Activin A Plays a Critical Role in Proliferation and Differentiation of Human Adipose Progenitors

International audienceAbstractObjective: Growth of white adipose tissue takes place in normal development and in obesity. A pool of adipose progenitors is responsible for the formation of new adipocytes and for the potential of this tissue to expand in response to chronic energy overload. However, factors controlling self-renewal of human adipose progenitors are largely unknown. We investigated the expression profile and the role of activin A in this process. Research Design and Methods: Expression of INHBA/activin A has been investigated in three types of human adipose progenitors. We then analyzed at the molecular level the function of activin A during human adipogenesis. We finally investigated the status of activin A in adipose tissues of lean and obese subjects and analyzed macrophage-induced regulation of its expression. Results: INHBA/activin A is expressed by adipose progenitors from various fat depots and its expression dramatically decreases as progenitors differentiate into adipocytes. Activin A regulates the number of undifferentiated progenitors. Sustained activation or inhibition of the activin A pathway impairs or promotes respectively adipocyte differentiation via C/EBPbeta-LAP and Smad2 pathway in an autocrine/paracrine manner. Activin A is expressed at higher levels in adipose tissue of obese patients compared to lean subjects. Indeed, activin A levels in adipose progenitors are dramatically increased by factors secreted by macrophages derived from obese adipose tissue. Conclusions: Altogether, our data show that activin A plays a significant role in human adipogenesis. We propose a model in which macrophages which are located in adipose tissue regulate adipose progenitor self-renewal through activin A

Interactions entre les préadipocytes et les macrophages au sein du tissu adipeux humain

Le tissu adipeux obèse produit davantage de facteurs inflammatoires notamment par sa fraction stroma vasculaire incluant les macrophages. En présence de facteurs sécrétés par les macrophages, les préadipocytes humains développent, outre une altération de leur différenciation, un état inflammatoire ainsi que des capacités accrues à proliférer et à migrer. Ces modifications phénotypiques des préadipocytes s accompagnent d un profond remodelage de leur matrice extracellulaire. Des gènes d intérêt potentiel dans l obésité ont également été identifiés : CCL5 qui jouerait un rôle dans l accumulation et la survie des macrophages du tissu adipeux et l inhibine beta A dont nous montrons l activité profibrotique dans les préadipocytes. Ainsi, au cours de l obésité, le tissu adipeux serait le site d interactions majeures entre les préadipocytes et les macrophages, contribuant probablement aux perturbations morphologiques et fonctionnelles de ce tissu, à l instar de l apparition de fibrose.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes.: Human adipogenesis regulation by macrophages

Obesity is considered a chronic low-grade inflammatory state. The white adipose tissue produces a variety of inflammation-related proteins whose expression is increased in obese subjects. The nonadipose cell fraction, which includes infiltrated macrophages, is a determinant source of inflammation-related molecules within the adipose tissue. Our working hypothesis is that macrophage infiltration affects fat expansion through a paracrine action on adipocyte differentiation. Human primary preadipocytes were then differentiated in the presence of conditioned media obtained from macrophages differentiated from blood monocytes. Preadipocytes treated by macrophage-conditioned medium displayed marked reduction of adipogenesis as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic and lipogenic markers. In addition to this effect, the activation of macrophages by lipopolysaccharides stimulated nuclear factor kappaB signaling, increased gene expression and release of proinflammatory cytokines and chemokines, and induced preadipocyte proliferation. This phenomenon was associated with increased cyclin D1 gene expression and maintenance of the fibronectin-rich matrix. Anti-TNFalpha neutralizing antibody inhibits the inflammatory state of preadipocytes positioning TNFalpha as an important mediator of inflammation in preadipocytes. Strikingly, conditioned media produced by macrophages isolated from human adipose tissue exerted comparable effects with activated macrophages, i.e. decreased adipogenesis and increased inflammatory state in the preadipocytes. These data show that macrophage-secreted factors inhibit the formation of mature adipocytes, suggesting possible role in limiting adipose tissue expansion in humans

Set-up of Z- and E-guggulsterones purification method from guggul-gum extracts by liquid chromatography and study of their activities on human preadipocytes differentiation

The rising prevalence of obesity within both industrialized and emerging societies is a major public health problem. Indeed obesity is a usual risk factor in the development of metabolic and cardiovascular diseases which nowadays rank among the highest causes of premature death. Therefore, modulating fat mass expansion represents a worldwide challenge. In this context, adipocyte differentiation, which corresponds to the cellular transition of a fibroblastic cell (the preadipocyte) to a highly specialized cell accumulating triglycerides (the adipocyte), is a decisive process in the expansion of adipose tissue during life span and consequently, in the development of obesity. Adipogenesis markers such as PPARg2, C/EBPa, lipoprotein lipase (LPL), perilipin (PLIN) and the adipokines (leptin and adinopectin) are known to be expressed throughout the different stages of adipocyte differentiation. Guggulsterones are the principal bioactive steroidal components found in the oleoresin (guggul gum) collected from the indian guggul tree, Commiphora mukul (Hook, ex Stocks) Engl. The objective of this study was to investigate the effects of the two purified diastereoisomeric forms of guggulsterones (Z- and E-) on the human preadipocytes proliferation and differentiation

The effects of purified Z- and E-guggulsterones from guggul-gum extract on human preadipocytes proliferation and differentiation through the study of gene expression of adipose markers.

The rising prevalence of obesity within both industrialized and emerging societies is a major public health problem. Indeed obesity is a usual risk factor in the development of metabolic and cardiovascular diseases which nowadays rank among the highest causes of premature death. Therefore, modulating fat mass expansion represents a worldwide challenge. In this context, adipocyte differentiation, which corresponds to the cellular transition of a fibroblastic cell (the preadipocyte) to a highly specialized cell accumulating triglycerides (the adipocyte), is a decisive process in the expansion of adipose tissue during life span and consequently, in the development of obesity. Adipogenesis markers such as PPARg2, C/EBPa, lipoprotein lipase (LPL), perilipin (PLIN) and the adipokines (leptin and adinopectin) are known to be expressed throughout the different stages of adipocyte differentiation. Guggulsterones are the principal bioactive steroidal components found in the oleoresin (guggul gum) collected from the indian guggul tree, Commiphora mukul (Hook, ex Stocks) Engl. The objective of this study was to investigate the effects of the two purified diastereoisomeric forms of guggulsterones (Z- and E-) on the human preadipocytes proliferation and differentiation