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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 -
Journal of Hepatology Dec 2023While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of... (Review)
Review
While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of the direct and indirect effects of endocrine dysregulation on the severity of MASLD, with strong evidence that low levels of growth hormone, sex hormones, and thyroid hormone promote the development and progression of disease. The impact of steroid hormones, e.g. cortisol and dehydroepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and management of non-insulin endocrine axes is essential in the evaluation and management of MASLD. Multiple therapeutic options have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in MASH.
Topics: Humans; Insulin Resistance; Metabolic Diseases; Fatty Liver; Adipocytes
PubMed: 37730124
DOI: 10.1016/j.jhep.2023.08.030 -
Current Opinion in Genetics &... Dec 2023White adipose tissue stores fatty acid (FA) as triglyceride in the lipid droplet organelle of highly specialized cells known as fat cells or adipocytes. Depending on the... (Review)
Review
White adipose tissue stores fatty acid (FA) as triglyceride in the lipid droplet organelle of highly specialized cells known as fat cells or adipocytes. Depending on the nutritional state and energy demand, hormonal and biochemical signals converge on activating an elegant and fundamental process known as lipolysis, which involves triglyceride hydrolysis to FAs. Almost six decades of work have vastly expanded our knowledge of lipolysis from enzymatic processes to complex protein assembly, disassembly, and post-translational modification. Research in recent decades ushered in the discovery of new lipolytic enzymes and coregulators and the characterization of numerous factors and signaling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels. This review will discuss recent developments with particular emphasis on the past two years in enzymatic lipolytic pathways and transcriptional regulation of lipolysis. We will summarize the positive and negative regulators of lipolysis, the adipose tissue microenvironment in lipolysis, and the systemic effects of lipolysis. The dynamic nature of adipocyte lipolysis is emerging as an essential regulator of metabolism and energy balance, and we will discuss recent developments in this area.
Topics: Lipolysis; Lipid Metabolism; Adipose Tissue; Adipocytes; Triglycerides
PubMed: 37738733
DOI: 10.1016/j.gde.2023.102114 -
Nature Reviews. Molecular Cell Biology Apr 2024The prevalence of obesity and associated chronic diseases continues to increase worldwide, negatively impacting on societies and economies. Whereas the association... (Review)
Review
The prevalence of obesity and associated chronic diseases continues to increase worldwide, negatively impacting on societies and economies. Whereas the association between excess body weight and increased risk for developing a multitude of diseases is well established, the initiating mechanisms by which weight gain impairs our metabolic health remain surprisingly contested. In order to better address the myriad of disease states associated with obesity, it is essential to understand adipose tissue dysfunction and develop strategies for reinforcing adipocyte health. In this Review we outline the diverse physiological functions and pathological roles of human white adipocytes, examining our current knowledge of why white adipocytes are vital for systemic metabolic control, yet poorly adapted to our current obesogenic environment.
Topics: Humans; Adipocytes, White; Obesity; Adipose Tissue
PubMed: 38086922
DOI: 10.1038/s41580-023-00680-1 -
Nature Aug 2023Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1). The propensity of...
Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1). The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.
Topics: Animals; Female; Male; Mice; Adipocytes; Adipose Tissue, White; Epithelium; Thermogenesis; Uncoupling Protein 1; Mammary Glands, Animal; Cold Temperature; Sympathetic Nervous System; Energy Metabolism; Oxidation-Reduction; Sex Characteristics
PubMed: 37495690
DOI: 10.1038/s41586-023-06361-5 -
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 -
Endocrine Reviews Nov 2023Adipose tissue is the largest endocrine organ and an accepted contributor to overall energy homeostasis. There is strong evidence linking increased adiposity to the...
Adipose tissue is the largest endocrine organ and an accepted contributor to overall energy homeostasis. There is strong evidence linking increased adiposity to the development of 13 types of cancer. With increased adiposity comes metabolic dysfunction and insulin resistance, and increased systemic insulin and glucose support the growth of many cancers, including those of the colon and endometrium. There is also an important direct crosstalk between adipose tissue and various organs. For instance, the healthy development and function of the mammary gland, as well as the development, growth, and progression of breast cancer, are heavily impacted by the breast adipose tissue in which breast epithelial cells are embedded. Cells of the adipose tissue are responsive to external stimuli, including overfeeding, leading to remodeling and important changes in the secretion of factors known to drive the development and growth of cancers. Loss of factors like adiponectin and increased production of leptin, endotrophin, steroid hormones, and inflammatory mediators have been determined to be important mediators of the obesity-cancer link. Obesity is also associated with a structural remodeling of the adipose tissue, including increased localized fibrosis and disrupted angiogenesis that contribute to the development and progression of cancers. Furthermore, tumor cells feed off the adipose tissue, where increased lipolysis within adipocytes leads to the release of fatty acids and stromal cell aerobic glycolysis leading to the increased production of lactate. Both have been hypothesized to support the higher energetic demands of cancer cells. Here, we aim to provide an update on the state of the literature revolving around the role of the adipose tissue in cancer initiation and progression.
Topics: Female; Humans; Adipose Tissue; Adipocytes; Obesity; Insulin Resistance; Adiposity; Neoplasms
PubMed: 37260403
DOI: 10.1210/endrev/bnad015 -
Frontiers in Immunology 2023Lipedema is a painful subcutaneous adipose tissue (SAT) disease characterized by adipocyte hypertrophy, immune cell recruitment, and fibrosis in the affected areas....
INTRODUCTION
Lipedema is a painful subcutaneous adipose tissue (SAT) disease characterized by adipocyte hypertrophy, immune cell recruitment, and fibrosis in the affected areas. These features are thought to contribute to the development and progression of the condition. However, the relationship between lipedema disease stage and the associated adipose tissue changes has not been determined so far.
METHODS
SAT biopsies of 32 lipedema patients, ranging across the pathological stages I to III, and 14 BMI- and age-matched controls were harvested from lipedema-affected thighs and non-symptomatic lower abdominal regions. Histological and immunohistochemical (IHC) staining and expression analysis of markers for adipogenesis, immunomodulation, and fibrosis were performed on the tissue biopsies.
RESULTS
Lipedema patients showed increased adipocyte areas and a stage-dependent shift towards larger cell sizes in the thighs. Lipedema SAT was linked with increased interstitial collagen accumulation in the thighs, but not the lower abdominal region when compared to controls. There was a trend toward progressive SAT fibrosis of the affected thighs with increasing lipedema stage. Elevated gene expression levels of macrophage markers were found for thigh SAT biopsies, but not in the abdominal region. IHC staining of lipedema thigh biopsies confirmed a transiently elevated macrophage polarization towards an M2-like (anti-inflammatory) phenotype.
CONCLUSIONS
In summary, lipedema SAT is associated with stage-dependent adipocyte hypertrophy, stage-progressive interstitial fibrosis and elevated proportion of M2-like macrophages. The character of the inflammatory response differs from primary obesity and may possess an essential role in the development of lipedema.
Topics: Humans; Lipedema; Subcutaneous Fat; Adipocytes; Inflammation; Fibrosis; Hypertrophy
PubMed: 37575263
DOI: 10.3389/fimmu.2023.1223264 -
Cell Metabolism Aug 2023Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the...
Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.
Topics: Animals; Mice; Lipolysis; RNA, Small Nucleolar; Interleukin-15; Rejuvenation; Adipocytes; Obesity; Killer Cells, Natural
PubMed: 37329887
DOI: 10.1016/j.cmet.2023.05.009 -
Nature Metabolism May 2024Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by... (Review)
Review
Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by greatly increased prevalence of cardiometabolic disease, type 2 diabetes and disorders associated with impaired immune surveillance. Adipose tissue displays species-conserved, temporal changes with ageing, including redistribution from peripheral to central depots, loss of thermogenic capacity and expansion within the bone marrow. Adipose tissue is localized to discrete depots, and also diffusely distributed within multiple organs and tissues in direct proximity to specialized cells. Thus, through their potent endocrine properties, adipocytes are capable of modulating tissue and organ function throughout the body. In addition to adipocytes, multipotent progenitor/stem cells in adipose tissue play a crucial role in maintenance and repair of tissues throughout the lifetime. Adipose tissue may therefore be a central driver for organismal ageing and age-associated diseases. Here we review the features of adipose tissue during ageing, and discuss potential mechanisms by which these changes affect whole-body metabolism, immunity and longevity. We also explore the potential of adipose tissue-targeted therapies to ameliorate age-associated disease burdens.
Topics: Humans; Aging; Adipose Tissue; Animals; Adipocytes; Longevity
PubMed: 38783156
DOI: 10.1038/s42255-024-01046-3