How obesity affects adipocyte turnover.

Cellular turnover is fundamental for tissue homeostasis and integrity. Adipocyte turnover, accounting for 4% of the total cellular mass turnover in humans, is essential for adipose tissue homeostasis during metabolic stress. In obesity, an altered adipose tissue microenvironment promotes adipocyte death. To clear dead adipocytes, macrophages are recruited and form a distinctive structure known as crown-like structure; subsequently, new adipocytes are generated from adipose stem and progenitor cells in the adipogenic niche to replace dead adipocytes. Accumulating evidence indicates that adipocyte death, clearance, and adipogenesis are sophisticatedly orchestrated during adipocyte turnover. In this Review, we summarize our current understandings of each step in adipocyte turnover, discussing its key players and regulatory mechanisms.

From fasting to fat reshaping: exploring the molecular pathways of intermittent fasting-induced adipose tissue remodeling.

Obesity, characterised by excessive fat accumulation, is a complex chronic condition that results from dysfunctional adipose tissue expansion due to prolonged calorie surplus. This leads to rapid adipocyte enlargement that exceeds the support capacity of the surrounding neurovascular network, resulting in increased hypoxia, inflammation, and insulin resistance. Intermittent fasting (IF), a dietary regimen that cycles between periods of fasting and eating, has emerged as an effective strategy to combat obesity and improve metabolic homeostasis by promoting healthy adipose tissue remodeling. However, the precise molecular and cellular mechanisms behind the metabolic improvements and remodeling of white adipose tissue (WAT) driven by IF remain elusive. This review aims to summarise and discuss the relationship between IF and adipose tissue remodeling and explore the potential mechanisms through which IF induces alterations in WAT. This includes several key structural changes, including angiogenesis and sympathetic innervation of WAT. We will also discuss the involvement of key signalling pathways, such as PI3K, SIRT, mTOR, and AMPK, which potentially play a crucial role in IF-mediated metabolic adaptations.

Adipose Tissue Dynamics, Thermogenesis, and Interorgan Connections for Preventing Obesity and Metabolic Disorders.

Adipose tissues, such as white, brown, and beige tissues, play pivotal roles in maintaining energy balance and metabolic health. Whereas white adipocytes store energy, brown and beige adipocytes exhibit high energy expenditure owing to their distinct mitochondrial density and UCP1 expression. Dysfunction in these tissues contributes to metabolic disorders such as type 2 diabetes and cardiovascular diseases. Adipose tissue expansion through cell enlargement or increased cell numbers caused by excess energy storage in white adipocytes substantially influences metabolic health. In obesity, hypertrophic adipocytes trigger inflammation, fibrosis, and hypoxia, whereas smaller adipocytes exert favorable metabolic effects, contributing to insulin sensitivity. Brown and beige adipocytes consume energy for thermogenesis to maintain body temperature, contributing to metabolic homeostasis. The intricate interactions between brown adipose tissues and various organs, such as the liver and heart, highlight the systemic implications of adipose tissue functions. Understanding the complex underlying mechanisms may lead to the development of innovative therapies targeting metabolic disorders by modulating the functions of brown adipose tissue and its interactions with other physiological systems. In this review, we discuss insights into the mechanisms underlying the dysregulation of metabolism owing to abnormalities in adipose tissue remodeling. We focus on the endocrine functions of thermogenic brown and beige adipocytes and explore the interorgan interactions that influence whole-body metabolism.

Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities.

White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.

Physical activity and batokines.

Brown and beige adipose tissue share similar functionality, being both tissues specialized in producing heat through nonshivering thermogenesis and also playing endocrine roles through the release of their secretion factors called batokines. This review elucidates the influence of physical exercise, and myokines released in response, on the regulation of thermogenic and secretory functions of these adipose tissues and discusses the similarity of batokines actions with physical exercise in the remodeling of adipose tissue. This adipose tissue remodeling promoted by autocrine and paracrine batokines or physical exercise seems to optimize its functionality associated with better health outcomes.

The Emerging Importance of Mitochondria in White Adipocytes: Neither Last nor Least.

The growing recognition of mitochondria's crucial role in the regulation of white adipose tissue remodeling and energy balance underscores its significance. The marked metabolic diversity of mitochondria provides the molecular and cellular foundation for enabling adipose tissue plasticity in response to various metabolic cues. Effective control of mitochondrial function at the cellular level, not only in thermogenic brown and beige adipocytes but also in energy-storing white adipocytes, exerts a profound influence on adipose homeostasis. Furthermore, mitochondria play a pivotal role in intercellular communication within adipose tissue via production of metabolites with signaling properties. A more comprehensive understanding of mitochondrial regulation within white adipocytes will empower the development of targeted and efficacious strategies to enhance adipose function, leading to advancements in overall metabolic health.

Pathological beige remodeling induced by cancer cachexia depends on the disease severity and involves mainly the trans-differentiation of mature white adipocytes.

In cancer associated cachexia (CAC), white adipose tissue undergoes morphofunctional and inflammatory changes that lead to tissue dysfunction and remodeling. In addition to metabolic changes in white adipose tissues (WAT), adipose tissue atrophy has been implicated in several clinical complications and poor prognoses associated with cachexia. Adipocyte atrophy may be associated with increased beige remodeling in human CAC as evidenced by the "beige remodeling" observed in preclinical models of CAC. Even though beige remodeling is associated with CAC-induced WAT dysfunction, there are still some open questions regarding their cellular origins. In this study, we investigated the development of beige remodeling in CAC from a broader perspective. In addition, we used a grading system to identify the scAT as being affected by mice weight loss early and intensely. Using different in vitro and ex-vivo techniques, we demonstrated that Lewis LLC1 cells can induce a switch from white to beige adipocytes, which is specific to this type of tumor cell. During the more advanced stages of CAC, beige adipocytes are mainly formed from the transdifferentiation of cells. According to our results, humanizing the CAC classification system is an efficient approach to defining the onset of the syndrome in a more homogeneous manner. Pathological beige remodeling occurred early in the disease course and exhibited phenotypic characteristics specific to LLC cells' secretomes. Developing therapeutic strategies that recruit beige adipocytes in vivo may be better guided by an understanding of the cellular origins of beige adipocytes emitted by CAC.

Characteristic and fate determination of adipose precursors during adipose tissue remodeling.

Adipose tissues are essential for actively regulating systemic energy balance, glucose homeostasis, immune responses, reproduction, and longevity. Adipocytes maintain dynamic metabolic needs and possess heterogeneity in energy storage and supply. Overexpansion of adipose tissue, especially the visceral type, is a high risk for diabetes and other metabolic diseases. Changes in adipocytes, hypertrophy or hyperplasia, contribute to the remodeling of obese adipose tissues, accompanied by abundant immune cell accumulation, decreased angiogenesis, and aberrant extracellular matrix deposition. The process and mechanism of adipogenesis are well known, however, adipose precursors and their fate decision are only being defined with recent information available to decipher how adipose tissues generate, maintain, and remodel. Here, we discuss the key findings that identify adipose precursors phenotypically, with special emphasis on the intrinsic and extrinsic signals in instructing and regulating the fate of adipose precursors under pathophysiological conditions. We hope that the information in this review lead to novel therapeutic strategies to combat obesity and related metabolic diseases.

Promotion of healthy adipose tissue remodeling ameliorates muscle inflammation in a mouse model of sarcopenic obesity.

A large subset of elders is classified as having sarcopenic obesity, a prevalence of obesity in combination with sarcopenia which places an aging population at the risk of adverse health consequences from both conditions. However, its complex etiology has restrained the development of effective therapeutic strategies. Recent progress has highlighted that the mode by which adipose tissue (AT) remodels is a determinant of metabolic health in the context of obesity. Healthy AT remodeling confers metabolic protection including insulin-sensitizing and anti-inflammatory effects to non-adipose tissues including skeletal muscle. Here, we employed a doxycycline-inducible adipocyte Hif1a knockout system to evaluate the muscle-protective effects associated with HIF1α inactivation-induced healthy AT remodeling in a model of sarcopenic obesity. We found that adipocyte HIF1α inactivation leads to improved AT metabolic health, reduced serum levels of lipids and pro-inflammatory cytokines, and increase of circulating adipokine (APN) in ovariectomized obese mice fed with obesogenic high-fat diet (HFD). Concomitantly, muscle inflammation is evidently lower in obese OVX mice when adipocyte HIF1α is inactivated. Furthermore, these protective effects against muscle inflammation can be mimicked by the administration of adiponectin receptor agonist AdipoRon. Collectively, our findings underscore the importance of AT metabolic health in the context of concurrent sarcopenia and obesity, and promotion of healthy AT remodeling may represent a new therapeutic strategy to improve muscle health in sarcopenic obesity.

The Influence of Ambient Temperature on Adipose Tissue Homeostasis, Metabolic Diseases and Cancers.

Adipose tissue is a recognized energy storage organ during excessive energy intake and an endocrine and thermoregulator, which interacts with other tissues to regulate systemic metabolism. Adipose tissue dysfunction is observed in most obese mouse models and humans. However, most studies using mouse models were conducted at room temperature (RT), where mice were chronically exposed to mild cold. In this condition, energy use is prioritized for thermogenesis to maintain body temperature in mice. It also leads to the activation of the sympathetic nervous system, followed by the activation of ß-adrenergic signaling. As humans live primarily in their thermoneutral (TN) zone, RT housing for mice limits the interpretation of disease studies from mouse models to humans. Therefore, housing mice in their TN zone (~28-30 °C) can be considered to mimic humans physiologically. However, factors such as temperature ranges and TN pre-acclimatization periods should be examined to obtain reliable results. In this review, we discuss how adipose tissue responds to housing temperature and the outcomes of the TN zone in metabolic disease studies. This review highlights the critical role of TN housing in mouse models for studying adipose tissue function and human metabolic diseases.

Sirtuins: Key players in obesity-associated adipose tissue remodeling.

Obesity, a complex disease involving an excessive amount of body fat and a major threat to public health all over the world, is the determining factor of the onset and development of metabolic disorders, including type 2 diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease. Long-term overnutrition results in excessive expansion and dysfunction of adipose tissue, inflammatory responses and over-accumulation of extracellular matrix in adipose tissue, and ectopic lipid deposit in other organs, termed adipose tissue remodeling. The mammalian Sirtuins (SIRT1-7) are a family of conserved NAD+-dependent protein deacetylases. Mounting evidence has disclosed that Sirtuins and their prominent substrates participate in a variety of physiological and pathological processes, including cell cycle regulation, mitochondrial biogenesis and function, glucose and lipid metabolism, insulin action, inflammatory responses, and energy homeostasis. In this review, we provided up-to-date and comprehensive knowledge about the roles of Sirtuins in adipose tissue remodeling, focusing on the fate of adipocytes, lipid mobilization, adipose tissue inflammation and fibrosis, and browning of adipose tissue, and we summarized the clinical trials of Sirtuin activators and inhibitors in treating metabolic diseases, which might shed light on new therapeutic strategies for obesity and its associated metabolic diseases.

Macrophage-Specific Connexin 43 Knockout Protects Mice from Obesity-Induced Inflammation and Metabolic Dysfunction.

Adipose tissue macrophages are a major immune cell type contributing to homeostatic maintenance and pathological adipose tissue remodeling. However, the mechanisms underlying macrophage recruitment and polarization in adipose tissue during obesity remain poorly understood. Previous studies have suggested that the gap junctional protein, connexin 43 (Cx43), plays a critical role in macrophage activation and phagocytosis. Herein, we investigated the macrophage-specific roles of Cx43 in high fat diet (HFD)-induced pathological remodeling of adipose tissue. Expression levels of Cx43 were upregulated in macrophages co-cultured with dying adipocytes in vitro, as well as in macrophages associated with dying adipocytes in the adipose tissue of HFD-fed mice. Cx43 knockdown reduced lipopolysaccharide (LPS)-induced ATP release from macrophages and decreased inflammatory responses of macrophages co-cultured with dying adipocytes. Based on global gene expression profiling, macrophage-specific Cx43-knockout (Cx43-MKO) mice were resistant to HFD-induced inflammatory responses in adipose tissue, potentially via P2X7-mediated signaling pathways. Cx43-MKO mice exhibited reduced HFD-induced macrophage recruitment in adipose tissue. Moreover, Cx43-MKO mice showed reduced inflammasome activation in adipose tissues and improved glucose tolerance. Collectively, these findings demonstrate that Cx43 expression in macrophages facilitates inflammasome activation, which, in turn, contributes to HFD-induced metabolic dysfunction.

α-Linolenic acid rich-chia seed modulates visceral adipose tissue collagen deposition, lipolytic enzymes expression, insulin signaling and GLUT-4 levels in a diet-induced adiposity rodent model.

Given obesity and its associated metabolic disorders have reached epidemic proportions, the study of therapeutic strategies targeting white adipose tissue (WAT) are of main research interest. We previously shown that α-linolenic acid-rich chia seed was able to ameliorate a wide range of metabolic disorders including body fat accretion in sucrose-rich diet (SRD)-fed rats, an experimental model of visceral adiposity and insulin resistance. However, the mechanisms involved are not fully clarified. The aim of this study was to evaluate the effect of chia seed administration upon WAT remodeling and key enzymes that controls lipolysis, insulin signaling (tAKT, pAKT), and GLUT-4 levels in different visceral fat pad depots (epididymal -eWAT- and retroperitoneal -rWAT- adipose tissues) of SRD-fed rats. Results showed that chia seed reduces adipocytes hypertrophy, the increased lipid content and collagen deposition in both WAT. These changes were accompanied by a significant reduction of HSL and ATGL protein levels in eWAT and HSL protein levels in rWAT. Moreover, chia seed restored the altered expression pattern of the pAKT observed in SRD-fed rats, and modulated GLUT-4 levels. Chia seed could be a dietary intervention of great relevance with potential beneficial effects in the management of body fat excess and WAT function.

Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics.

In mammals, white adipose tissues are largely divided into visceral epididymal adipose tissue (EAT) and subcutaneous inguinal adipose tissue (IAT) with distinct metabolic properties. Although emerging evidence suggests that subpopulations of adipose stem cells (ASCs) would be important to explain fat depot differences, ASCs of two fat depots have not been comparatively investigated. Here, we characterized heterogeneous ASCs and examined the effects of intrinsic and tissue micro-environmental factors on distinct ASC features. We demonstrated that ASC subpopulations in EAT and IAT exhibited different molecular features with three adipogenic stages. ASC transplantation experiments revealed that intrinsic ASC features primarily determined their adipogenic potential. Upon obesogenic stimuli, EAT-specific SDC1+ ASCs promoted fibrotic remodeling, whereas IAT-specific CXCL14+ ASCs suppressed macrophage infiltration. Moreover, IAT-specific BST2high ASCs exhibited a high potential to become beige adipocytes. Collectively, our data broaden the understanding of ASCs with new insights into the origin of white fat depot differences.

Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obesity.

Obesity is characterized by chronic, low-grade inflammation, which is driven by macrophage infiltration of adipose tissue. PPARγ is well established to have an anti-inflammatory function in macrophages, but the mechanism that regulates its function in these cells remains to be fully elucidated. PPARγ undergoes post-translational modifications (PTMs), including acetylation, to mediate ligand responses, including on metabolic functions. Here, we report that PPARγ acetylation in macrophages promotes their infiltration into adipose tissue, exacerbating metabolic dysregulation. We generated a mouse line that expresses a macrophage-specific, constitutive acetylation-mimetic form of PPARγ (K293Qflox/flox:LysM-cre, mK293Q) to dissect the role of PPARγ acetylation in macrophages. Upon high-fat diet feeding to stimulate macrophage infiltration into adipose tissue, we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice, including responses to the PPARγ agonist Rosiglitazone. Macrophage-specific PPARγ K293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue, but not in subcutaneous or brown adipose tissue, leading to decreased energy expenditure, insulin sensitivity, glucose tolerance, and adipose tissue function. Furthermore, mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling. Our study reveals that acetylation is a new layer of PPARγ regulation in macrophage activation, and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.

Astaxanthin, a Marine Carotenoid, Maintains the Tolerance and Integrity of Adipose Tissue and Contributes to Its Healthy Functions.

Recently, obesity-induced insulin resistance, type 2 diabetes, and cardiovascular disease have become major social problems. We have previously shown that Astaxanthin (AX), which is a natural antioxidant, significantly ameliorates obesity-induced glucose intolerance and insulin resistance. It is well known that AX is a strong lipophilic antioxidant and has been shown to be beneficial for acute inflammation. However, the actual effects of AX on chronic inflammation in adipose tissue (AT) remain unclear. To observe the effects of AX on AT functions in obese mice, we fed six-week-old male C57BL/6J on high-fat-diet (HFD) supplemented with or without 0.02% of AX for 24 weeks. We determined the effect of AX at 10 and 24 weeks of HFD with or without AX on various parameters including insulin sensitivity, glucose tolerance, inflammation, and mitochondrial function in AT. We found that AX significantly reduced oxidative stress and macrophage infiltration into AT, as well as maintaining healthy AT function. Furthermore, AX prevented pathological AT remodeling probably caused by hypoxia in AT. Collectively, AX treatment exerted anti-inflammatory effects via its antioxidant activity in AT, maintained the vascular structure of AT and preserved the stem cells and progenitor's niche, and enhanced anti-inflammatory hypoxia induction factor-2α-dominant hypoxic response. Through these mechanisms of action, it prevented the pathological remodeling of AT and maintained its integrity.

Vascular reactivity contributes to adipose tissue remodeling in obesity.

Vascular reactivity of adipose tissue (AT) is hypothesized to play an important role in the development of obesity. However, the exact role of vascular reactivity in the development of obesity remains unclear. In this study, we investigated the chronological changes in vascular reactivity and the microenvironments of the visceral AT (VAT) and subcutaneous AT (SAT) in lean and obese mice. Changes in blood flow levels induced by a ß-adrenoceptor agonist (isoproterenol) were significantly lower in the VAT of the mice fed a high-fat diet (HFD) for 1 and 12 weeks than those in the VAT of the mice fed a low-fat diet (LFD) for the same period; no significant change was observed in the SAT of any mouse group, suggesting depot-specific vascular reactivity of AT. Moreover, the hypoxic area and the expression of genes associated with angiogenesis and macrophage recruitment were increased in the VAT (but not in the SAT) of mice fed an HFD for 1 week compared with mice fed an LFD. These changes occurred with no morphological changes, including those related to adipocyte size, AT vessel density, and the diameter and pericyte coverage of the endothelium, suggesting a determinant role of vascular reactivity in the type of AT remodeling. The suppression of vascular reactivity was accompanied by increased endothelin1 (Edn1) gene expression and extracellular matrix (ECM) stiffness only in the VAT, implying enhanced contractile activities of the vasculature and ECM. The results suggest a depot-specific role of vascular reactivity in AT remodeling during the development of obesity.

Resident macrophages restrain pathological adipose tissue remodeling and protect vascular integrity in obese mice.

Tissue-resident macrophages in white adipose tissue (WAT) dynamically adapt to the metabolic changes of their microenvironment that are often induced by excess energy intake. Currently, the exact contribution of these macrophages in obesity-driven WAT remodeling remains controversial. Here, using a transgenic CD169-DTR mouse strain, we provide new insights into the interplay between CD169+ adipose tissue macrophages (ATMs) and their surrounding WAT microenvironment. Using targeted in vivo ATM ablation followed by transcriptional and metabolic WAT profiling, we found that ATMs protect WAT from the excessive pathological remodeling that occurs during obesity. As obesity progresses, ATMs control not only vascular integrity, adipocyte function, and lipid and metabolic derangements but also extracellular matrix accumulation and resultant fibrosis in the WAT. The protective role of ATMs during obesity-driven WAT dysfunction supports the notion that ATMs represent friends, rather than foes, as has previously assumed.

Short-term fasting reshapes fat tissue.

Intermittent fasting, which can effectively reduce obesity and improve the related metabolic syndrome has become an exciting research area in recent years. Adipose tissue is pivotal in regulating the metabolism and determining the occurrence of obesity. In the current study, we aimed to investigate the effects of acute fasting (AF) on fat tissue. Mice were subjected to AF for 36 h, receiving normal chow (low-fat diet [LFD]) or a high-fat diet (HFD), with free ad libitum access to drinking water, and those fed on free-diet counterparts without fasting serveding as controls. We found that AF obviously reshaped the morphology of fat tissue (WAT) and promoted the beiging of white adipose tissue in both LFD- and HFD-fed mice. AF principally improved the lipid metabolism, and increased the M2- polarization of macrophages in WAT white fat tissue of HFD-fed mice. Interestingly, we found that AF dramatically upregulated Sirt5 expression levels and fat tissue succinylation, suggesting that AF-induced beneficial effects on fat might occur via the regulation of Sirt5 levels and altered succinylation in fatty tissues. Our study clearly showed the remodeling function of adipose tissue during AF; in terms of mechanism, the regulation of succinylation levels by AF might provide new insights into the mechanism(s) underlying the improvement in fat metabolism by energy restriction.

Adipogenesis in Different Body Depots and Tumor Development.

Adipose tissue (AT) forms depots at different anatomical locations throughout the body, being in subcutaneous and visceral regions, as well as the bone marrow. These ATs differ in the adipocyte functional profile, their insulin sensitivity, adipokines' production, lipolysis, and response to pathologic conditions. Despite the recent advances in lineage tracing, which have demonstrated that individual adipose depots are composed of adipocytes derived from distinct progenitor populations, the cellular and molecular dissection of the adipose clonogenic stem cell niche is still a great challenge. Additional complexity in AT regulation is associated with tumor-induced changes that affect adipocyte phenotype. As an integrative unit of cell differentiation, AT microenvironment regulates various phenotype outcomes of differentiating adipogenic lineages, which consequently may contribute to the neoplastic phenotype manifestations. Particularly interesting is the capacity of AT to impose and support the aberrant potency of stem cells that accompanies tumor development. In this review, we summarize the current findings on the communication between adipocytes and their progenitors with tumor cells, pointing out to the co-existence of healthy and neoplastic stem cell niches developed during tumor evolution. We also discuss tumor-induced adaptations in mature adipocytes and the involvement of alternative differentiation programs.