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La Clinica Terapeutica 2023Lipedema, a complex and enigmatic adipose tissue disorder, remains poorly understood despite its significant impact on the patients' quality of life. Genetic... (Review)
Review
BACKGROUND
Lipedema, a complex and enigmatic adipose tissue disorder, remains poorly understood despite its significant impact on the patients' quality of life. Genetic investigations have uncovered potential contributors to its pathogenesis, including somatic mutations, which are nonheritable genetic alterations that can play a pivotal role in the development of this disease.
AIM
This review aims to elucidate the role of somatic mutations in the etiology of lipedema by examining their implications in adipose tissue biology, inflammation, and metabolic dysfunction.
RESULTS
Studies focusing on leukocyte clones, genetic alterations like TET2 and DNMT3A, and the intricate interplay between adipose tissue and other organs have shed light on the underlying mechanisms driving lipedema. From the study of the scientific literature, mutations to genes correlated to three main pathways could be involved in the somatic development of lipedema: genes related to mitochondrial activity, genes related to localized disorders of subcutaneous adipose tissue, and genes of leukocyte clones.
CONCLUSIONS
The insights gained from these diverse studies converge to highlight the complex genetic underpinnings of lipedema and offer potential avenues for therapeutic interventions targeting somatic mutations to alleviate the burden of this condition on affected individuals.
Topics: Humans; Lipedema; Quality of Life; Subcutaneous Fat; Adipose Tissue; Inflammation
PubMed: 37994772
DOI: 10.7417/CT.2023.2495 -
Philosophical Transactions of the Royal... Sep 2023Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been... (Review)
Review
Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been preserved throughout evolution. One of oestrogens actions, and the focus of this review, is their ability to determine adipose tissue distribution, function and adipose tissue 'health'. Body fat distribution is sexually dimorphic, affecting males and females differently. These differences are also apparent in the development of the metabolic syndrome and other chronic conditions where oestrogens are critical. In this review, we summarize the different molecular mechanisms, pathways and resulting pathophysiology which are a result of oestrogens actions in and on adipose tissues. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.
Topics: Male; Female; Humans; Estrogens; Adipose Tissue; Obesity; Sex Characteristics; Sexual Behavior
PubMed: 37482787
DOI: 10.1098/rstb.2022.0207 -
Journal of Translational Medicine Jul 2023The tumor-adipose microenvironment (TAME) is characterized by the enrichment of adipocytes, and is considered a special ecosystem that supports cancer progression....
BACKGROUND
The tumor-adipose microenvironment (TAME) is characterized by the enrichment of adipocytes, and is considered a special ecosystem that supports cancer progression. However, the heterogeneity and diversity of adipocytes in TAME remains poorly understood.
METHODS
We conducted a single-cell RNA sequencing analysis of adipocytes in mouse and human white adipose tissue (WAT). We analyzed several adipocyte subtypes to evaluate their relationship and potential as prognostic factors for overall survival (OS). The potential drugs are screened by using bioinformatics methods. The tumor-promoting effects of a typical adipocyte subtype in breast cancer are validated by performing in vitro functional assays and immunohistochemistry (IHC) in clinical samples.
RESULTS
We profiled a comprehensive single-cell atlas of adipocyte in mouse and human WAT and described their characteristics, origins, development, functions and interactions with immune cells. Several cancer-associated adipocyte subtypes, namely DPP4 adipocytes in visceral adipose and ADIPOQ adipocytes in subcutaneous adipose, are identified. We found that high levels of these subtypes are associated with unfavorable outcomes in four typical adipose-associated cancers. Some potential drugs including Trametinib, Selumetinib and Ulixertinib are discovered. Emphatically, knockdown of adiponectin receptor 1 (AdipoR1) and AdipoR2 impaired the proliferation and invasion of breast cancer cells. Patients with AdipoR2-high breast cancer display significantly shorter relapse-free survival (RFS) than those with AdipoR2-low breast cancer.
CONCLUSION
Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future.
Topics: Humans; Mice; Animals; Female; Ecosystem; Neoplasm Recurrence, Local; Adipocytes; Breast Neoplasms; Adipose Tissue, White; Obesity; Single-Cell Analysis; Adipose Tissue; Tumor Microenvironment
PubMed: 37454080
DOI: 10.1186/s12967-023-04256-7 -
Immunological Investigations Nov 2023Adipose tissue macrophages (ATM) are an essential type of immune cells in adipose tissue. Obesity induces the inflammation of adipose tissues, as expressed by ATM... (Review)
Review
Adipose tissue macrophages (ATM) are an essential type of immune cells in adipose tissue. Obesity induces the inflammation of adipose tissues, as expressed by ATM accumulation, that is more likely to become a source of systemic metabolic diseases, including insulin resistance. The process is characterized by the transcriptional regulation of inflammatory pathways by virtue of signaling molecules such as cytokines and free fatty acids. Notably, posttranslational modification (PTM) is a key link for these signaling molecules to trigger the proinflammatory or anti-inflammatory phenotype of ATMs. This review focuses on summarizing the functions and molecular mechanisms of ATMs regulating inflammation in obese adipose tissue. Furthermore, the role of PTM is elaborated, hoping to identify new horizons of treatment and prevention for obesity-mediated metabolic disease.
Topics: Animals; Mice; Adipose Tissue; Macrophages; Obesity; Insulin Resistance; Inflammation; Protein Processing, Post-Translational; Mice, Inbred C57BL
PubMed: 37129471
DOI: 10.1080/08820139.2023.2205883 -
Reviews in Endocrine & Metabolic... Dec 2023White adipose tissue (WAT) is an important endocrine organ that regulates systemic energy metabolism. In metabolically unhealthy obesity, adipocytes become dysfunctional... (Review)
Review
White adipose tissue (WAT) is an important endocrine organ that regulates systemic energy metabolism. In metabolically unhealthy obesity, adipocytes become dysfunctional through hypertrophic mechanisms associated with a reduced endocrine function, reduced mitochondrial function, but increased inflammation, fibrosis, and extracellular remodelling. A pathologic WAT remodelling promotes systemic lipotoxicity characterized by fat accumulation in tissues such as muscle and liver, leading to systemic insulin resistance and type 2 diabetes. Several lines of evidence from human and animal studies suggest a link between unhealthy obesity and adipocyte mitochondrial dysfunction, and interventions that improve mitochondrial function may reduce the risk of obesity-associated diseases. This review discusses the importance of mitochondrial function and metabolism in human adipocyte biology and intercellular communication mechanisms within WAT. Moreover, a selected interventional approach for better adipocyte mitochondrial metabolism in humans is reviewed. A greater understanding of mitochondrial bioenergetics in WAT might provide novel therapeutic opportunities to prevent or restore dysfunctional adipose tissue in obesity-associated diseases.
Topics: Animals; Humans; Diabetes Mellitus, Type 2; Adipose Tissue, White; Adipose Tissue; Energy Metabolism; Metabolic Diseases; Obesity; Mitochondria
PubMed: 37558853
DOI: 10.1007/s11154-023-09827-z -
Nutrients Nov 2023Adipose tissue encompasses various types, including White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and beige adipose tissue, each having distinct roles in... (Review)
Review
Adipose tissue encompasses various types, including White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and beige adipose tissue, each having distinct roles in energy storage and thermogenesis. Vitamin D (VD), a fat-soluble vitamin, maintains a complex interplay with adipose tissue, exerting significant effects through its receptor (VDR) on the normal development and functioning of adipocytes. The VDR and associated metabolic enzymes are widely expressed in the adipocytes of both rodents and humans, and they partake in the regulation of fat metabolism and functionality through various pathways. These encompass adipocyte differentiation, adipogenesis, inflammatory responses, and adipokine synthesis and secretion. This review primarily appraises the role and mechanisms of VD in different adipocyte differentiation, lipid formation, and inflammatory responses, concentrating on the pivotal role of the VD/VDR pathway in adipogenesis. This insight furnishes new perspectives for the development of micronutrient-related intervention strategies in the prevention and treatment of obesity.
Topics: Humans; Vitamin D; Adipogenesis; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Obesity; Vitamins; Thermogenesis
PubMed: 38004226
DOI: 10.3390/nu15224832 -
Hypertension (Dallas, Tex. : 1979) Jan 2024Alterations in microcirculation play a crucial role in the pathogenesis of cardiovascular and metabolic disorders such as obesity and hypertension. The small resistance... (Review)
Review
Alterations in microcirculation play a crucial role in the pathogenesis of cardiovascular and metabolic disorders such as obesity and hypertension. The small resistance arteries of these patients show a typical remodeling, as indicated by an increase of media or total wall thickness to lumen diameter ratio that impairs organ flow reserve. The majority of blood vessels are surrounded by a fat depot which is termed perivascular adipose tissue (PVAT). In recent years, data from several studies have indicated that PVAT is an endocrine organ that can produce a variety of adipokines and cytokines, which may participate in the regulation of vascular tone, and the secretory profile varies with adipocyte phenotype and disease status. The PVAT of lean humans largely secretes the vasodilator adiponectin, which will act in a paracrine fashion to reduce peripheral resistance and improve nutrient uptake into tissues, thereby protecting against the development of hypertension and diabetes. In obesity, PVAT becomes enlarged and inflamed, and the bioavailability of adiponectin is reduced. The inevitable consequence is a rise in peripheral resistance with higher blood pressure. The interrelationship between obesity and hypertension could be explained, at least in part, by a cross-talk between microcirculation and PVAT. In this article, we propose an integrated pathophysiological approach of this relationship, in order to better clarify its role in obesity and hypertension, as the basis for effective and specific prevention and treatment.
Topics: Humans; Adiponectin; Microcirculation; Adipose Tissue; Hypertension; Obesity
PubMed: 37937425
DOI: 10.1161/HYPERTENSIONAHA.123.19437 -
Physiological Research Jul 2023In recent years, there has been an increasing incidence of metabolic syndrome, type 2 diabetes, and cardiovascular events related to insulin resistance. As one of the... (Review)
Review
In recent years, there has been an increasing incidence of metabolic syndrome, type 2 diabetes, and cardiovascular events related to insulin resistance. As one of the target organs for insulin, adipose tissue is essential for maintaining in vivo immune homeostasis and metabolic regulation. Currently, the specific adipose tissue mechanisms involved in insulin resistance remain incompletely understood. There is increasing evidence that the process of insulin resistance is mostly accompanied by a dramatic increase in the number and phenotypic changes of adipose tissue macrophages (ATMs). In this review, we discuss the origins and functions of ATMs, some regulatory factors of ATM phenotypes, and the mechanisms through which ATMs mediate insulin resistance. We explore how ATM phenotypes contribute to insulin resistance in adipose tissue. We expect that modulation of ATM phenotypes will provide a novel strategy for the treatment of diseases associated with insulin resistance.
Topics: Humans; Insulin Resistance; Diabetes Mellitus, Type 2; Inflammation; Adipose Tissue; Macrophages
PubMed: 37449743
DOI: 10.33549/physiolres.935046 -
Current Opinion in Genetics &... Aug 2023Body fat is stored in anatomically distinct adipose depots that vary in their cell composition and play specialized roles in systemic metabolic homeostasis via secreted... (Review)
Review
Body fat is stored in anatomically distinct adipose depots that vary in their cell composition and play specialized roles in systemic metabolic homeostasis via secreted products. Their local effects on nearby tissues (e.g. the gut and visceral adipose tissues) are increasingly recognized and this local crosstalk is being elucidated. The major subcutaneous fat depots, abdominal and gluteal-femoral, exert opposite effects on the risk of metabolic disease. The pace of research into developmental, sex, and genetic determinants of human adipose depot growth and function is rapidly accelerating, providing insight into the pathogenesis of metabolic dysfunction in persons with obesity.
Topics: Humans; Obesity; Adipose Tissue; Adiposity; Subcutaneous Fat; Intra-Abdominal Fat
PubMed: 37406429
DOI: 10.1016/j.gde.2023.102079 -
Nutrients Sep 2023Brown and beige adipocytes are renowned for their unique ability to generate heat through a mechanism known as thermogenesis. This process can be induced by exposure to... (Review)
Review
Brown and beige adipocytes are renowned for their unique ability to generate heat through a mechanism known as thermogenesis. This process can be induced by exposure to cold, hormonal signals, drugs, and dietary factors. The activation of these thermogenic adipocytes holds promise for improving glucose metabolism, reducing fat accumulation, and enhancing insulin sensitivity. However, the translation of preclinical findings into effective clinical therapies poses challenges, warranting further research to identify the molecular mechanisms underlying the differentiation and function of brown and beige adipocytes. Consequently, research has focused on the development of drugs, such as mirabegron, ephedrine, and thyroid hormone, that mimic the effects of cold exposure to activate brown fat activity. Additionally, nutritional interventions have been explored as an alternative approach to minimize potential side effects. Brown fat and beige fat have emerged as promising targets for addressing nutritional imbalances, with the potential to develop strategies for mitigating the impact of metabolic diseases. Understanding the influence of nutritional factors on brown fat activity can facilitate the development of strategies to promote its activation and mitigate metabolic disorders.
Topics: Adipose Tissue, Brown; Nutritional Status; Adipocytes; Adipocytes, Beige; Adipose Tissue, Beige
PubMed: 37764855
DOI: 10.3390/nu15184072