OBJECTIVEGrowth 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 METHODSExpression of INHBA/activin A was 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.RESULTSINHBA/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 the C/EBPβ-LAP and Smad2 pathway in an autocrine/paracrine manner. Activin A is expressed at higher levels in adipose tissue of obese patients compared with the expression levels in lean subjects. Indeed, activin A levels in adipose progenitors are dramatically increased by factors secreted by macrophages derived from obese adipose tissue.CONCLUSIONSAltogether, our data show that activin A plays a significant role in human adipogenesis. We propose a model in which macrophages that are located in adipose tissue regulate adipose progenitor self-renewal through activin A.
This article is available online at http://www.jlr.org able to genetic factors as it has occurred relatively recently and is observed in a wide range of human populations. High-fat diets are considered to be obesogenic in that they produce a consistent increase in fat mass that is directly related to the content of the diet and duration of feeding. However, the contribution of dietary fats compared with an excess energy intake in increasing body weight remains controversial, as no major change in the total amount of ingested fats has occurred in the last two decades ( 1, 2 ).In addition to caloric excess, a qualitative issue has emerged as a risk factor for obesity in rodents and possibly in humans; i.e., the disequilibrium in polyunsaturated fatty acid (PUFA) metabolism with a high ratio of linoleic acid (C18:2 6, LA) versus ␣ -linolenic acid (C18:3 3, LNA) ( 3 ). Notably, in rodents, reducing this ratio from 59 to 2 under isolipidic, isoenergetic conditions (40% energy as fat) by inclusion of dietary LNA counteracted the enhancing effects of LA on body weight and fat mass, which then became similar to that observed with a chow diet ( 4 ).6 PUFAs were more potent than 3 PUFAs in promoting adipogenesis ( 5-7 ). When combined with high carbohydrate content, a linoleic acid-enriched diet was found to be pro-adipogenic in vivo through cAMP-dependent signaling ( 8 ). LA acts through arachidonic acid (C20:4 6, ARA) and prostacyclin, as pups from mice invalidated for the prostacyclin receptor (IP-R) and fed a LA-rich diet exhibit reduced body weight and fat mass compared with wild-type mice fed the same diet ( 4 ). Overall, these results emphasize the importance of adipose tissue development Abstract The prevalence of obesity has steadily increased over the last few decades. During this time, populations of industrialized countries have been exposed to diets rich in fat with a high content of linoleic acid and a low content of ␣ -linolenic acid compared with recommended intake. To assess the contribution of dietary fatty acids, male and female mice fed a high-fat diet (35% energy as fat, linoleic acid: ␣ -linolenic acid ratio of 28) were mated randomly and maintained after breeding on the same diet for successive generations. Offspring showed, over four generations, a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in food intake. Transgenerational alterations in adipokine levels were accompa nied by hyperinsulinemia. Gene expression analyses of the stromal vascular fraction of adipose tissue, over generations, revealed discrete and steady changes in certain important players, such as CSF3 and Nocturnin. Thus, under conditions of genome stability and with no change in the regimen over four generations, we show that a Western-like fat diet induces a gradual fat mass enhancement, in accordance with the increasing prevalence of obesity observed in humans. -Massiera, F., P. Barbry, P. Guesnet, A. Joly, S. The prevalence of obesity and the risk of developing associated diseases ha...
Identification of molecular mechanisms involved in generation of different types of adipocytes is progressing substantially in mice. However, much less is known regarding characterization of brown (BAP) and white adipocyte progenitors (WAPs) in humans, highlighting the need for an in vitro model of human adipocyte development. Here, we report a procedure to selectively derive BAP and WAPs from human-induced pluripotent stem cells. Molecular characterization of APs of both phenotypes revealed that BMP4, Hox8, Hoxc9, and HoxA5 genes were specifically expressed in WAPs, whereas expression of PRDM16, Dio2, and Pax3 marked BAPs. We focused on Pax3 and we showed that expression of this transcription factor was enriched in human perirenal white adipose tissue samples expressing UCP1 and in human classical brown fat. Finally, functional experiments indicated that Pax3 was a critical player of human AP fate as its ectopic expression led to convert WAPs into brown-like APs. Together, these data support a model in which Pax3 is a new marker of human BAPs and a molecular mediator of their fate. The findings of this study could lead to new anti-obesity therapies based on the recruitment of APs and constitute a platform for investigating in vitro the developmental origins of human white and brown adipocytes.
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