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Science Translational Medicine Nov 2023Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive... (Review)
Review
Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.
Topics: Humans; Obesity; Adipose Tissue; Inflammation
PubMed: 37992150
DOI: 10.1126/scitranslmed.adf9382 -
Nature Communications Feb 2024Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate...
Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.
Topics: Animals; Male; Mice; Adipocytes; Adipocytes, Beige; Adipogenesis; Adipose Tissue; Adipose Tissue, White; Macrophages; Obesity; Thermogenesis
PubMed: 38388532
DOI: 10.1038/s41467-024-45899-4 -
Diabetes Aug 2023Obesity is a global health threat, and the induction of white adipose tissue (WAT) browning presents a promising therapeutic method for it. Recent publications revealed...
UNLABELLED
Obesity is a global health threat, and the induction of white adipose tissue (WAT) browning presents a promising therapeutic method for it. Recent publications revealed the essential role of protein arginine methyltransferase 4 (PRMT4) in lipid metabolism and adipogenesis, but its involvement in WAT browning has not been investigated. Our initial studies found that the expression of PRMT4 in adipocytes was upregulated in cold-induced WAT browning but downregulated in obesity. Besides, PRMT4 overexpression in inguinal adipose tissue accelerated WAT browning and thermogenesis to protect against high-fat diet-induced obesity and metabolic disruptions. Mechanistically, our work demonstrated that PRMT4 methylated peroxisome proliferator-activated receptor-γ (PPARγ) on Arg240 to enhance its interaction with the coactivator PR domain-containing protein 16 (PRDM16), leading to the increased expression of thermogenic genes. Taken together, our results uncover the essential role of the PRMT4/PPARγ/PRDM16 axis in the pathogenesis of WAT browning.
ARTICLE HIGHLIGHTS
Protein arginine methyltransferase 4 (PRMT4) expression was upregulated during cold exposure and negatively correlated with body mass of mice and humans. PRMT4 overexpression in inguinal white adipose tissue of mice improved high-fat diet-induced obesity and associated metabolic impairment due to enhanced heat production. PRMT4 methylated peroxisome proliferator-activated receptor-γ on Arg240 and facilitated the binding of the coactivator PR domain-containing protein 16 to initiate adipose tissue browning and thermogenesis. PRMT4-dependent methylation of peroxisome proliferator-activated receptor-γ on Arg240 is important in the process of inguinal white adipose tissue browning.
Topics: Humans; Animals; Mice; PPAR gamma; Adipose Tissue, Brown; Adipose Tissue, White; Transcription Factors; Obesity; Thermogenesis; Mice, Inbred C57BL
PubMed: 37216643
DOI: 10.2337/db22-1016 -
Advanced Science (Weinheim,... Jul 2023Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most... (Review)
Review
Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most advantageous cell type for regenerative therapies owing to their easy accessibility, multipotency, and active paracrine activity. This review highlights current challenges in translating ADSC-based therapies into clinical settings and discusses novel strategies to overcome the limitations of ADSCs. To further establish ADSC-based therapies as an emerging platform for regenerative medicine, this review also provides an update on the advancements in this field, including fat grafting, wound healing, bone regeneration, skeletal muscle repair, tendon reconstruction, cartilage regeneration, cardiac repair, and nerve regeneration. ADSC-based therapies are expected to be more tissue-specific and increasingly important in regenerative medicine.
Topics: Regenerative Medicine; Adipose Tissue; Adipocytes; Plastic Surgery Procedures; Stem Cells
PubMed: 37162248
DOI: 10.1002/advs.202207334 -
The Journal of Clinical Endocrinology... Jul 2023The worldwide increase in the prevalence of diabetes mellitus has raised the demand for new therapeutic strategies targeting diabetic symptoms and its chronic... (Review)
Review
The worldwide increase in the prevalence of diabetes mellitus has raised the demand for new therapeutic strategies targeting diabetic symptoms and its chronic complications. Among different treatment options for diabetes, adipose-derived mesenchymal stem cells (ADMSCs) therapy attract the most attention. The therapeutic effects of ADMSCs are based primarily on their paracrine release of immunomodulatory, anti-inflammatory, and trophic factors. Animal models of diabetes as well as human clinical trials have shown that ADMSCs can effectively facilitate endogenous β cell regeneration, preserve residual β cell mass, reduce islet graft rejection, regulate the immune system, and ultimately improve insulin sensitivity or ameliorate insulin resistance in peripheral tissues. Nevertheless, transplantation of mesenchymal stem cells is associated with certain risks; therefore recently much attention has been devoted to ADMSCs derivatives, such as exosomes or conditioned media, as therapeutic agents for the treatment of diabetes. Compared to ADMSCs, cell-free therapy has even better therapeutic potential. This narrative review summarizes recent outcomes and molecular mechanisms of ADMSCs action in the treatment for both type 1 DM and type 2 DM, as well as shows their feasibility, benefits, and current limitations.
Topics: Humans; Diabetes Mellitus; Adipose Tissue; Mesenchymal Stem Cells; Insulin Resistance
PubMed: 36916961
DOI: 10.1210/clinem/dgad142 -
Diabetes & Metabolism Journal Sep 2023In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and... (Review)
Review
In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and exploiting adipocyte biology. Adipose tissue plays critical roles in the regulation of systemic glucose and lipid metabolism and secretes bioactive molecules possessing endocrine, paracrine, and autocrine functions. Dysfunctional adipose tissue has a detrimental impact on metabolic health and is intimately involved in key aspects of metabolic diseases such as insulin resistance, lipid overload, inflammation, and organelle stress. Differences in the distribution of fat depots and adipose characteristics relate to divergent degrees of metabolic dysfunction found in metabolically healthy and unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning as a metabolic sink and participating in crosstalk with other metabolic organs. Manipulation of adipose tissue provides a wealth of opportunities to intervene and combat the progression of associated metabolic diseases. We discuss current treatment modalities for obesity including incretin hormone analogs and touch upon emerging strategies with therapeutic potential including exosome-based therapy, pharmacological activation of brown and beige adipocyte thermogenesis, and administration or inhibition of adipocyte-derived factors.
Topics: Humans; Obesity; Adipose Tissue; Energy Metabolism; Thermogenesis; Insulin Resistance; Lipid Metabolism; Animals; Adipocytes; Metabolic Diseases
PubMed: 37482656
DOI: 10.4093/dmj.2023.0011 -
Nature Communications Jul 2023Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are...
Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway.
Topics: Animals; Humans; Male; Mice; Adipose Tissue, Beige; Adipose Tissue, White; Homeostasis; Mammals; Mice, Inbred C57BL; Muscles; Obesity; Thermogenesis
PubMed: 37468484
DOI: 10.1038/s41467-023-39710-z -
Current Opinion in Genetics &... Aug 2023Exercise induces various beneficial whole-body adaptations and can delay the onset of obesity, type 2 diabetes, and cardiovascular disease. While many of the beneficial... (Review)
Review
Exercise induces various beneficial whole-body adaptations and can delay the onset of obesity, type 2 diabetes, and cardiovascular disease. While many of the beneficial effects of exercise on skeletal muscle and the cardiovascular system have been well established, recent studies have highlighted the role of exercise-induced improvements to adipose tissue that affect metabolic and whole-body health. Studies investigating exercise-induced adaptations of white adipose tissue (WAT) and brown adipose tissue (BAT) demonstrate modifications to glucose uptake, mitochondrial activity, and endocrine profile, and a beiging of WAT in rodents. This review discusses recent studies of the exercise-induced adaptations to WAT and BAT and their implications.
Topics: Exercise; Adipose Tissue; Humans; Mitochondria
PubMed: 37295241
DOI: 10.1016/j.gde.2023.102058 -
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 -
Adipocyte Dec 2023Technologies are transforming the understanding of adipose tissue as a complex and dynamic tissue that plays a critical role in energy homoeostasis and metabolic health.... (Review)
Review
Technologies are transforming the understanding of adipose tissue as a complex and dynamic tissue that plays a critical role in energy homoeostasis and metabolic health. This mini-review provides a brief overview of the potential impact of novel technologies in biomedical research and aims to identify areas where these technologies can make the most significant contribution to adipose tissue research. It discusses the impact of cutting-edge technologies such as single-cell sequencing, multi-omics analyses, spatial transcriptomics, live imaging, 3D tissue engineering, microbiome analysis, imaging, and artificial intelligence/machine learning. As these technologies continue to evolve, we can expect them to play an increasingly important role in advancing our understanding of adipose tissue and improving the treatment of related diseases.
Topics: Artificial Intelligence; Adipose Tissue; Gene Expression Profiling; Homeostasis; Multiomics
PubMed: 37599422
DOI: 10.1080/21623945.2023.2248673