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating...
Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating metabolite exchange remains unclear. Here, we quantified metabolite exchange in BAT and skeletal muscle by arteriovenous metabolomics during cold exposure in fed male mice. This identified unexpected metabolites consumed, released and shared between organs. Quantitative analysis of tissue fluxes showed that glucose and lactate provide ~85% of carbon for adaptive thermogenesis and that cold and CL316,243 trigger markedly divergent fuel utilization profiles. In cold adaptation, BAT also dramatically increases nitrogen uptake by net consuming amino acids, except glutamine. Isotope tracing and functional studies suggest glutamine catabolism concurrent with synthesis via glutamine synthetase, which avoids ammonia buildup and boosts fuel oxidation. These data underscore the ability of BAT to function as a glucose and amino acid sink and provide a quantitative and comprehensive landscape of BAT fuel utilization to guide translational studies.
Topics: Male; Animals; Mice; Adipose Tissue, Brown; Glutamine; Glucose; Thermogenesis; Muscle, Skeletal
PubMed: 37337122
DOI: 10.1038/s42255-023-00825-8 -
Adaptive thermogenesis by dietary n-3 polyunsaturated fatty acids: Emerging evidence and mechanisms.Biochimica Et Biophysica Acta.... Jan 2019Brown/beige fat plays a crucial role in maintaining energy homeostasis through non-shivering thermogenesis in response to cold temperature and excess nutrition (adaptive... (Review)
Review
Brown/beige fat plays a crucial role in maintaining energy homeostasis through non-shivering thermogenesis in response to cold temperature and excess nutrition (adaptive thermogenesis). Although numerous molecular and genetic regulators have been identified, relatively little information is available regarding thermogenic dietary molecules. Recently, a growing body of evidence suggests that high consumption of n-3 polyunsaturated fatty acids (PUFA) or activation of GPR120, a membrane receptor of n-3 PUFA, stimulate adaptive thermogenesis. In this review, we summarize the emerging evidence that n-3 PUFA promote brown/beige fat formation and highlight the potential mechanisms whereby n-3 PUFA require GPR120 as a signaling platform or act independently. Human clinical trials are revisited in the context of energy expenditure. Additionally, we explore some future perspective that n-3 PUFA intake might be a useful strategy to boost or sustain metabolic activities of brown/beige fat at different lifecycle stages of pregnancy and senescence. Given that a high ratio of n-6/n-3 PUFA intake is associated with the development of obesity and type 2 diabetes, understanding the impact of n-6/n-3 ratio on energy expenditure and adaptive thermogenesis will inform the implementation of a novel nutritional strategy for preventing obesity.
Topics: Animals; Dietary Fats; Dietary Supplements; Fatty Acids, Omega-3; Humans; Thermogenesis
PubMed: 29679742
DOI: 10.1016/j.bbalip.2018.04.012