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Frontiers in Endocrinology 2023Obesity occurs when overall energy intake surpasses energy expenditure. White adipose tissue is an energy storage site, whereas brown and beige adipose tissues... (Review)
Review
Obesity occurs when overall energy intake surpasses energy expenditure. White adipose tissue is an energy storage site, whereas brown and beige adipose tissues catabolize stored energy to generate heat, which protects against obesity and obesity-associated metabolic disorders. Metabolites are substrates in metabolic reactions that act as signaling molecules, mediating communication between metabolic sites (i.e., adipose tissue, skeletal muscle, and gut microbiota). Although the effects of metabolites from peripheral organs on adipose tissue have been extensively studied, their role in regulating adipocyte thermogenesis requires further investigation. Skeletal muscles and intestinal microorganisms are important metabolic sites in the body, and their metabolites play an important role in obesity. In this review, we consolidated the latest research on skeletal muscles and gut microbiota-derived metabolites that potentially promote adipocyte thermogenesis. Skeletal muscles can release lactate, kynurenic acid, inosine, and β-aminoisobutyric acid, whereas the gut secretes bile acids, butyrate, succinate, cinnabarinic acid, urolithin A, and asparagine. These metabolites function as signaling molecules by interacting with membrane receptors or controlling intracellular enzyme activity. The mechanisms underlying the reciprocal exchange of metabolites between the adipose tissue and other metabolic organs will be a focal point in future studies on obesity. Furthermore, understanding how metabolites regulate adipocyte thermogenesis will provide a basis for establishing new therapeutic targets for obesity.
Topics: Humans; Adipose Tissue, Brown; Gastrointestinal Microbiome; Adipocytes; Obesity; Thermogenesis; Muscle, Skeletal
PubMed: 37867516
DOI: 10.3389/fendo.2023.1265175 -
Current Opinion in Genetics &... Aug 2023White adipocytes possess extraordinary plasticity with an unparalleled capacity to expand in size with nutritional overload. Several lines of evidence indicate that... (Review)
Review
White adipocytes possess extraordinary plasticity with an unparalleled capacity to expand in size with nutritional overload. Several lines of evidence indicate that limitations to this plasticity, as found in both lipodystrophy and obesity, drive several of the comorbidities of these disease, thereby underscoring the need to understand the mechanisms of healthy and unhealthy adipose expansion. Recent single-cell technologies and studies of isolated adipocytes have allowed researchers to gain insight into the molecular mechanisms of adipocyte plasticity. Here, we review current insight into the effect of nutritional overload on white adipocyte gene expression and function. We review the role of adipocyte size and heterogeneity and discuss the challenges and future directions.
Topics: Humans; Obesity; Adipocytes; Adiposity; Gene Expression
PubMed: 37331148
DOI: 10.1016/j.gde.2023.102060 -
Nature Metabolism May 2024White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic...
White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents. Additionally, we identify C19orf12 as a differentiation-induced adipocyte lipid droplet protein that interacts with the translocase of the outer membrane complex of lipid droplet-associated mitochondria and regulates adipocyte lipid storage by determining the capacity of mitochondria to metabolize fatty acids. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field.
Topics: Humans; Adipogenesis; Proteomics; Lipid Metabolism; Mitochondria; Lipid Droplets; Proteome; Adipocytes; Cell Differentiation
PubMed: 38565923
DOI: 10.1038/s42255-024-01025-8 -
Adipocyte Dec 2023Alterations of the extracellular matrix contribute to adipose tissue dysfunction in metabolic disease. We studied the role of matrix density in regulating human...
Alterations of the extracellular matrix contribute to adipose tissue dysfunction in metabolic disease. We studied the role of matrix density in regulating human adipocyte phenotype in a tunable hydrogel culture system. Lipid accumulation was maximal in intermediate hydrogel density of 5 weight %, relative to 3% and 10%. Adipogenesis and lipid and oxidative metabolic gene pathways were enriched in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways were enriched in 3% hydrogels. These data demonstrate that the intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. These observations contribute to a growing literature describing the role of matrix density in regulating adipose tissue function.
Topics: Humans; Adipocytes; Adipose Tissue; Adipogenesis; Hydrogels; Phenotype; Lipids
PubMed: 37815174
DOI: 10.1080/21623945.2023.2268261 -
Frontiers in Endocrinology 2023An energy imbalance cause obesity: more energy intake or less energy expenditure, or both. Obesity could be the origin of many metabolic disorders, such as type 2... (Review)
Review
An energy imbalance cause obesity: more energy intake or less energy expenditure, or both. Obesity could be the origin of many metabolic disorders, such as type 2 diabetes and cardiovascular disease. UCP1 (uncoupling protein1), which is highly and exclusively expressed in the thermogenic adipocytes, including beige and brown adipocytes, can dissipate proton motive force into heat without producing ATP to increase energy expenditure. It is an attractive strategy to combat obesity and its related metabolic disorders by increasing non-shivering adipocyte thermogenesis. Adipocyte thermogenesis has recently been reported to be regulated by several new genes. This work provided novel and potential targets to activate adipocyte thermogenesis and resist obesity, such as secreted proteins ADISSP and EMC10, enzyme SSU72, etc. In this review, we have summarized the latest research on adipocyte thermogenesis regulation to shed more light on this topic.
Topics: Humans; Diabetes Mellitus, Type 2; Genes, Regulator; Adipocytes, Brown; Obesity; Thermogenesis; Phosphoprotein Phosphatases; Membrane Proteins
PubMed: 37680891
DOI: 10.3389/fendo.2023.1250487 -
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 -
Nature Reviews. Urology Oct 2023Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical... (Review)
Review
Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical observations, including effects of diet and lifestyle, systemic changes in energy balance and hormonal regulation and activation of signalling by growth factors and cytokines and other components of the immune system. Over the past decade, research on obesity has shifted towards investigating the role of peri-prostatic white adipose tissue as an important source of locally produced factors that stimulate prostate cancer progression. Cells that comprise white adipose tissue, the adipocytes and their progenitor adipose stromal cells (ASCs), which proliferate to accommodate white adipose tissue expansion in obesity, have been identified as important drivers of obesity-associated cancer progression. Accumulating evidence suggests that adipocytes are a source of lipids that are used by adjacent prostate cancer cells. However, results of preclinical studies indicate that ASCs promote tumour growth by remodelling extracellular matrix and supporting neovascularization, contributing to the recruitment of immunosuppressive cells, and inducing epithelial-mesenchymal transition through paracrine signalling. Because epithelial-mesenchymal transition is associated with cancer chemotherapy resistance and metastasis, ASCs are considered to be potential targets of therapies that could be developed to suppress cancer aggressiveness in patients with obesity.
Topics: Male; Humans; Adipose Tissue; Adipocytes; Obesity; Prostatic Neoplasms; Neovascularization, Pathologic
PubMed: 37198266
DOI: 10.1038/s41585-023-00764-9 -
Cells Sep 2023Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte...
Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.
Topics: Animals; Humans; Mice; Adipocytes; Autophagy; DNA, Mitochondrial; Inflammation; Interferon Type I; Membrane Proteins
PubMed: 37830559
DOI: 10.3390/cells12192345 -
Nature Communications Nov 2023Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms...
Sympathetic innervation is essential for the development of functional beige fat that maintains body temperature and metabolic homeostasis, yet the molecular mechanisms controlling this innervation remain largely unknown. Here, we show that adipocyte YAP/TAZ inhibit sympathetic innervation of beige fat by transcriptional repression of neurotropic factor S100B. Adipocyte-specific loss of Yap/Taz induces S100b expression to stimulate sympathetic innervation and biogenesis of functional beige fat both in subcutaneous white adipose tissue (WAT) and browning-resistant visceral WAT. Mechanistically, YAP/TAZ compete with C/EBPβ for binding to the zinc finger-2 domain of PRDM16 to suppress S100b transcription, which is released by adrenergic-stimulated YAP/TAZ phosphorylation and inactivation. Importantly, Yap/Taz loss in adipocytes or AAV-S100B overexpression in visceral WAT restricts both age-associated and diet-induced obesity, and improves metabolic homeostasis by enhancing energy expenditure of mice. Together, our data reveal that YAP/TAZ act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
Topics: Mice; Animals; Adipose Tissue, Beige; Transcription Factors; Adipocytes; Obesity; Adipose Tissue, White; Adipose Tissue, Brown; Thermogenesis
PubMed: 37925548
DOI: 10.1038/s41467-023-43021-8 -
Nature Reviews. Endocrinology Nov 2023Adipose tissue is a dynamic component of the bone marrow, regulating skeletal remodelling and secreting paracrine and endocrine factors that can affect haematopoiesis,... (Review)
Review
Adipose tissue is a dynamic component of the bone marrow, regulating skeletal remodelling and secreting paracrine and endocrine factors that can affect haematopoiesis, as well as potentially nourishing the bone marrow during periods of stress. Bone marrow adipose tissue is regulated by multiple factors, but particularly nutrient status. In this Review, we examine how bone marrow adipocytes originate, their function in normal and pathological states and how bone marrow adipose tissue modulates whole-body homoeostasis through actions on bone cells, haematopoietic stem cells and extra-medullary adipocytes during nutritional challenges. We focus on both rodent models and human studies to help understand the unique marrow adipocyte, its response to the external nutrient environment and its effects on the skeleton. We finish by addressing some critical questions that to date remain unanswered.
Topics: Humans; Adipocytes; Adipose Tissue; Bone Marrow; Bone Marrow Cells; Obesity; Weight Loss
PubMed: 37587198
DOI: 10.1038/s41574-023-00879-4