Transforming Growth Factor-β3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue.

White adipose tissue (WAT) mass is determined by adipocyte size and number. While adipocytes are continuously turned over, the mechanisms controlling fat cell number in WAT upon weight changes are unclear. Herein, prospective studies of human subcutaneous WAT demonstrate that weight gain increases both adipocyte size and number, but the latter remains unaltered after weight loss. Transcriptome analyses associate changes in adipocyte number with the expression of 79 genes. This gene set is enriched for growth factors, out of which one, transforming growth factor-β3 (TGFβ3), stimulates adipocyte progenitor proliferation, resulting in a higher number of cells undergoing differentiation in vitro. The relevance of these observations was corroborated in vivo where Tgfb3+/- mice, in comparison with wild-type littermates, display lower subcutaneous adipocyte progenitor proliferation, WAT hypertrophy, and glucose intolerance. TGFβ3 is therefore a regulator of subcutaneous adipocyte number and may link WAT morphology to glucose metabolism

Epigenetic mechanisms in the programming of adiposity in rat offspring from obese dams

Selon le concept de l'origine développementale de la santé et des maladies (DOHaD), l'obésité aurait des origines développementales et précoces. Nous posons l'hypothèse que l'obésité maternelle altérerait les processus épigénétiques au cours du développement du tissu adipeux blanc de la descendance. Ces modifications précoces installeraient une « empreinte épigénétique » au niveau de gènes clefs du métabolisme adipocytaire en modifiant durablement leur activité transcriptionnelle et favorisant l’expansion du tissu adipeux. Dans ce travail, nous avons montré que l'obésité maternelle entraine des remodelages épigénomiques (i.e., méthylation/hydroxyméthylation de l'ADN et modifications d'histones) qui contrôlent l'expression des gènes codant pour la leptine et PPARγ ; la lactation est une période clé du remodelage épigénomique dans le tissu adipeux blanc ; certaines de ces marques épigénomiques persistent à l'âge adulte. Ces mécanismes épigénomiques participeraient aux phénomènes de programmation transcriptionnelle de gènes adipogéniques et lipogéniques impliqués dans l'expansion du tissu adipeux blanc. De plus, le remodelage épigénétique des régions génomiques régulant l'expression génique se met en place et persiste de façon spécifique en fonction de la localisation des dépôts de tissu adipeux blanc et du sexe de la descendance. Ainsi, la persistance des marques épigénétiques serait impliquée dans la sensibilisation des descendants de mères obèses à l'obésité.According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity predisposes offspring to white adipose tissue (WAT) accumulation. The mechanisms underlying the phenomenon known as developmental programming are poorly understood. We hypothesized that long-term modifications of gene expression occur, at least in part, via epigenetic malprogramming which may take place during the early postnatal period. Epigenetic marks may serve as a memory of exposure, in early life, to inappropriate environments. These persistent marks may ultimately induce long-term changes in gene expression. Here, we focused on epigenetic modifications (i.e., DNA methylation, DNA hydroxymethylation and histone modifications) of regulatory sequences involved in leptin and PPARγ gene expression in different fat pads. Lactation period is an active period for epigenomic remodeling within regulatory sequences of both genes in HF offspring's WAT, consistent with modified hormonal status and enzymatic components of the epigenetic machinery. Some of these epigenetic modifications were still visible in weaned HF male offspring. Retained marks were observed in 9-month-old HF male rats. The long-term epigenetic malprogramming was correlated with long-lasting modified gene expression and depot phenotype. Overall, we showed that editing of epigenetic marks takes place early in life during WAT’s development and might persist throughout life in a depot- and sex-specific manner. Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions of key adipogenic and lipogenic genes that might account for increased adiposity in adult HF male offspring

Obesity-Related Adipose Tissue Remodeling in the Light of Extracellular Mitochondria Transfer

Adipose tissue dysfunction is strongly associated with obesity and its metabolic complications such as type 2 diabetes and cardiovascular diseases. It is well established that lipid-overloaded adipose tissue produces a large range of secreted molecules that contribute a pro-inflammatory microenvironment which subsequently disseminates towards multi-organ metabolic homeostasis disruption. Besides physiopathological contribution of adipose-derived molecules, a new paradigm is emerging following the discovery that adipocytes have a propensity to extrude damaged mitochondria in the extracellular space, to be conveyed through the blood and taken up by cell acceptors, in a process called intercellular mitochondria transfer. This review summarizes the discovery of mitochondria transfer, its relation to cell quality control systems and recent data that demonstrate its relevant implication in the context of obesity-related adipose tissue dysfunction

Importance of the Microenvironment and Mechanosensing in Adipose Tissue Biology

The expansion of adipose tissue is an adaptive mechanism that increases nutrient buffering capacity in response to an overall positive energy balance. Over the course of expansion, the adipose microenvironment undergoes continual remodeling to maintain its structural and functional integrity. However, in the long run, adipose tissue remodeling, typically characterized by adipocyte hypertrophy, immune cells infiltration, fibrosis and changes in vascular architecture, generates mechanical stress on adipose cells. This mechanical stimulus is then transduced into a biochemical signal that alters adipose function through mechanotransduction. In this review, we describe the physical changes occurring during adipose tissue remodeling, and how they regulate adipose cell physiology and promote obesity-associated dysfunction in adipose tissue

Obesity-Related Adipose Tissue Remodeling in the Light of Extracellular Mitochondria Transfer

International audienceAdipose tissue dysfunction is strongly associated with obesity and its metabolic complications such as type 2 diabetes and cardiovascular diseases. It is well established that lipid-overloaded adipose tissue produces a large range of secreted molecules that contribute a pro-inflammatory microenvironment which subsequently disseminates towards multi-organ metabolic homeostasis disruption. Besides physiopathological contribution of adipose-derived molecules, a new paradigm is emerging following the discovery that adipocytes have a propensity to extrude damaged mitochondria in the extracellular space, to be conveyed through the blood and taken up by cell acceptors, in a process called intercellular mitochondria transfer. This review summarizes the discovery of mitochondria transfer, its relation to cell quality control systems and recent data that demonstrate its relevant implication in the context of obesity-related adipose tissue dysfunction

Importance of the Microenvironment and Mechanosensing in Adipose Tissue Biology

International audienceThe expansion of adipose tissue is an adaptive mechanism that increases nutrient buffering capacity in response to an overall positive energy balance. Over the course of expansion, the adipose microenvironment undergoes continual remodeling to maintain its structural and functional integrity. However, in the long run, adipose tissue remodeling, typically characterized by adipocyte hypertrophy, immune cells infiltration, fibrosis and changes in vascular architecture, generates mechanical stress on adipose cells. This mechanical stimulus is then transduced into a biochemical signal that alters adipose function through mechanotransduction. In this review, we describe the physical changes occurring during adipose tissue remodeling, and how they regulate adipose cell physiology and promote obesity-associated dysfunction in adipose tissue

Depot- and sex-specific effects of maternal obesity in offspring's adipose tissue

International audienceAccording to the Developmental Origin of Health and Disease (DOHaD) concept, alterations of nutrient supply in the fetus or neonate result in long-term programming of individual body weight set-point. In particular, maternal obesity, excessive nutrition and accelerated growth in neonates have been shown to sensitize offspring to obesity. The white adipose tissue may represent a prime target of metabolic programming induced by maternal obesity. In order to unravel the underlying mechanisms, we have developed a rat model of maternal obesity using a high-fat (HF) diet (containing 60% lipids) before and during gestation and lactation. At birth, newborns from obese dams (called HF) were normotrophs. However, HF neonates exhibited a rapid weight gain during lactation, a key period of adipose tissue development in rodents. In males, increased body weight at weaning (+ 30%) persists until 3 months of age. Nine-month-old HF male offspring were normoglycemic but showed mild glucose intolerance, hyperinsulinemia and hypercorticosteronemia. Despite no difference in body weight and energy intake, HF adult male offspring were predisposed to fat accumulation showing increased visceral (gonadal and perirenal) depots weights and hyperleptinemia. However, only perirenal adipose tissue depot exhibited marked adipocyte hypertrophy and hyperplasia with elevated lipogenic (i.e., SREBP1, FAS, leptin) and diminished adipogenic (i.e., PPARγ, 11β-HSD1) mRNA levels. By contrast, very few metabolic variations were observed in HF female offspring. Thus, maternal obesity and accelerated growth during lactation program offspring for higher adiposity via transcriptional alterations of visceral adipose tissue in a depot- and sex-specific manner