No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Adipose Tissue Cellularity in Human Obesity
Abstract
All human obesity is characterised by adipocyte hypertrophy and when body weight exceeds 170 per cent of ideal, a maximum cell size of roughly twice normal is achieved. With greater severity, hyperplasia becomes increasingly manifest and when body weight exceeds 170 per cent of ideal, the degree of hyperplasia is well correlated with severity. Although severity and hypercellularity are often found in those with early onset of obesity, individuals can be found who are hypercellular but have had a later onset of obesity. Until the details of cellular development in man are more fully understood, the precise timing of 'critical' periods for cellular development must remain speculative.
... Il représente 10 à 20% du stockage des graisses dans l'organisme chez les sujets sains et, comme son nom l'indique, entoure les viscères. L'augmentation de la taille du TAV est généralement associée aux dérégulations métaboliques liées à l'obésité (Hirsch & Batchelor, 1976). En effet, la présence d'adipocytes de grande taille (hypertrophiques) dans ce tissu est corrélée à la dyslipidémie indépendamment de la masse et de la répartition graisseuse (Veilleux et al., 2011). ...
... Les adipocytes différenciés ont un potentiel hypertrophique remarquable, pouvant atteindre jusqu'à plusieurs centaines de micromètres de diamètre. Le nombre d'adipocytes dans un dépôt donné est principalement déterminé au début de la vie et est généralement stable à l'âge adulte (Hirsch & Batchelor, 1976;Spalding et al., 2008). En effet, il existe un très Introduction faible renouvellement adipocytaire chez l'Homme estimé à 10% des adipocytes du TASC remplacés chaque année (Spalding et al., 2008). ...
... L'expansion de la masse grasse, telle qu'elle intervient au cours de l'obésité, conduit à de profondes modifications morphologiques et fonctionnelles du TA associées à une hyperplasie (augmentation du nombre) et hypertrophie (augmentation de la taille) des adipocytes qui affectent leur métabolisme et celui d'autres organes (Boden, 1997;Boden et al., 2002;DeFronzo et al., 1981;Engeli et al., 2005;Hirsch & Batchelor, 1976;Shulman, 2000;Warram et al., 1990;Weisberg et al., 2003). (Laurencikiene et al., 2011), une sécrétion accrue de cytokines inflammatoires (Skurk et al., 2007) et une sécrétion réduite d'adipokines antiinflammatoires telles que la leptine (Skurk et al., 2007) et l'adiponectine (Bambace et al., 2011;Meyer et al., 2013). ...
L’obésité est une pathologie dont la fréquence est en constante augmentation. Elle correspond à un excès de tissu adipeux (TA) dont les fonctions peuvent être altérées. Parmi les dérégulations métaboliques, il peut exister une hyperactivation du système endocannabinoïde (SEC). Ce système, composé de récepteurs aux cannabinoïdes (CB1R et CB2R), de leurs ligands endogènes (EndoCannabinoïdes – ECs) et des enzymes impliquées dans leur biosynthèse et leur dégradation, est présent dans le système nerveux central ainsi que dans divers tissus périphériques.Le blocage des CB1R par le Rimonabant, premier antagoniste commercialisé en 2006, s’est révélé être une approche thérapeutique efficace en réduisant la prise alimentaire, la masse corporelle et en améliorant significativement les paramètres métaboliques. Néanmoins, les troubles psychiatriques sévères associés, consécutifs aux effets centraux, ont valu à ce composé d’être retiré du marché 2 ans plus tard.Depuis, l’utilisation d’antagonistes ne franchissant pas la barrière hémato-encéphalique a permis de démontrer que l’inactivation des CB1R périphériques était suffisante pour diminuer le risque cardio-métabolique chez la souris obèse. Compte tenu du rôle central joué par le TA dans l’étiologie des pathologies associées à l’obésité, il apparait important de préciser la relation existante entre le SEC et le métabolisme adipocytaire. Dans ce contexte, ces travaux de thèse ont pour objectifs de préciser le rôle des ECs sur l’activité lipolytique adipocytaire, d’évaluer les capacités sécrétoires des différents dépôts de TA et d’étudier l’impact d’agonistes et d’antagonistes des CB1R sur l’adipogenèse. Une dernière partie, est consacrée à la caractérisation de l’activité biologique de nouveaux antagonistes des CB1R.Tout d’abord, l’étude des conséquences de la modulation du SEC sur l’activité lipolytique a permis de démontrer que l’activation des CB1R, en stimulant la voie de signalisation PI3K/Akt, conduit à une diminution de la lipolyse. Les résultats suggèrent également que les ECs produits par le TA, pourraient alimenter le pool d’ECs circulants et être à l’origine d’effets exocrines néfastes.L’étude de la production des ECs in vitro, par des explants de TA viscéral et sous-cutané chez la souris et chez l’Homme obèses, a confirmé la modification des capacités sécrétoires en ECs. Ces résultats préliminaires valident une approche méthodologique originale qui nous permet d’envisager une exploration plus poussée des mécanismes de la production des ECs.Par ailleurs, le rôle des ECs sur la différenciation de cellules souches issues de la fraction stroma-vasculaire de TA sain et pathologique de souris a été étudié. Des essais préliminaires ont permis de suggérer l’existence d’un lien entre différenciation adipocytaire et activité des CB1R.Enfin, les études de caractérisation de nouveaux antagonistes des CB1R ont démontré des effets intéressants des molécules JM-00266 et HR-0133 sur la masse corporelle et le métabolisme glucido-lipidique. Toutefois, l’optimisation, le développement et la caractérisation de ces nouveaux types d’antagonistes à des fins thérapeutiques apparait essentiel dans la lutte contre l’obésité et ses complications.Mots clés : Obésité, Système Endocannabinoïde, Tissu Adipeux, Métabolisme glucido-lipidique
... Studies performed in humans and rodents in the 1970s established that individuals with obesity had larger adipocytes than lean individuals [18,21,51]. Furthermore, cell size was shown to be variable among individuals within the same group, between different fat depots, and even within depots [18], revealing enormous heterogeneity within adipocyte sizes. ...
... Due to their terminally differentiated nature, it was long thought that human adipocytes could not be acquired during adulthood and WAT expansion occurred via hypertrophic growth (i.e., obesity) [51]. Nevertheless, several studies have reported that increased adipocyte volume does not entirely account for the variability in fat mass either within or between lean individuals or those with obesity [26,45]. ...
The alarming increase in obesity and its related metabolic health complications, such as type 2 diabetes, has evolved into a global pandemic. Obesity is mainly characterized by excessive accumulation of adipose tissue, primarily due to an imbalance between energy intake and expenditure. Prolonged positive energy balance leads to the expansion of existing adipocytes (hypertrophy) and/or an increase in preadipocyte and adipocyte number (hyperplasia) to accommodate excess energy intake. However, obesity is not solely defined by increases in adipocyte size and number. The turnover of adipose tissue cells also plays a crucial role in the development and progression of obesity. Cell turnover encompasses the processes of cell proliferation, differentiation, and apoptosis, which collectively regulate the overall cell population within adipose tissue. Lipid turnover represents another critical factor that influences how adipose tissue stores and releases energy. Our understanding of adipose tissue lipid turnover in humans remains limited due to the slow rate of turnover and methodological constraints. Nonetheless, disturbances in lipid metabolism are strongly associated with altered adipose tissue lipid turnover. In obesity, there is a decreased rate of triglyceride removal (lipolysis followed by oxidation), leading to the accumulation of triglycerides over time. This review provides a comprehensive summary of findings from both in vitro and in vivo methods used to study the turnover of adipose cells and lipids in metabolic health and disease. Understanding the mechanisms underlying cellular and lipid turnover in obesity is essential for developing strategies to mitigate the adverse effects of excess adiposity.
... Despite multivariant changes in cell subtype changes, we did not see obvious changes in iWAT cellularity, relative to the dramatic changes in cellular status. This coincides with the fact that the cellular development (hypercellularity) in adipose tissue is mainly found in early onset of obesity or under extreme obese condition and stays constant in adulthood [51,52]. It is also worth noting that in a recent comprehensive sn-seq analysis of adipose tissue between lean and obese individuals, similar conclusion is obtained that little cellularity is observed between different groups of people [18]. ...
... Briefly, cells with <20% mitochondrial DNA [50], >200 unique UMI counts, and <6,000 unique UMI counts based on their distribution in the sample were remained for further analysis. Counts were normalized to obtain correct relative gene expression abundances between cells [51]. Sn-seq and sc-seq data were integrated through the FindIntegrationAnchors and IntegratedData functions of the Seurat package, where the FindIntegrationAnchors function was used to identify anchors and the IntegrateData function was used the identified anchors to integrate the dataset [52]. ...
Adipose browning has demonstrated therapeutic potentials in several diseases. Here, by conducting transcriptomic profiling at the single-cell and single-nucleus resolution, we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue (iWAT) at thermoneutrality or chronic cold condition. All major nonimmune cells within the iWAT, including adipose stem and progenitor cells (ASPCs), mature adipocytes, endothelial cells, Schwann cells, and smooth muscle cells, were recovered, allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling. Our findings also unravel the existence of subpopulations in mature adipocytes, ASPCs, and endothelial cells, as well as new insights on their interconversion and reprogramming in response to cold. The adipocyte subpopulation competent of major histocompatibility complex class II (MHCII) antigen presentation is potentiated. Furthermore, a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCII+ adipocyte. Beige adipocytes are transdifferented from preexisting lipid generating adipocytes, which exhibit developmental trajectory from de novo differentiation of amphiregulin cells (Aregs). Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold. Our data reveal fundamental changes during cold-evoked adipose browning.
... index equal or higher than 30 kg/m 2 , with an increase in adipocyte number and size [3]. Obesity leads to augmented cardiovascular and diabetes risk factors [4] with some disorders such as dyslipidaemia, non-alcoholic fatty liver disease, as well as oxidative and inflammatory disruptions [5][6][7][8]. ...
... 1) had 125-µm isotropic voxels (each of an array of elements of volume that constitute a notional three-dimensional space, especially each of an array of discrete elements into which a representation of a three-dimensional object is divided) and was analysed through PMOD software (PMOD Technologies, Zurich, Switzerland). Finally, images were segmented according to adipose tissue density and voxels corresponding to adipose tissue were interpreted as total fat volume, expressed as mm 3 . ...
Oxidative damage and chronic inflammation have been proven as one of the major factors associated with obesity, which increases the incidence of non-communicable chronic diseases. In this sense, the development of new functional products aiming at the palliation of oxidative stress and inflammatory disruption can be a determining factor for public health as seen in previous researches. In this study, a blend of potentially bioavailable dietary phenolics was added to low sodium and low-fat cooked ham. A diet-induced obesity model in C57/BL6J mice has been used for testing the effectiveness of the phenolic blend and the new functionalized product, which bioavailability was tested by UPLC-ESI-QTOF-MS. After obesity induction, different oxidative and inflammatory biomarkers were evaluated. Results in the murine induced obesity model, demonstrate a robust statistically significant improvement in key parameters related with obesity risk in the groups feed with a phenolic-enriched diets (P) + high-fat diet (HFD) and phenolic enriched cooked ham (PECH) + HFD. In both groups there was an improvement in body composition parameters, inflammatory biomarkers and antioxidant enzymes levels. Specifically in the group feed with the phenolic enriched cooked ham (PECH + HFD) there was an improvement of total fat volume (23.08% reduction), spleen index (22.04% of reduction), plasmatic MCP-1 (18% reduction), IL-6 (38.94% reduction), IL-10 (13.28% reduction), TNF-α (21.32% reduction), gut IL-1β (10.86% reduction), gut IL-6 (13.63% reduction) and GPx (60.15% increase) and catalase (91.37% increase) enzymes. Thus, the functionalized ham could be considered an appropriate dietary polyphenol source, which might improve the oxidative and inflammatory status and could finally result in the potential decrease of the risk of certain non-communicable chronic diseases.
... The understanding of obesity-induced changes in adipose tissue microenvironment better explains the impact of obesity on the metabolic function and immunological processes. [1,2] Obesity initiated by the intake of excessive calories, [3,4] leads to adipocyte hypertrophy altering the cellular composition of the adipose tissue and modulating the activity and population of other cells within the adipose tissue. [1] Adipose tissue from obese organisms when compared to adipose tissue from lean organisms is infiltrated with a large number of macrophages associated with systemic inflammation and insulin resistance. ...
Background: Low-grade inflammation, characterized by increase of pro-inflammatory cytokines and decrease of anti-inflammatory cytokines, has been implicated in the pathogenesis of obesity and its associated complications. The study determined the levels of Adipokines (Leptin and Adiponectin) in obese and non-obese subjects with or without hypertension in a Nigerian population, in comparison with healthy (control) subjects. Method: This cross-sectional study involved 60 physician diagnosed obese subjects attending the Endocrine and cardiology Clinics of the University of Port Harcourt Teaching Hospital, and 60 sex matched non-obese subjects recruited from the blood donor centre. Obese subjects were divided into two groups: subjects with (30) and without (30) hypertension based on Physician assessment. Controls were also divided into two groups: controls with (30) and without (30) hypertension based on Physician assessment. Serum levels of leptin and adiponectin were evaluated using commercial Enzyme linked immunosorbent assay (ELISA) technique. Result: The results showed that the mean serum level of leptin was significantly (P<0.05) higher in the subjects (1598.65+151.1; 2833.35+297.1) compared to controls (1408.28+503.4;1269.85+511.3). Also, the mean serum level of adiponectin was significantly (P<0.05) lower in the subjects (6.64+4.0;7.12+1.3) compared to controls (8.34+5.4;18.25+8.2). Conclusion: The results suggest that serum levels of leptin and adiponectin were altered, and that obesity and hypertension are associated with elevated and decreased serum concentration of leptin and adiponectin, respectively in the Nigerian population studied, which greatly affects the physiology of the immune cells and hereby generating a pathogenic environment in obesity and hypertension. Key words: Obesity, Hypertension, Adipokines, Leptin, Adiponectin.
... The role of adipogenesis in regulating obesity phenotypes is controversial in the field. Some studies showed that adipogenesis increases significantly during both genetic and diet-induced obesity (Faust et al., 1978(Faust et al., , 1984Hirsch & Batchelor, 1976). Others have shown that adipocyte hypertrophy is the main contributor to obesity (Hirsch & Han, 1969;Johnson & Hirsch, 1972). ...
Obesity is a global health problem characterized by excessive fat accumulation, driven by adipogenesis and lipid accumulation. Long non‐coding RNAs (lncRNAs) have recently been implicated in regulating adipogenesis and adipose tissue function. Mouse lncRNA U90926 was previously identified as a repressor of in vitro adipogenesis in 3T3‐L1 preadipocytes. Consequently, we hypothesized that, in vivo, U90926 may repress adipogenesis, and hence its deletion would increase weight gain and adiposity. We tested the hypothesis by applying U90926 ‐deficient (U9‐KO) mice to a high‐throughput phenotyping pipeline. Compared with WT, U9‐KO mice showed no major differences across a wide range of behavioral, neurological, and other physiological parameters. In mice fed a standard diet, we have found no differences in obesity‐related phenotypes, including weight gain, fat mass, and plasma concentrations of glucose, insulin, triglycerides, and free fatty acids, in U9‐KO mice compared to WT. U90926 deficiency lacked a major effect on white adipose tissue morphology and gene expression profile. Furthermore, in mice fed a high‐fat diet, we found increased expression of U90926 in adipose tissue stromal vascular cell fraction, yet observed no effect of U90926 deficiency on weight gain, fat mass, adipogenesis marker expression, and immune cell infiltration into the adipose tissue. These data suggest that the U90926 lacks an essential role in obesity‐related phenotypes and adipose tissue biology in vivo.
... Their contents that is triglycerides (oil) are released after disruption of the cell membrane. Adipose tissue consists in volume of approximately 90% adipocytes [30], although the volume of adipocytes also depends on donor adipocyte cell hypertrophy which is influenced by factors such as body mass index [31]. Mechanical fractionation should therefore result in a ratio of approximately 9:1 of oil:tSVF. ...
Clinical indications for adipose tissue therapy are expanding towards a regenerative-based approach. Adipose-derived stromal vascular fraction consists of extracellular matrix and all nonadipocyte cells such as connective tissue cells including fibroblasts, adipose-derived stromal cells (ASCs) and vascular cells. Tissue stromal vascular fraction (tSVF) is obtained by mechanical fractionation, forcing adipose tissue through a device with one or more small hole(s) or cutting blades between syringes. The aim of this scoping review was to assess the efficacy of mechanical fractionation procedures to obtain tSVF. In addition, we provide an overview of the clinical, that is, therapeutic, efficacy of tSVF isolated by mechanical fraction on skin rejuvenation, wound healing and osteoarthritis. Procedures to obtain tissue stromal vascular fraction using mechanical fractionation and their associated validation data were included for comparison. For clinical outcome comparison, both animal and human studies that reported results after tSVF injection were included. We categorized mechanical fractionation procedures into filtration (n = 4), centrifugation (n = 8), both filtration and centrifugation (n = 3) and other methods (n = 3). In total, 1465 patients and 410 animals were described in the included clinical studies. tSVF seems to have a more positive clinical outcome in diseases with a high proinflammatory character such as osteoarthritis or (disturbed) wound healing, in comparison with skin rejuvenation of aging skin. Isolation of tSVF is obtained by disruption of adipocytes and therefore volume is reduced. Procedures consisting of centrifugation prior to mechanical fractionation seem to be most effective in volume reduction and thus isolation of tSVF. tSVF injection seems to be especially beneficial in clinical applications such as osteoarthritis or wound healing. Clinical application of tSVF appeared to be independent of the preparation procedure, which indicates that current methods are highly versatile.
... Obesity is the result of both hypertrophy, an increase in adipocyte size, and hyperplasia, an increase in cell numbers (Hirsch and Batchelor, 1976;Lane and Tang, 2005). Adipocyte hyperplasia arises through adipogenesis, a complex process involving proliferation and differentiation of precursors into mature adipocytes (Rosen et al., 2000). ...
Background: Overweight or obesity poses a significant risk of many obesity-related metabolic diseases. Among all the potential new therapies, stem cell-based treatments hold great promise for treating many obesity-related metabolic diseases. However, the mechanisms regulating adipocyte stem cells/progenitors (precursors) are unknown. The aim of this study is to investigate if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation.
Methods: Cyclin-dependent kinase 6 ( Cdk6 ) mouse models together with stem cells derived from stromal vascular fraction (SVF) or mouse embryonic fibroblasts (MEFs) of Cdk6 mutant mice were used to determine if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation.
Results: We found that mice with a kinase inactive CDK6 mutants ( K43M ) had fewer precursor residents in the SVF of adult white adipose tissue (WAT). Stem cells from the SVF or MEFs of K43M mice had defects in proliferation and differentiation into the functional fat cells. In contrast, mice with a constitutively active kinase CDK6 mutant ( R31C ) had the opposite traits. Ablation of RUNX1 in both mature and precursor K43M cells, reversed the phenotypes.
Conclusion: These results represent a novel role of CDK6 in regulating precursor numbers, proliferation, and differentiation, suggesting a potential pharmacological intervention for using CDK6 inhibitors in the treatment of obesity-related metabolic diseases.
... Genetics also plays a role in an individual's predisposition to adipose tissue hyperplasia, although our understanding on the subject is still evolving, and it is mostly investigated in animal models [65][66][67]. Genetic factors contribute to the development and maintenance of adipose tissue by controlling processes such as cell proliferation, differentiation, and apoptosis. One of the key genetic factors playing a role in adipose tissue hyperplasia regulation is leptin. ...
Obesity is a metabolic state generated by the expansion of adipose tissue. Adipose tissue expansion depends on the interplay between hyperplasia and hypertrophy, and is mainly regulated by a complex interaction between genetics and excess energy intake. However, the genetic regulation of adipose tissue expansion is yet to be fully understood. Obesity can be divided into common multifactorial/polygenic obesity and monogenic obesity, non-syndromic and syndromic. Several genes related to obesity were found through studies of monogenic non-syndromic obesity models. However, syndromic obesity, characterized by additional features other than obesity, suggesting a more global role of the mutant genes related to the syndrome and, thus, an additional peripheral influence on the development of obesity, were hardly studied to date in this regard. This review summarizes present knowledge regarding the hyperplasia and hypertrophy of adipocytes in common obesity. Additionally, we highlight the scarce research on syndromic obesity as a model for studying adipocyte hyperplasia and hypertrophy, focusing on Bardet–Biedl syndrome (BBS). BBS obesity involves central and peripheral mechanisms, with molecular and mechanistic alternation in adipocyte hyperplasia and hypertrophy. Thus, we argue that using syndromic obesity models, such as BBS, can further advance our knowledge regarding peripheral adipocyte regulation in obesity.
... The chronic disease of obesity can be categorized into two main types: hyperplasia, in which the number of fat cells increases, and hypertrophy, in which the volume of fat cells increases (18)(19). Hypertrophy is the most prominent feature in most obese patients, but it has a stronger correlation with severe obesity and is highly characteristic of patients with severe obesity (20). At the cellular level, obesity was originally considered a hypertrophic disease, in which both the number and size of adipose cells increases (21). ...
Obesity, a chronic disease characterized by excessive body fat accumulation, is associated with significant health risks. The state of being overweight or obese leads to a number of chronic diseases, including cardiovascular disease, type 2 diabetes, cancer, and osteoarthritis. Accordingly, the regulation of adipocyte proliferation and differentiation has been the focus of many studies. The goal of the present study was to investigate the function of fucoxanthin, extracted from Sargassum horneri, in adipocyte (3T3-L1 cells) differentiation. A quantitative real-time polymerase chain reaction was conducted to investigate the mRNA expression levels of adipocyte differentiation-related genes under fucoxanthin stimulation. All adipocyte-related genes responded to PIC stimuli. Additionally, using western blotting, we confirmed that fucoxanthin reduced adipocyte differentiation. These results indicate that fucoxanthin extracted from Sargassum horneri can regulate adipogenesis. Further studies are needed to reveal the signaling pathways that lead to reduced adipocyte differentiation induced by fucoxanthin.
... Physiologically, adipose tissue has a remarkable ability to rapidly expand in times of nutrient surplus by increasing both the adipocyte size and number, accompanied by increased vascularisation [5,6]. However, chronic nutrient excess, as occurs in obesity, can result in the excessive expansion of adipose tissue, which leads to its dysfunction and is associated with increased inflammation, reduced vascularisation, hypoxia, mitochondrial dysfunction, oxidative stress, changes to the adipokine secretome, and insulin resistance [7,8]. ...
Obesity is associated with significant metabolic co-morbidities, such as diabetes, hypertension, and dyslipidaemia, as well as a range of cardiovascular diseases, all of which lead to increased hospitalisations, morbidity, and mortality. Adipose tissue dysfunction caused by chronic nutrient stress can result in oxidative stress, mitochondrial dysfunction, inflammation, hypoxia, and insulin resistance. Thus, we hypothesised that reducing adipose tissue oxidative stress via adipose tissue-targeted overexpression of the antioxidant mitochondrial catalase (mCAT) may improve systemic metabolic function. We crossed mCAT (floxed) and Adipoq-Cre mice to generate mice overexpressing catalase with a mitochondrial targeting sequence predominantly in adipose tissue, designated AdipoQ-mCAT. Under normal diet conditions, the AdipoQ-mCAT transgenic mice demonstrated increased weight gain, adipocyte remodelling, and metabolic dysfunction compared to the wild-type mice. Under obesogenic dietary conditions (16 weeks of high fat/high sucrose feeding), the AdipoQ-mCAT mice did not result in incremental impairment of adipose structure and function but in fact, were protected from further metabolic impairment compared to the obese wild-type mice. While AdipoQ-mCAT overexpression was unable to improve systemic metabolic function per se, our results highlight the critical role of physiological H2O2 signalling in metabolism and adipose tissue function.
... Increases in fat tissue are usually related to two processes that are a rise in the size of the fat cells which is called adipocyte hypertrophy and in the number of fat cells which is called adipocyte hyperplasia. The adipocyte life cycle is the formation of mature adipocytes from the precursor fat cells called preadipocytes (Hirsch & Batchelor, 1976;Rayalam et al., 2008). This cycle includes apoptosis of preadipocytes or mature adipocytes in addition to the proliferation of preadipocytes, differentiation of adipocytes (adipogenesis), and lipolytic activity. ...
Abstract Obesity is a rapidly rising global public health concern in both developed and developing countries. Tea components, especially caffeine and catechins, may have beneficial effects in the treatment of obesity. Tea is a widely consumed beverage all over the world and it is a significant part of the culture, especially in Asian countries. Among the tea types, white tea is the least processed and the content of catechins is higher than the others. Many studies have been conducted on tea's health effects, especially on weight management. The beneficial effects of the consumption of tea containing polyphenols and caffeine such as helping to maintain body weight and playing crucial roles in fat metabolism have been shown in many studies. While there are many studies on green tea in the literature, interestingly, studies conducted with white tea are insufficient but showed significant results. Considering the positive health effects of bioactive components in tea species, the results of studies with white tea may be promising. Tea components have many promising health effects; however, these effects are not clearly understood yet, particularly regarding body weight management mechanisms such as fat oxidation and thermogenesis. Therefore, further well‐planned preclinical and clinical research is required to understand the effectiveness and mechanisms of white tea on body weight.
... Increases in fat tissue are usually related to two processes that are a rise in the size of the fat cells which is called adipocyte hypertrophy and in the number of fat cells which is called adipocyte hyperplasia. The adipocyte life cycle is the formation of mature adipocytes from the precursor fat cells called preadipocytes (Hirsch & Batchelor, 1976;Rayalam et al., 2008). This cycle includes apoptosis of preadipocytes or mature adipocytes in addition to the proliferation of preadipocytes, differentiation of adipocytes (adipogenesis), and lipolytic activity. ...
... If it reaches the human body's physiological requirements, excess calorie consumption can be responded to and adapted to at the cellular level. There is a strong link between obesity and enlarged adipocyte size, and once body weight exceeds 170% of optimal body weight, maximal cell size doubles that of normal, affecting adipose tissue functionality [7,20]. The recruitment of adipogenic progenitors and growth factors including insulin-like growth factor (IGF)-I, IGF-binding proteins, tumor necrosis factor (TNF)-α, angiotensin II, and macrophage colony-stimulating factor drive adipocyte hyperplasia induced by caloric overload [7,21]. ...
Obesity has recently emerged as one of the most severe health concerns. It is a key autonomous risk factor for heart failure and contributes to cardiovascular disease (CVD) risk factors such as hypertension, type 2 diabetes, and metabolic abnormalities. Obesity is caused by a metabolic imbalance, which occurs when calories burnt are fewer than the number of calories consumed. There are several pathways accountable for the adverse impacts of obesity on the cardiovascular system. Inflammatory cell infiltration develops in the adipose tissue, the pancreas, and other issues similar to the progression of obesity. Inflammation is triggered by immune cells that invade dysfunctional adipose tissue. The atherosclerotic inflammation phase, related to obesity, induces coronary calcification. Obesity is linked to elevated levels of leptin and high blood pressure. Leptin causes systemic vasoconstriction, sodium retention, and increased blood pressure by influencing the synthesis of nitric oxide and activating the sympathetic nervous system. Obesity is a well-known risk factor for CVD and is one of the leading causes of the greater risk of diseases, including dyslipidemia, hypertension, depression, metabolic syndrome, atrial fibrillation, and heart failure in adults and children. When used with dietary improvements, antiobesity drugs improve the probability of experiencing clinically healthy (5%) weight loss. This review aimed to address the consequences of obesity on cardiac structure and function, risk factors, the impact of the obesity paradox, pharmacological treatment strategies for managing and recommended exercise and diet.
... Adipocytes secrete different peptides that control a wide range of functions including whole-body energy balance, inflammation, insulin sensitivity, blood pressure regulation, angiogenesis and cell development (6) . A lean adult has about 35 billion adipocytes and each adipocyte contains about 0.4 to 0.6 ug of triglyceride; an extremely obese adult can have 4 times as many adipocytes (125 billion), each containing twice as much lipid (0.8 to 1.2 u g of triglyceride) (7) . ...
... As a complex, active, and dynamically changing multifunctional organelle, the lipid droplet is mainly composed of TG and sterol esters and is involved in lipid metabolism and storage as well as protein storage and degradation (Ploegh, 2007), membrane transport (Bartz et al., 2007), signal transduction, and other metabolic processes (Cohen et al., 2011). Generally, adipocytes grow and accumulate lipids with limits in order to avoid tissue damage lesions (Hirsch and Batchelor, 1976). Our results showed that serum IGF-1 content was increased and the expression of PCK1 gene was upregulated in BA-TL group, and the results of liver Oil Red O staining showed that the B.A-TL promoted lipid droplet formation, indicating that B.A-TL enhanced gluconeogenesis to produce TG via IGF-1-regulated GLU internalization process. ...
Bacillus amyloliquefaciens TL (B.A-TL) is well-known for its capability of promoting protein synthesis and lipid metabolism, in particular, the abdominal fat deposition in broilers. However, the underlying molecular mechanism remains unclear. In our study, the regulations of lipid metabolism of broilers by B.A-TL were explored both in vivo and in vitro. The metabolites of B.A-TL were used to simulate in vitro the effect of B.A-TL on liver metabolism based on the chicken hepatocellular carcinoma cell line (i.e., LMH cells). The effects of B.A-TL on lipid metabolism by regulating insulin/IGF signaling pathways were investigated by applying the signal pathway inhibitors in vitro. The results showed that the B.A-TL metabolites enhanced hepatic lipid synthesis and stimulated the secretion of IGF-1. The liver transcriptome analysis revealed the significantly upregulated expressions of four genes (SI, AMY2A, PCK1, and FASN) in the B.A-TL treatment group, mainly involved in carbohydrate digestion and absorption as well as biomacromolecule metabolism, with a particularly prominent effect on fatty acid synthase (FASN). Results of cellular assays showed that B.A-TL metabolites were involved in the insulin/IGF signaling pathway, regulating the expressions of lipid metabolism genes (e.g., FASN, ACCα, LPIN, and ACOX) and the FASN protein, ultimately regulating the lipid metabolism via the IGF/PI3K/FASN pathway in broilers.
... Adipose tissue can expand by recruiting more adipocytesi.e., hyperplasia, likely from adipocyte progenitor cells present within the tissue, and/or by increasing adipocyte size/volume (hypertrophy) (7)(8)(9). Indeed, the adipocyte can uniquely vary in size, ranging from <20 to 300 µm in diameter (10). Cross-sectional studies, even if not unanimously, link larger adipocytes with clinical parameters consistent with greater metabolic risk [ Table 1, tier 1, and excellently reviewed in (10,44)]. ...
Obesity is a heterogenous condition that affects the life and health of patients to different degrees and in different ways. Yet, most approaches to treat obesity are not currently prescribed, at least in a systematic manner, based on individual obesity sub-phenotypes or specifically-predicted health risks. Adipose tissue is one of the most evidently affected tissues in obesity. The degree of adipose tissue changes – “adiposopathy”, or as we propose to relate to herein as Obesity-related Adipose tissue Disease (OrAD), correspond, at least cross-sectionally, to the extent of obesity-related complications inflicted on an individual patient. This potentially provides an opportunity to better personalize anti-obesity management by utilizing the information that can be retrieved by assessing OrAD. This review article will summarize current knowledge on histopathological OrAD features which, beyond cross-sectional analyses, had been shown to predict future obesity-related endpoints and/or the response to specific anti-obesity interventions. In particular, the review explores adipocyte cell size, adipose tissue inflammation, and fibrosis. Rather than highly-specialized methods, we emphasize standard pathology laboratory approaches to assess OrAD, which are readily-available in most clinical settings. We then discuss how OrAD assessment can be streamlined in the obesity/weight-management clinic. We propose that current studies provide sufficient evidence to inspire concerted efforts to better explore the possibility of predicting obesity related clinical endpoints and response to interventions by histological OrAD assessment, in the quest to improve precision medicine in obesity.
... Adipose tissue can expand by recruiting more adipocytesi.e., hyperplasia, likely from adipocyte progenitor cells present within the tissue, and/or by increasing adipocyte size/volume (hypertrophy) (7)(8)(9). Indeed, the adipocyte can uniquely vary in size, ranging from <20 to 300 µm in diameter (10). Cross-sectional studies, even if not unanimously, link larger adipocytes with clinical parameters consistent with greater metabolic risk [ Table 1, tier 1, and excellently reviewed in (10,44)]. ...
Obesity is a heterogenous condition that affects the life and health of patients to different degrees and in different ways. Yet, most approaches to treat obesity are not currently prescribed, at least in a systematic manner, based on individual obesity sub-phenotypes or specifically-predicted health risks. Adipose tissue is one of the most evidently affected tissues in obesity. The degree of adipose tissue changes – “adiposopathy”, or as we propose to relate to herein as Obesity-related Adipose tissue Disease (OrAD), correspond, at least cross-sectionally, to the extent of obesity-related complications inflicted on an individual patient. This potentially provides an opportunity to better personalize anti-obesity management by utilizing the information that can be retrieved by assessing OrAD. This Review article will summarize current knowledge on histopathological OrAD features which, beyond cross-sectional analyses, had been shown to predict future obesity-related endpoints and/or the response to specific anti-obesity interventions. In particular, the review explores adipocyte cell size, adipose tissue inflammation, and fibrosis. Rather than highly-specialized methods, we emphasize standard pathology laboratory approaches to assess OrAD, which are readily-available in most clinical settings. We then discuss how OrAD assessment can be streamlined in the obesity/weight-management clinic. We propose that current studies provide sufficient evidence to inspire concerted efforts to better explore the possibility of predicting obesity related clinical endpoints and response to interventions by histological OrAD assessment, in the quest to improve precision medicine in obesity.
... First, obese subjects have both more adipocytes and larger, more hypertrophic adipocytes than normal-weight controls (Salans et al., 1973). Adipocyte size increases up to the point of moderate obesity, after which subsequent increases in fat mass are characterized by increases in adipocyte number (Hirsch and Batchelor, 1976). Notably, there is substantial interindividual variation; at any given fat mass, people can exhibit a more hypertrophic or more hyperplastic adipose-tissue phenotype. ...
Adipose tissue, colloquially known as “fat,” is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and immune responses. A crucial property of adipose tissue is its high degree of plasticity. Physiologic stimuli induce dramatic alterations in adipose-tissue metabolism, structure, and phenotype to meet the needs of the organism. Limitations to this plasticity cause diminished or aberrant responses to physiologic cues and drive the progression of cardiometabolic disease along with other pathological consequences of obesity.
... The excessive consumption of high calories and low energy expenditure are major causative factors for obesity and its comorbidities [22]. Obesity is characterized as an excessive accumulation of adipose tissue in the body [23]. When adipocyte becomes overly accumulated, it may result in adipocyte endocrine dysfunction, promoting dyslipidemia [24]. ...
Background/objectives:
Aster yomena (Kitam.) Honda (AY) has remarkable bioactivities, such as antioxidant, anti-inflammation, and anti-cancer activities. On the other hand, the effects of AY against obesity-induced insulin resistance have not been reported. Therefore, this study examined the potential of AY against obesity-associated insulin resistance in high-fat diet (HFD)-fed mice.
Materials/methods:
An obesity model was established by feeding C57BL/6J mice a 60% HFD for 16 weeks. The C57BL6/When ethyl acetate fraction from AY (EFAY) at doses of 100 and 200 mg/kg/day was administered orally to mice fed a HFD for the last 4 weeks. Normal and control groups were administered water orally. The body weight and fasting blood glucose were measured every week. Dietary intake was measured every other day. After dissection, blood and tissues were collected from the mice.
Results:
The administration of EFAY reduced body and organ weights significantly compared to HFD-fed control mice. The EFAY-administered groups also improved the serum lipid profile by decreasing the triglyceride, total cholesterol, and low-density lipoprotein compared to the control group. In addition, EFAY ameliorated the insulin resistance-related metabolic dysfunctions, including the fasting blood glucose and serum insulin level, compared to the HFD-fed control mice. The EFAY inhibited lipid synthesis and insulin resistance by down-regulation of hepatic fatty acid synthase and up-regulation of the AMP-activated protein kinase pathway. EFAY also reduced lipid peroxidation in the liver, indicating that EFAY protected hepatic injury induced by obesity.
Conclusions:
These results suggest that EFAY improved obesity-associated insulin resistance by regulating the lipid and glucose metabolism, suggesting that AY could be used as a functional food to prevent obesity and insulin resistance.
... The accumulation of vWAT facilitates the development of obesity-associated comorbidities, while the accumulation of scWAT, especially in the gluteofemoral area, seems to have beneficial effects against metabolic syndrome [9,10]. In obesity, the expansion of adipose tissue is due to an increase in size (hypertrophy) and in the adipocyte number (hyperplasia) [11]. Additionally, triglycerides can also ectopically deposit in the liver, muscle and heart. ...
Aging usually comes associated with increased visceral fat accumulation, reaching even an obesity state, and favoring its associated comorbidities. One of the processes involved in aging is cellular senescence, which is highly dependent on the activity of the regulators of the cell cycle. The aim of this study was to analyze the changes in the expression of p27 and cdk2 in different adipose tissue depots during aging, as well as their regulation by obesity in mice. Changes in the expression of p27 and CDK2 in visceral and subcutaneous white adipose tissue (WAT) biopsies were also analyzed in a human cohort of obesity and type 2 diabetes. p27, but not cdk2, exhibits a lower expression in subcutaneous than in visceral WAT in mice and humans. p27 is drastically downregulated by aging in subcutaneous WAT (scWAT), but not in gonadal WAT, of female mice. Obesity upregulates p27 and cdk2 expression in scWAT, but not in other fat depots of aged mice. In humans, a significant upregulation of p27 was observed in visceral WAT of subjects with obesity. Taken together, these results show a differential adipose depot-dependent regulation of p27 and cdk2 in aging and obesity, suggesting that p27 and cdk2 could contribute to the adipose-tissue depot’s metabolic differences. Further studies are necessary to fully corroborate this hypothesis.
... Conversely, chronic caloric excess or declines in energy utilization results in adipose tissue expansion through the hypertrophy of existing adipocytes and the recruitment and adipogenic differentiation of tissue progenitor cells. 1,2 The linkage between prolonged energy excess that leads to obesity and a subsequent increase in the risk for type 2 diabetes, cardiovascular disease, and renal disease 3,4 highlights the need to fully understand the genetic and endocrine networks that regulate adipocyte development. ...
The Wnt signaling antagonist, sclerostin, is a potent suppressor of bone acquisition that also mediates endocrine communication between bone and adipose. As a result, Sost−/− mice exhibit dramatic increases in bone formation but marked decreases in visceral and subcutaneous adipose that are secondary to alterations in lipid synthesis and utilization. While interrogating the mechanism by which sclerostin influences adipocyte metabolism, we observed paradoxical increases in the adipogenic potential and numbers of CD45⁻:Sca1⁺:PDGFRα⁺ adipoprogenitors in the stromal vascular compartment of fat pads isolated from male Sost−/− mice. Lineage tracing studies indicated that sclerostin deficiency blocks the differentiation of PDGFRα⁺ adipoprogenitors to mature adipocytes in association with increased Wnt/β‐catenin signaling. Importantly, osteoblast/osteocyte‐specific Sost gene deletion mirrors the accumulation of PDGFRα⁺ adipoprogenitors, reduction in fat mass, and improved glucose metabolism evident in Sost−/− mice. These data indicate that bone‐derived sclerostin regulates multiple facets of adipocyte physiology ranging from progenitor cell commitment to anabolic metabolism.
... However, several studies have demonstrated that the adipocyte number increases when body fat reaches 25% of the total body weight in children and adults [2,3]. Interestingly, adipocyte precursors from obese subjects proliferate more rapidly in culture than the cells from lean individuals [4,5]. New adipocytes constantly arise from a preexisting population of undifferentiated progenitor cells. ...
Adipogenic differentiation from stem cells has become a research target due to the increasing interest in obesity. It has been indicated that adipocytes can secrete palmitic acid methyl ester (PAME), which is able to regulate stem cell proliferation. However, the effects of PAME on adipogenic differentiation in stem cell remain unclear. Here, we present that the adipogenic differentiation medium supplemented with PAME induced the differentiation of rat adipose tissue-derived mesenchymal stem cells (rAD-MSCs) into adipocyte. rAD-MSCs were treated with PAME for 12 days and then subjected to various analyses. The results from the present study show that PAME significantly increased the levels of adipogenic differentiation markers, PPARγ and Gpd1, and enhanced adipogenic differentiation in rAD-MSCs. Furthermore, the level of GPR40/120 protein increased during induction of adipocyte differentiation in rAD-MSCs. Cotreatment with PAME and a GPR40/120 antagonist together inhibited the PAME-enhanced adipogenic differentiation. Moreover, PAME significantly increased phosphorylation of extracellular signal-regulated kinases (ERK), but not AKT and mTOR. Cotreatment with PAME and a GPR40/120 antagonist together inhibited the PAME-enhanced ERK phosphorylation and adipogenic differentiation. PAME also increased the intracellular Ca²⁺ levels. Cotreatment with PAME and a Ca²⁺ chelator or a phospholipase C (PLC) inhibitor prevented the PAME-enhanced ERK phosphorylation and adipogenic differentiation. Our data suggest that PAME activated the GPR40/120/PLC-mediated pathway, which in turn increased the intracellular Ca²⁺ levels, thereby activating the ERK, and eventually enhanced adipogenic differentiation in rAD-MSCs. The findings from the present study might help get insight into the physiological roles and molecular mechanism of PAME in regulating stem cell differentiation.
... Visceral WAT expands via two distinct mechanisms: hypertrophy (increase in the size of adipocytes) and hyperplasia (increase in the number of adipocytes). Hyperplasia is correlated more strongly with the severity of obesity and is most marked in the severely obese [49]. Prolonged periods of weight gain in adulthood increase the number of adipocytes [50]. ...
IL-20 is a proinflammatory cytokine of the IL-10 family and involved in several diseases. However, the regulatory role of IL-20 in obesity is not well understood. We explored the function of IL-20 in the pathogenesis of obesity-induced insulin resistance by ELISA, western blotting, and flow cytometry. The therapeutic potential of IL-20 monoclonal antibody 7E for ameliorating diet-induced obesity was analyzed in murine models. Higher serum IL-20 levels were detected in obese patients. It was upregulated in leptin-deficient (ob/ob), leptin-resistant (db/db), and high-fat diet (HFD)-induced murine obesity models. In vitro, IL-20 regulated the adipocyte differentiation and the polarization of bone marrow-derived macrophages into proinflammatory M1 type. It also caused inflammation and macrophage retention in adipose tissues by upregulating TNF-α, monocyte chemotactic protein-1 (MCP-1), netrin-1, and unc5b (netrin receptor) expression in macrophages, and netrin-1, leptin, and MCP-1 in adipocytes. IL-20 promoted insulin resistance by inhibiting glucose uptake in mature adipocytes through the SOCS-3 pathway. In HFD-induced obesity in mice, 7E treatment reduced body weight, and improved glucose tolerance and insulin sensitivity; it also reduced local inflammation and the number of M1-like macrophages in adipose tissues. We have identified a critical role of IL-20 in obesity-induced inflammation and insulin resistance, and we conclude that IL-20 may be a novel target for treating obesity and insulin resistance in patients with metabolic disorders.
... Both obesity and lipoma formation are characterized by adipose tissue overgrowth. While it is known that in obesity both hypertrophy and hyperplasia contribute to adipose tissue expansion (29), it remains unclear whether these mechanisms also promote lipoma formation. Within this study, we investigated the mechanisms leading to aberrant adipose tissue growth and lipoma formation in patients with heterozygous PTEN mutations. ...
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN Hamartoma Tumor Syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, while APCs from PHTS patients’ lipomas retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development we performed functional assays and RNA sequencing of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. FOXO1 transcriptional activity is known to be regulated by insulin signaling and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis activating transcription factor SREBP1. SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared to controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA sequencing of PTEN knockdown vs. control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in PHTS patients.
... These adipose tissues consist of lipid-storing adipocytes, stromal cells, and immune cells such as macrophages. Landmark studies have firmly established that recruitment of monocytes into adipose and peripheral tissues of obese animals promotes inflammation, ectopic fat deposition in the liver, and insulin resistance, via production of inflammatory cytokines such as Tumor necrosis factor (TNF) by monocyte-derived macrophages (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Genetic or pharmacological inhibition of the C-C chemokine receptor type 2 (Ccr2)-dependent recruitment of bone marrow-derived monocytes into tissues prevents or alleviates metabolic syndrome in obese animals (11,(15)(16)(17)(18)21). ...
Macrophages: key mediators of fat storage
Recent work has suggested that macrophages may regulate adiposity, but the mechanisms underlying this process remain unresolved. Cox et al. report that a macrophage-derived growth factor, Pvf3, and its receptor on fat body cells are needed for lipid storage in fruit fly larvae (see the Perspective by O'Brien and Domingos). The mouse Pvf3 ortholog, PDGFcc, was similarly required to store fat in newborn and adult mice. When PDGFcc was blocked or deleted, food intake and absorption were normal, but mice increased their energy expenditure partly due to enhanced brown adipose tissue thermogenesis. PDGFcc was produced exclusively by fat-resident macrophages rather than by those mediating inflammation and insulin resistance. This work may inform future treatments for lipodystrophy, cachexia, and obesity.
Science , abe9383, this issue p. eabe9383 ; see also abj5072, p. 24
... WAT is a vital organ in energy storage, which can excessively accumulate in obese patients (3). The increase of WAT is the result of both hyperplasia and hypertrophy of adipocytes (4). In addition to WAT, there are two types of adipose tissue: brown adipose tissue (BAT) and beige adipose tissue. ...
Brown adipose tissue (BAT), consisted of brown adipocytes and stromal vascular fraction, which includes endothelial cells, lymphocytes, fibroblasts and stem cells, plays a vital role in regulating cardiovascular health and diseases. As a thermogenic organ, BAT can influence body through strengthening energy expenditure by promoting glucose and lipid metabolism. In addition, BAT is also an endocrine organ which is able to secret adipokines in an autocrine and/or paracrine fashion. BAT plays a protective role in cardiovascular system through attenuating cardiac remodeling and suppressing inflammatory response. In this review, we summarize the advances from the discovery of BAT to the present and provide an overview on the role of BAT dysfunction in cardiovascular diseases.
... There was also a significant positive correlation between fasting blood glucose level and SAT TFEB expression, while a tendency for positive correlation without statistical significance was observed between fasting blood glucose level and VAT TFEB expression (Extended Data Fig. 1e,f). In contrast, a significant correlation was not observed between adipocyte size and TFEB expression in VAT or SAT (Extended Data Fig. 1e,f), probably because adipocyte size might not increase further in extreme obesity requiring bariatric surgery 31,32 . Indeed, there was no significant correlation between body weight and adipocyte size in VAT or SAT of obese individuals with or without T2DM ( Supplementary Fig. 1). ...
TFEB, a key regulator of lysosomal biogenesis and autophagy, is induced not only by nutritional deficiency but also by organelle stress. Here, we find that Tfeb and its downstream genes are upregulated together with lipofuscin accumulation in adipose tissue macrophages (ATMs) of obese mice or humans, suggestive of obesity-associated lysosomal dysfunction/stress in ATMs. Macrophage-specific TFEB-overexpressing mice display complete abrogation of diet-induced obesity, adipose tissue inflammation and insulin resistance, which is independent of autophagy, but dependent on TFEB-induced GDF15 expression. Palmitic acid induces Gdf15 expression through lysosomal Ca²⁺-mediated TFEB nuclear translocation in response to lysosomal stress. In contrast, mice fed a high-fat diet with macrophage-specific Tfeb deletion show aggravated adipose tissue inflammation and insulin resistance, accompanied by reduced GDF15 level. Finally, we observe activation of TFEB–GDF15 in ATMs of obese humans as a consequence of lysosomal stress. These findings highlight the importance of the TFEB–GDF15 axis as a lysosomal stress response in obesity or metabolic syndrome and as a promising therapeutic target for treatment of these conditions.
... WAT increases its capacity for storing lipids, via both adipocyte hyperplasia and hypertrophy [19,20]. WAT is also able to undergo a process known as "beiging". ...
Obesity is reaching epidemic proportions and imposes major negative health crises and an economic burden in both high and low income countries. The multifaceted nature of obesity represents a major health challenge, with obesity affecting a variety of different organs and increases the risk of many other noncommunicable diseases, such as type 2 diabetes, fatty liver disease, dementia, cardiovascular diseases, and even cancer. The defining organ of obesity is the adipose tissue, highlighting the need to more comprehensively understand the development and biology of this tissue to understand the pathogenesis of obesity. Adipose tissue is a miscellaneous and highly plastic endocrine organ. It comes in many different sizes and shades and is distributed throughout many different locations in the body. Though its development begins prenatally, quite uniquely, it has the capacity for unlimited growth throughout adulthood. Adipose tissue is also a highly sexually dimorphic tissue, patterning men and women in different ways, which means the risks associated with obesity are also sexually dimorphic. Recent studies show that environmental factors during prenatal and early stages of postnatal development have the capacity to programme the structure and function of adipose tissue, with implications for the development of obesity. This review summarizes the evidence for a role for early environmental factors, such as maternal malnutrition, hypoxia, and exposure to excess hormones and endocrine disruptors during gestation in the programming of adipose tissue and obesity in the offspring. We will also discuss the complexity of studying adipose tissue biology and the importance of appreciating nuances in adipose tissue, such as sexual dimorphism and divergent responses to metabolic and endocrine stimuli. Given the rising levels of obesity worldwide, understanding how environmental conditions in early life affects adipose tissue phenotype and the subsequent development of obesity is of absolute importance.
... 16 Generally, the total number of adipocytes is pre-defined since childhood and remains the same throughout life. 17,18 However, it can be increased in young obesity and adults with over-feeding. 19 In response to lipid flux, subcutaneous pre-adipocytes have increased proliferation, 25,26 whereas visceral adipocytes have tended to have hypertrophy of existing adipocytes for lipid storage. ...
The complex links between obesity, chronic kidney disease (CKD) and cardiovascular disease (CVD) are not completely understood. The objective of this review is to describe and discuss the anatomy, physiology, and biochemistry of the adipose tissue, as well as its involvement in the pathophysiology of CVD and CKD. We searched for original articles in PubMed. The search terms used were “obesity”, “CKD”, and “CVD”. In addition, we also identified publications from our personal databases of literature about obesity, CKD and CVD to identify any important studies that might have been missing from the PubMed search. We further searched the reference lists of identified articles for further relevant papers. Epidemiological studies show that obesity is associated with obesity-related glomerulopathy (ORG) as well as an increase in the risk of CKD in the general population. A number of pathophysiological mechanisms, including renal hemodynamic changes, neurohumoral pathways that activate the sympathetic and renin-angiotensin-aldosterone systems, proinflammatory and profibrotic effects of various adipokines, and insulin resistance may explain the excessive risk of CKD development and progression in obese patients. In patients with mild to moderate CKD, obesity per se contributes a modest increase in cardiovascular risk, while the effect of obesity on the cardiovascular risk of patients with advanced CKD is probably due to the concurrent metabolic syndrome and coexisting cardiovascular risk factors, but the effect of obesity on the cardiovascular risk of patients with advanced CKD is probably the result of the concomitant metabolic syndrome and coexisting cardiovascular risk factors. There are recent data suggesting that subcutaneous and visceral adipose tissue have different and probably opposite effects on the CVD risk in CKD. Further studies are necessary to distinguish the specific clinical implication of different adipose tissue compartments, and to determine the principal mediators that connect obesity, CKD and CVD.
... Generally, obesity is tightly related to adipocyte hypertrophy, and the size of the maximum fat cell was about twice higher than that of normal cells when the body mass was more than 170% to standard [32]. The enlargement of adipocyte size was attributed to the accumulation of TG in adipocytes [33]. ...
Obesity is a common disease over the world and is tightly associated with diabetes mellitus, cardiovascular and cancer disease. Although our previous study showed that the synthetic vanadium-protein (V-P) complex had a better effect on antioxidant and antidiabetic, the relative molecular mechanisms are still entirely unknown. Hence, we investigated the effect of the synthetic V-P complex on adipocyte differentiation (adipogenesis) using human preadipocytes to clarify its molecular mechanisms of action. The primary human preadipocytes were cultured with and without V-P complex during adipocyte differentiation. The cell proliferation, lipid accumulation, and the protein expression of transcription factors and related enzymes were determined for the differentiated human preadipocytes. In this study, the 20 μg/mL of V-P complex reduced the lipid and triglyceride (TG) content by 74.47 and 57.39% (p < 0.05), respectively, and down-regulated the protein expressions of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), sterol regulatory element-binding protein 1 (SREBP-1) and fatty acid synthase (FAS). Additionally, the V-P complex significantly up-regulated the protein levels of total β-catenin (t-β-catenin), nuclear β-catenin (n-β-catenin), phosphorylated adenosine monophosphate-activated protein kinase alpha (p-AMPKα) and liver kinase B1 (p-LKB1). These showed that the inhibitory effect of V-P complex on human adipogenesis was mediated by activating Wnt/β-catenin and LKB1/AMPK-dependent signaling pathway. Therefore, the synthetic V-P complex could be considered as a candidate for prevention and treatment of obesity.
... Adipocyte, which is the central body of adipose tissue, affects body weight and metabolism of lipids by increasing the number and size. 15,[17][18][19][20][21][22][23][24][25] Adipocytes are in the process of continuous self-renewal. Old adipocytes are senescent and apoptotic, and new adipocytes, differentiating from ADSCs, are recruited constantly under appropriate conditions. ...
Background:
Glucagon-like peptide-1 (GLP-1) has been reported to have beneficial impacts on improving human's metabolism and ameliorating insulin resistance. While insulin is another important and conventional drug in diabetes treatment, but it has an adverse effect on weight gain.
Purpose:
To make sure whether GLP-1 and insulin play different roles in human adipose-derived stem cells (hADSCs).
Methods:
We examined the in vitro roles and molecular mechanisms of liraglutide, a GLP-1 analogue, and human insulin on hADSCs isolated from subcutaneous adipose tissue. Different concentrations (0, 0.1, 1, 10, 100nM) of liraglutide and insulin were added to proliferation and differentiation medium of hADSCs, respectively.
Results:
Liraglutide inhibits while insulin promotes the proliferation and differentiation at the concentration of 100nM. Moreover, the levels of GSK-3 increase during differentiation and liraglutide could down-regulate it when compared with insulin. We also find that the activation of phosphorylated GSK-3α and GSK-3β is involved in the differentiation roles. And classical and non-classical Wnt pathways all play roles in the differentiation, which are characterized with the up/down-regulation of the expression of adipogenesis genes such as PPAR-γ and CEBP-α.
Conclusion:
Liraglutide and insulin have contrary effects on the proliferation and adipogenesis via Wnt pathway in primary cultured ADSCs. Those effects could partly explain the different roles of GLP-1 and insulin on weight gain and insulin resistance.
... In obese women, it was reported that hyperplasia is predominant in the subcutaneous fat pad, and that hypertrophy occurs both in the omental and subcutaneous depots [106]. In adult humans, the increased lipid storage in adipocytes seems to be the most important process to accumulate fat mass [107,108]. Recently, Spalding et al. observed that the number of fat cells remains constant in lean and obese individuals, and that the number of adipocytes seems to be established at an early age [109]. Although adipogenesis in adult declines, it can still occur; this may be due, in part, to the expression of peroxisome proliferator-activated receptor γ2 (PPARγ2). ...
Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.
... Instead, adipose tissue actively participates in regulating multiple physiological functions. The process of adipose tissue enlargement due to nutrition oversupply leads to consequences such as chronic inflammation, hypoxia, aberrant adipokine secretion and dysfunction [23,24]. Rapid adipose expansion has been implicated in the pathogenesis of T2DM and the related complications. ...
The expansion of adipose tissue mass is the primary characteristic of the process of becoming obesity, which causes chronic adipose inflammation and is closely associated with type 2 diabetes mellitus (T2DM). Adipocyte hypertrophy restricts oxygen availability, leading to microenvironmental hypoxia and adipose dysfunction. This study aimed at investigating the effects of oxygenated water (OW) on adipocyte differentiation (adipogenesis) and the metabolic function of mature adipocytes. The effects of OW on adipogenesis and the metabolic function of mature adipocytes were examined. Meanwhile, the in vivo metabolic effects of long-term OW consumption on diet-induced obesity (DIO) mice were investigated. OW inhibited adipogenesis and lipid accumulation through down-regulating critical adipogenic transcription factors and lipogenic enzymes. While body weight, blood and adipose parameters were not significantly improved by long-term OW consumption, transient circulatory triglyceride-lowering and glucose tolerance-improving effects were identified. Notably, hepatic lipid contents were significantly reduced, indicating that the DIO-induced hepatic steatosis was attenuated, despite no improvements in fibrosis and lipid contents in adipose tissue being observed in the OW-drinking DIO mice. The study provides evidence regarding OW’s effects on adipogenesis and mature adipocytes, and the corresponding molecular mechanisms. OW exhibits transient triglyceride-lowering and glucose tolerance-improving activity as well as hepatic steatosis-attenuating functions.
Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study was to investigate the effect...
The obesity epidemic is a global issue affecting over 650 million individuals worldwide. In addition, almost two billion people in the world are overweight, and these numbers are expected only to grow. Elevated body weight increases the risk of developing cardiovascular and metabolic diseases such as metabolic syndrome, insulin resistance, and type 2 diabetes (T2D). Obesity is a complex disorder influenced by genetic and environmental factors and is characterized by low-grade chronic inflammation. This chapter will provide an overview of the molecular mechanisms of obesity-induced adipose tissue inflammation and highlight some of the most critical factors involved. Overall, the chapter aims to provide a comprehensive overview of the link between obesity and obesity-related inflammation and to highlight the potential health implications.
This paper presents two inter-dependent frameworks for understanding the etiology of obesity and the regain of body and fat mass after weight loss. The ‘Invisible Hand of Metabolism’ illustrates how physiologic states such as body and fat mass and blood glucose levels arise from the unregulated, uncontrolled, yet competitive behavior of trillions of semi-autonomous cells. The ‘Competition Model of Metabolism’ is an explanatory (mechanistic) framework that details how organismal and cell-specific behaviors generate the apparent stability of physiologic states despite metabolic perturbations (e.g., weight-loss and exercise). Together, these frameworks show that body and fat mass and blood glucose levels are not regulated, controlled, or defended but emerge from the complexity and functional plasticity of competitive cellular relations. Therefore, we argue that the use of abstract constructs such as ‘regulation’, ‘control’, ‘glucostats’, ‘adipostats’, and ‘set−/settling-points’ hinders the understanding of obesity and cardiometabolic diseases in human and nonhuman mammals.
Interindividual differences in generation of new fat cells determine body fat and type 2 diabetes risk. We utilized the GENiAL cohort, which consists of participants who have undergone abdominal adipose biopsy, to perform a genome-wide association study (GWAS) of fat cell number (n=896). Candidate genes from the genetic study were knocked down by siRNA in human adipose derived stem cells. We report 318 SNPs and 17 genetic loci displaying suggestive (p<1x10-5) association with fat cell number. Two loci pass threshold for GWAS-significance, on chromosome 2 (lead SNP rs149660479-G) and 7 (rs147389390-deletion). We filtered for fat cell number-associated SNPs (p<1.00x10-5) using evidence of genotype-specific expression. Where this was observed we selected genes for follow-up investigation and hereby identified SPATS2L and KCTD18 as regulators of cell proliferation consistent with the genetic data. Furthermore, 30 reported type 2 diabetes-associated SNPs displayed nominal and consistent associations with fat cell number. Functional follow up of candidate genes identified RPL8, HSD17B12 and PEPD displaying effects on cell proliferation consistent with genetic association and gene expression findings. In conclusion findings presented herein identify SPATS2L, KCTD18, RPL8, HSD17B12, and PEPD of potential importance in controlling fat cell numbers (plasticity), the size of body fat and diabetes risk.
Emerging evidence delineates that obesity, a complex metabolic disorder, impairs the structure and function of stromal cells residing in various tissues. The exuberant adipose tissue mass observed in obesity is, in part, associated with hyperplasia of adipocytes resulting from recruitment of multipotent stromal cells within the stromal vascular fraction of adipose tissues. However, a clear understanding of the causal role of stromal cells and biological factors in obesity is lacking. In our quest to understanding the role of kinesin family member 26B (KIF26B), we found that KIF26B regulates osteogenic and chondrogenic differentiation of stromal/progenitor cells. In this study, we sought to examine the effects of Kif26b loss-of-function on adipogenic differentiation of murine C3H10T1/2 multipotent stromal cells. In-vitro loss-of-function studies demonstrated that Kif26b knockdown by lentivirus mediated shRNA markedly dampened the differentiation potential of C3H10T1/2 cells to adipocytes and suppressed the expression of adipogenesis-related genes e.g., Pparg, C/ebpα, Fabp4 and Adipoq. Analysis of cell-cycle revealed that Kif26b knockdown resulted in elevated expression of cyclins (Ccnd1, Ccnb1, Ccna2) along with rapid cell-cycle progression from G0/G1 to S and G2 phases. Mechanistically, reduced adipogenic differentiation of Kif26b-deficient cells was partly dependent on PPARγ, a key transcription factor implicated in adipogenesis. This observation was experimentally supported as loss of adipogenesis was partially rescued by the addition of PPARγ agonist, rosiglitazone in Kif26b-deficient cells. We further found that silencing of Kif26b lessened the protein levels of phospho-Akt(Ser473), phospho-S6(Ser235/236), and phospho-mTOR(Ser2448), the major component of Akt/mTOR complex 1 (mTORC1) signaling at the basal level. Together, these data define a novel role of Kif26b in regulating commitment of C3H10T1/2 multipotent stromal cells to the adipocyte lineage and provide a practical framework for further experiments to establish its therapeutic potential for the treatment of problems associated with adipogenesis such as obesity at the cellular and molecular level.
Il existe deux types de tissus adipeux (TA). Le tissu adipeux blanc stocke les lipides sous forme de triglycérides. Le tissu adipeux brun possède une signature thermogénique via la protéine UCP1 utilisant les lipides pour former de la chaleur. Il existe aussi des adipocytes qui ont des caractéristiques similaires aux adipocytes bruns (adipocytes beiges) au sein du TA blanc. Le TA sécrète également des hormones lui conférant une fonction endocrinienne. Il maintient l’homéostasie énergétique et peut être altéré de différentes façons, ce qui conduit à des dysfonctionnements métaboliques : Une perte importante du TA dans les lipoatrophies est observée lors d’un traitement antirétroviral hautement actif contre le VIH (thérapie HAART). Ceci amène à des modifications métaboliques graves, dues à des niveaux élevés de lipides circulants et à une résistance à l’insuline systémique. Cette thérapie HAART est composée d’inhibiteurs de la protéase du VIH (IPs) ou de la transcriptase inverse (INTI). Les effets inhibiteurs des IPs sur le processus de différenciation adipocytaire blanche sont bien connus. Cependant, les mécanismes spécifiques qui affectent les différents dépôts adipeux humains distinctement ainsi que la différenciation adipocytaire brune le sont moins. Le cancer est une pathologie caractérisée par la prolifération dérégulée de cellules capables de former des métastases. Les cellules tumorales interagissent activement avec leur microenvironnement, notamment avec le TA qui est présent autour de nombreux organes et qui peut favoriser la progression tumorale (tissu adipeux associé au cancer). Le TA promeut la prolifération des cellules cancéreuses par la sécrétion d’adipocytokines. De plus, les cellules tumorales modifient le TA pour tirer leur énergie des lipides ce qui favorise leur expansion et leur dissémination. Nous avons étudié les interactions entre adipocytes et cellules tumorales de sein puisque le TA fait partie intégrante de la glande mammaire. Mon travail de thèse a consisté à identifier de nouveaux mécanismes moléculaires importants pour le développement physiopathologique et/ou l’altération du TA. Nous avons d’abord étudié les effets des IPs sur la perte de l’auto-renouvellement des progéniteurs adipeux (PAs) (1) et sur les modifications métaboliques des adipocytes (2). Nous étudions aussi les interactions entre les cellules de cancer du sein et le microenvironnement adipeux (3). Tout d’abord, les IPs inhibent l’auto-renouvellement des PAs en diminuant IER3 ce qui déstabilise en aval la boucle autocrine de l’Activine A. Les IPs bloquent la différenciation des PAs en adipocytes. La perte de ces deux processus indique que les IPs induisent des lipoatrophies retrouvées au cours de la thérapie HAART. Par la suite, nous observons que les IPs réduisent l’expression des marqueurs thermogéniques dans les adipocytes beiges et bruns par l’inhibition de la transcription d’UCP1. Ils altèrent aussi l’expression des sirtuines, enzymes antivieillissement. L’utilisation d’un activateur de la sirtuine 1 permet de renverser partiellement les effets des IPs sur l’expression d’UCP1. Enfin, nos résultats démontrent que des mammosphères de cancer de sein induisent la protéine UCP1 dans les adipocytes adjacents. L’adrénomedulline produite par les mammosphères participe à ce processus et nous avons pu caractériser son mécanisme d’action. En conclusion, les travaux réalisés pendant ma thèse ont permis de mieux comprendre les mécanismes par lesquels les IPs inhibent l’auto-renouvellement des progéniteurs adipeux ainsi que l’altération de la signature thermogénique via la perte d’UCP1 dans les adipocytes bruns. Les cellules tumorales, quant à elles, induisent l’expression d’UCP1 résultant en une conversion métabolique des adipocytes blancs en adipocytes bruns.
Objective:
Expansion of adipose tissue during obesity through the recruitment of newly-generated adipocytes (hyperplasia) is metabolically healthy, whereas that through the enlargement of pre-existing adipocytes (hypertrophy) leads to metabolic complications. Accumulating evidence from genetic fate mapping studies suggests that in animal models receiving a high-fat diet (HFD), only adipocyte progenitors (APs) in gonadal white adipose tissue (gWAT) have proliferative potential. However, the proliferative potential and differentiating capacity of APs in the inguinal WAT (iWAT) of male mice remains controversial. The objective of this study was to investigate the proliferative and adipogenic potential of APs in iWAT of HFD-fed male mice.
Methods:
We generated PDGFRα-GFP-CreERT2/tdTomato (KI/td) mice and traced PRGFRα-positive APs in 8 weeks of HFD-fed male mice. We performed a comprehensive phenotypic analysis, including histology, immunohistochemistry, flow cytometry, and gene expression analysis, of KI/td mice fed HFD.
Results:
Contrary to the findings of others, we found increased numbers of newly-generated tdTomato+ adipocytes in the iWAT of male mice that remained smaller than those in gWAT. We found that in male mice, the iWAT has more proliferating tdTomato+ APs than gWAT. We also found that tdTomato+ APs showed higher expression of Dpp4 and Pi16 than tdTomato- APs, and the expression of these genes was significantly higher in iWAT than gWAT in mice fed HFD for 8 weeks. Collectively, our results reveal that HFD feeding induces the proliferation of tdTomato+ APs in the iWAT of male mice.
Conclusion:
In male mice, compared with gWAT, iWAT undergoes hyperplasia in response to 8 weeks of HFD feeding through the recruitment of newly-generated adipocytes due to an abundance of APs with a high potential for proliferation and differentiation.
Adipose tissue comprises stromal cells, mature adipocytes, and macrophages supported by connective tissue surrounding fine capillaries. Stromal/stem cells have self-renewal potency restoring tissue vascularization and organ function (cartilage, bone, muscle and fat tissues) when isolated in vitro and are designated as preadipocytes and multipotent ASCs. Fat is generally considered as the ideal filling material due to its autologous nature, easily accessible, widely abundant in the body, and low immunogenic and allergic response.
Tartrate‐resistant acid phosphatase (TRAP, encoded by ACP5)‐overexpressing mice exhibit hyperplastic obesity. As the molecular mechanism remains elusive, the aims were to characterize the effect of TRAP on pre‐adipocyte proliferation. We investigated cell cycle entry and signal transduction i.e., insulin‐like growth factor 1 (IGF‐1)/ insulin receptor substrate 1 (IRS1) and the Akt signaling pathways, in 3T3‐L1 pre‐adipocytes treated with the TRAP 5a isoform. Results show that TRAP 5a increases S‐phase entry. TRAP 5a stimulation increases IGF‐1 mRNA and IRS1 activation, indicative of insulin‐like growth factor 1 receptor (IGF1R) activation. Furthermore, TRAP 5a stimulation resulted in Akt signaling pathway activation and subsequent increased nuclear translocation of β‐catenin. In conclusion, TRAP 5a increases proliferation of pre‐adipocytes in a dose‐dependent fashion by promoting entry into S‐phase. Part of this effect is likely due to increased IGF‐1 signaling through the Akt signaling pathway.
Background and aims
Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.
Methods
Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using¹⁴C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action.
Results
In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30mg/kg dose. Concomitant decreases in non-esterified fatty acids (-34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (-71% and -64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose-response efficacy.
Conclusions
Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.
Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of a plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it fit a pro- versus anti-inflammatory paradigm. This review presents and discusses current knowledge on the developmental biology of macrophages from an evolutionary perspective focused on the function of macrophages, which may aid in study of developmental, inflammatory, tumoral, and degenerative diseases. We also propose a framework to investigate the functions of macrophages in vivo and discuss how inherited germline and somatic mutations may contribute to the roles of macrophages in diseases.
The stromal-vascular fraction (SVF) of white adipose tissue (WAT) is remarkably heterogeneous and consists of numerous cell types that contribute functionally to the expansion and remodeling of WAT in adulthood. A tremendous barrier to studying the implications of this cellular heterogeneity is the inability to readily isolate functionally distinct cell subpopulations from WAT SVF for in vitro and in vivo analyses. Single-cell sequencing technology has recently identified functionally distinct fibro-inflammatory and adipogenic PDGFRβ+ perivascular cell subpopulations in intra-abdominal WAT depots of adult mice. Fibro-inflammatory progenitors (termed, “FIPs”) are non-adipogenic collagen producing cells that can exert a pro-inflammatory phenotype. PDGFRβ+ adipocyte precursor cells (APCs) are highly adipogenic both in vitro and in vivo upon cell transplantation. Here, we describe multiple methods for the isolation of these stromal cell subpopulations from murine intra-abdominal WAT depots. FIPs and APCs can be isolated by fluorescence-activated cell sorting (FACS) or by taking advantage of biotinylated antibody-based immunomagnetic bead technology. Isolated cells can be used for molecular and functional analysis. Studying the functional properties of stromal cell subpopulation in isolation will expand our current knowledge of adipose tissue remodeling under physiological or pathological conditions on the cellular level.
Four methods for the sizing of adipose cells in small samples of human or animal adipose tissue are compared. These methods depend on the preparation of cell suspensions by incubation of the tissue with collagenase or by prolonged fixation with osmium tetroxide and separation of the fixed cells. A Coulter electronic counter was used to count and size the suspended cells and a Zeiss particle size analyzer for the sizing of cells in photomicrographs. The use of the Coulter counter to count cells in a suspension derived from a known amount of tissue and subjected to osmium tetroxide fixation is recommended for accuracy and general applicability to adipose cells of all sizes in man and animals.
It has been shown by several investigators that adipocyte number is stable in mature human beings and several species of rodents. Although the number of new cells appearing in the adipose depot can be measured histometrically and by Coulter counting of osmium-fixed cells, such methods do not distinguish between "lipid filling" of preexistent adipocytes and synthesis of new adipocytes. The experiments reported here using in vivo injection of [(3)H]thymidine show that synthesis of new adipocytes in the Sprague-Dawley rat continues after birth and ceases before sexual maturity. Furthermore, during the second and third postnatal weeks, a "bed" of preadipocytes is synthesized. Preadipocytes may take as long as 30 days to appear as mature adipocytes.
Adipocyte cell size and number of three adipose depots, gonadal, subcutaneous, and retroperitoneal, were determined in several strains (aA(y), aA(iy), dbdb, obob, and NZO) of adult genetically obese mice, male and female, and in male gold thioglucose-treated mice. Epididymal pad cellularity was determined during development in yellow and viable yellow obese mice and their lean littermates, as well as in the NCS/R mouse. Cell number in the mouse epididymal pad in both lean and genetically obese animals is determined early in development, i.e., before weaning. Cell enlargement is the consistent and usually dominant morphological explanation for adipose depot enlargement in genetic and in gold thioglucose-induced mouse obesity. In some instances, hyperplasia accompanied the hypertrophy, occurring most often in the subcutaneous depot. Cell number in the subcutaneous pad of the obese-hyperglycemic female is four times that of the lean control and represents the most extreme case of hyperplasia observed. In fact, hyperplasia was consistently seen in the obob mouse. A classification for genetic obesity based primarily upon the cellularity characteristics of the adipose depots is proposed.
Cell size and number of three adipose depots, epididymal, retroperitoneal, and subcutaneous, were determined during growth of the obese Zucker rat ("fatty") and nonobese Zucker control. Cellularity of these depots in the adult "fatty" was compared with that in nonobese controls and in nonobese Zucker rats made obese by ventromedial hypothalamic lesions. Epididymal and retroperitoneal depots in the nonobese rat grew by cell enlargement and increase in cell number until the 14th wk, when number became fixed; further increase in depot size occurred by cell enlargement. The subcutaneous depot added cells until the 26th wk. In the Zucker "fatty," cell number increased until the 26th wk in all depots, accompanied by extreme cell enlargement. The enlarged adipose depots of the adult Zucker "fatty," when compared with the nonobese control, are the result of both hypertrophy and hyperplasia. Depot enlargement in the lesioned animal is the result of hypertrophy. "Fatties" have more cells in adipose depots than do lesioned rats. Genetic obesity in the Zucker rat is clearly different from the obesity produced by hypothalamic lesioning.
The size, number, and rate of formation of mature adipocytes were studied in the epididymal pads and retroperitoneal adipose depots of the Sprague-Dawley rat. Early growth of these depots was accompanied by progressive enlargement of adipose cells as well as by increases in number. Beyond the 15th wk of life, the depot grew exclusively by the process of cellular enlargement, with no further change in cell number. Severe starvation during the 6th wk of life followed by normal feeding had no lasting effect on cell size or cell number; prolonged semistarvation beginning in the 15th wk greatly reduced cell size while cell number was unaffected. Likewise, extreme increases in depot size produced by hypothalamic lesions did not change cell number, but only cell size. The concept of a fixed number of mature adipocytes in the adult organism may be of central importance in caloric and metabolic equilibrium.
Body composition, age at onset of obesity, adipose tissue cellularity and metabolic variables have been determined in 137 obese subjects and controls. Weight stability in 34 of the patients could also be judged by a repeated examination after about 10 months. Fat cell number correlated strongly with body fat, while fat cell size increased only within the control range of body fat. Above approximately 30 kg body fat, the fat cell enlargement was equally pronounced at all degrees of obesity. A cross-sectional analysis of the obese men and women indicated that fat cell size was larger at 30–40 years of age than before and after this age. Cell number was elevated but did not increase with age in the obese group. Groups of younger and older obese women did not differ in adipose tissue cellularity factors. This had the consequence that, in comparisons with age- and sex-matched control groups, obesity depending primarily on enlargement of fat cells seemed to be more frequent in the younger age groups, while in older obese subjects cell number seemed to be a more important factor for contribution to obesity. Fat cell number correlated positively with body cell mass. The earlier the onset of obesity the more fat cells, particularly when obesity could be traced to infancy. Obesity starting at adult age was characterized by larger fat cells. Two types of obesity can be distinguished. One is a hypercellular severe obesity with an early onset and an elevated body cell mass. The fat cells may be enlarged or not. The other type of obesity is characterized by fat cell hypertrophy, moderately increased body fat and a later onset. There is no increase in body cell mass. Plasma insulin was dependent on weight stability. Hypertriglyceridemia in obesity was associated with a decreased glucose tolerance, somewhat elevated insulin values, and elevated serum uric acid.
Eight patients are presented in whom obesity developed in association with documented hypothalamic lesions. These lesions included trauma, inflammatory disease, an aneurysm of the internal carotid artery, and five cases of tumor. Detailed metabolic studies were performed in four patients with hypothalamic obesity and in five age- and weight-matched patients with essential obesity(i.e., obesity with no definable etiology). Fasting insulin concentrations were significantly higher in the patients with hypothalamic obesity. During a seven-day fast the insulin levels in patients with essential obesity decreased by 24 to 48 hours, whereas patients with hypothalamic obesity showed a variety of changes; In three out of four of these patients with hypothalamic obesity there was no evidence for hyperplasia of the fat cells. Basal oxygen consumption, body composition, and metabolism of adipose tissue did not differ between the patients with essential obesity and those with hypothalamic obesity. There was no difference in activity of the enzymes in the glycerophosphate cycle. Our data on eight patients with hypothalamic obesity were compared with data on patients in literature. Most cases of hypothalamic obesity occur with space-occupying tumors arising at the base of the hypothalamus. However, trauma, inflammatory diseases, and leukemia are also associated with hypothalamic obesity. Patients with hypothalamic obesity rarely weigh more than 140 kg.
The effects of hormonal and nutritional circumstances on the growth in number of adipose cells have been studied in obese and light-for-dates children, and in children lacking growth hormone either as an isolated deficiency or after craniopharyngiomata had been removed. The findings suggest that the adipose organ in man has a finite sensitive period during which the basic complement of cells is determined. This extends from approximately thirty weeks' gestation to the age of about one year. The earlier events occur during this sensitive period, the more severe their effects; when the period has ended, adipose-cell growth in number seems to become resistant to adverse circumstances.
The cellular character of the adipose tissue of 21 nonobese and 78 obese patients has been examined. Adipose cell size (lipid per cell) was determined in three different subcutaneous and deep fat depots in each patient and the total number of adipose cells in the body estimated by division of total body fat by various combinations of the adipose cell sizes at six different sites. Cell number has also been estimated on the basis of various assumed distribution of total fat between the subcutaneous and deep fat depots. Obese patients, as a group, have larger adipose cells than do nonobese patients; cell size, however, varies considerably among the fat depots of individuals of either group. The variation in cell size exists not only between, but also within subcutaneous and deep sites. Estimates of total adipose cell number for a given individual based upon cell size can, therefore, vary by as much as 85%. On the basis of these studies it is suggested that the total adipose number of an individual is best and most practically estimated, at this time, by division of total body fat by the mean of the adipose cell sizes of at least three subcutaneous sites. IRRESPECTIVE OF THE METHOD BY WHICH TOTAL ADIPOSE CELL NUMBER IS ESTIMATED, TWO PATTERNS OF OBESITY EMERGE WITH RESPECT TO THE CELLULAR CHARACTER OF THE ADIPOSE TISSUE MASS OF THESE PATIENTS: hyperplastic, with increased adipose cell number and normal or increased size, and hypertrophic, with increased cell size alone. These two cellular patterns of obesity are independent of a variety of assumed distributions of fat among the subcutaneous and deep depots. When these different cellular patterns are examined in terms of various aspects of body size, body composition, and the degree, duration, and age of onset of obesity, only the latter uniquely distinguishes the hyperplastic from the hypertrophic: hyperplastic obesity is characterized by an early age of onset, hypertrophic, by a late age of onset. These studies indicate that there are two distinct periods early in life during which hypercellularity of the adipose tissue are most likely to occur: very early within the first few years, and again from age 9 to 13 yr.
: The affective responses to weight reduction of five severely obese patients with adult onset of obesity were studied during a long-term hospitalization. Anxious and depressive symptoms, measured by objective rating and self-rating procedures, did not increase with weight loss. These results are in contrast to earlier findings from this laboratory of disturbances in affective responses following weight loss for patients with juvenile-onset of obesity. These results suggest that the behavioral response to weight reduction is dependent upon age at onset of obesity. Copyright (C) 1973 by American Psychosomatic Society
Body composition, age at onset of obesity, adipose tissue cellularity and metabolic variables were determined in 137 obese subjects and controls. Weight stability in 34 of the patients could also be judged by a repeated examination after about 10 mth. Fat cell number correlated strongly with body fat, while fat cell size increased only within the control range of body fat. Above approximately 30 kg body fat, the fat cell enlargement was equally pronounced at all degrees of obesity. A cross sectional analysis of the obese men and women indicated that fat cell size was larger at 30-40 yr of age than before and after this age. Cell number was elevated but did not increase with age in the obese group. Groups of younger and older obese women did not differ in adipose tissue cellularity factors. This had the consequence that, in comparisons with age and sex matched control groups, obesity depending primarily on enlargement of fat cells seemed to be more frequent in the younger age groups, while in older obese subjects cell number seemed to be a more important factor for contribution to obesity. Fat cell number correlated positively with body cell mass. The earlier the onset of obesity the more fat cells, particularly when obesity could be traced to infancy. Obesity starting at adult age was characterized by larger fat cells. Two types of obesity can be distinguished. One is a hypercellular severe obesity with an early onset and an elevated body cell mass. The fat cells may be enlarged or not. The other type of obesity is characterized by fat cell hypertrophy, moderately increased body fat and a later onset. There is no increase in body cell mass. Plasma insulin was dependent on weight stability. Hypertriglyceridemia in obesity was associated with a decreased glucose tolerance, somewhat elevated insulin values, and elevated serum uric acid.
Studies of adipose tissue cellularity were carried out in a group of nonobese adult male volunteers who gained 15-25% of their body weight as the result of prolonged high caloric intake. Adipose cell size (lipid content per cell) was determined in tissue obtained from three subcutaneous sites (gluteal, anterior abdominal wall, and triceps) and total adipose cell number estimated from measurement of total body fat. Five experimental subjects gained an average of 16.2 kg of body weight, of which 10.4 kg was determined to be fat. Expansion of the adipose mass was accompanied by a significant and relatively uniform increase in fat cell size in each subcutaneous site tested. Total adipose cell number did not change as a result of weight gain and expansion of the adipose depot in adult life. Subsequent loss of weight and restoration of original body fat was associated with a reduction in adipose cell size at each subcutaneous site, but no change in total number. In two control subjects who neither gained nor lost weight there were no changes in total adipose cell number or cell size. These observations suggest that expansion and retraction of the adipose depot in adult life is accompanied by changes in adipose cell size only. Significant differences in both the size and total number of adipose cells were observed between subjects in both the experimental and control groups. In addition, within individuals of both groups there were significant differences in cell size when adipose cells from the three subcutaneous sites were compared. These findings indicate that wide variations in adipose cell size and number exist in nonobese individuals having similar adipose depot sizes.
The effect of infantile nutritional levels on adipose tissue cellularity and metabolism was studied in two groups of Sprague-Dawley rats. Caloric intake was varied during the suckling period by manipulating litter size immediately after birth; however, all animals had free access to food after weaning. The epididymal fat pads of animals raised in small litters were heavier than those of their paired siblings raised in large litters. Initially, the differences in pad weight were accounted for primarily by differences in total cell number; however, at 20 wk both cell number and cell size contributed equally. The rate of glucose incorporation into CO(2) and triglyceride during in vitro incubations was the same for both groups if expressed on a per cell basis; therefore total tissue incorporation was greater in animals with more cells. The results support the hypothesis that early nutritional experiences can effect permanent changes in the cell number and size of the epididymal fat depot and that total cell number is important in the total metabolism of this organ. These findings and the fact that extreme human obesity is accompanied by similar alterations in cellularity and metabolism indicate that early nutritional experiences should be studied further as a guide to the etiology of obesity in man.