Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome

International audienc

Differentiation of Human Adipose-Derived Stem Cells into “Brite” (Brown-in-White) Adipocytes

It is well established now that adult humans possess active brown adipose tissue (BAT) which represents a potential pharmacological target to combat obesity and associated diseases. Moreover thermogenic brown-like adipocytes (“brite adipocytes”) appear also in mouse white adipose tissue (WAT) upon β3-adrenergic stimulation. We had previously shown that human multipotent adipose-derived stem cells (hMADS) are able to differentiate into cells which exhibit the key properties of human white adipocytes, and then to convert into functional brown adipocytes upon PPARγ activation. In light of a wealth of data indicating that thermogenic adipocytes from BAT and WAT have a distinct cellular origin, we have characterized at the molecular level UCP1 positive hMADS adipocytes from both sexes as brite adipocytes. Conversion of white to brown hMADS adipocytes is dependent on PPARγ activation with rosiglitazone as the most potent agonist and is inhibited by a PPARγ antagonist. In contrast to mouse cellular models, hMADS cells conversion into brown adipocytes is weakly induced by BMP7 treatment and not modulated by activation of the Hedgehog pathway. So far no primary or clonal precursor cells of human brown adipocytes have been obtained that can be used as a tool to develop therapeutic drugs and to gain further insights into the molecular mechanisms of brown adipogenesis in humans. Thus hMADS cells represent a suitable human cell model to delineate the formation and/or the uncoupling capacity of brown/brite adipocytes that could help to dissipate caloric excess intake among individuals

Characterization of human mesenchymal stem cell secretome at early steps of adipocyte and osteoblast differentiation

<p>Abstract</p> <p>Background</p> <p>It is well established that adipose tissue plays a key role in energy storage and release but is also a secretory organ and a source of stem cells. Among different lineages, stem cells are able to differentiate into adipocytes and osteoblasts. As secreted proteins could regulate the balance between both lineages, we aimed at characterizing the secretome of human multipotent adipose-derived stem cell (hMADS) at an early step of commitment to adipocytes and osteoblasts.</p> <p>Results</p> <p>A proteomic approach, using mono-dimensional electrophoresis and tandem mass spectrometry, allowed us to identify a total of 73 proteins at day 0 and day 3 of adipocyte and osteoblast differentiation. Analysis of identified proteins showed that 52 % corresponded to classical secreted proteins characterized by a signal peptide, that 37 % previously described in the extracellular compartment were devoid of signal peptide and that 11 % neither exhibited a signal peptide nor had been previously described extracellularly. These proteins were classified into 8 clusters according to their function. Quantitative analysis has been performed for 8 candidates: PAI-1, PEDF, BIGH3, PTX3, SPARC, ENO1, GRP78 and MMP2. Among them, PAI-1 was detected at day 0 and day 3 of osteoblast differentiation but never in adipocyte secretome. Furthermore we showed that PAI-1 mRNA was down-regulated in the bone of ovariectomized mice.</p> <p>Conclusion</p> <p>Given its regulation during the early events of hMADS cell differentiation and its status in ovariectomized mice, PAI-1 could play a role in the adipocyte/osteoblast balance and thus in bone diseases such as osteoporosis.</p

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

Activation of Protein Kinase A and Exchange Protein Directly Activated by cAMP Promotes Adipocyte Differentiation of Human Mesenchymal Stem Cells

Human mesenchymal stem cells are primary multipotent cells capable of differentiating into several cell types including adipocytes when cultured under defined in vitro conditions. In the present study we investigated the role of cAMP signaling and its downstream effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in adipocyte conversion of human mesenchymal stem cells derived from adipose tissue (hMADS). We show that cAMP signaling involving the simultaneous activation of both PKA- and Epac-dependent signaling is critical for this process even in the presence of the strong adipogenic inducers insulin, dexamethasone, and rosiglitazone, thereby clearly distinguishing the hMADS cells from murine preadipocytes cell lines, where rosiglitazone together with dexamethasone and insulin strongly promotes adipocyte differentiation. We further show that prostaglandin I2 (PGI2) may fully substitute for the cAMP-elevating agent isobutylmethylxanthine (IBMX). Moreover, selective activation of Epac-dependent signaling promoted adipocyte differentiation when the Rho-associated kinase (ROCK) was inhibited. Unlike the case for murine preadipocytes cell lines, long-chain fatty acids, like arachidonic acid, did not promote adipocyte differentiation of hMADS cells in the absence of a PPARγ agonist. However, prolonged treatment with the synthetic PPARδ agonist L165041 promoted adipocyte differentiation of hMADS cells in the presence of IBMX. Taken together our results emphasize the need for cAMP signaling in concert with treatment with a PPARγ or PPARδ agonist to secure efficient adipocyte differentiation of human hMADS mesenchymal stem cells

Apports lipidiques et prise de poids : aspects qualitatifs

The importance of dietary fat in human obesity remains a controversial issue as the prevalence of overweight and obesity has increased despite no dramatic change in the amount of ingested fats over the last decades. However qualitative changes, i.e. the fatty acid composition of fats, have been largely disregarded. In this review, we summarize experimental evidence which supports polyunsaturated fatty acids of the x6 series as potent stimulators of both adipogenesis in vitro and adipose tissue development in vivo. Changes observed over the last decades in the fatty acid composition of dietary fats observed in breast milk and formula milk, i.e. increase in LA with lower or no change in LNA content, may be responsible at least in part of the dramatic rise in the prevalence of childhood overweight and obesity. Similar changes, which are observed in most consumed foods, can be traced to changes in human food habits and in the feeding pattern of breeding stock. These qualitative changes, acting in concert with a positive energy balance, should promote excessive adipose tissue development. Whether prevention of obesity appears critical to avoid difficult if not insurmountable health problems to solve in the future, the status of dietary lipids should be reconsidered from the very beginning of the food chain

Identification et caractérisation de trois nouvelles protéines impliquées dans les étapes précoces de la différenciation adipocytaire (ACLP, DIPA et TSC-22)

Depuis de nombreuses années, le tissu adipeux est le centre d intérêt de nombreuses études visant à comprendre son mode de fonctionnement. Ces études ont permis l identification d un certain nombre d inhibiteurs extracellulaires ou intracellulaires de la mise en place de l hypertrophie/hyperplasie des cellules adipeuses. Au cours de ma thèse, je me suis intéressé aux étapes précoces de l différenciation adipocytaire. Les études auxquelles j ai participé ont permis notamment l identification de deux nouveaux facteurs inhibiteurs de l adipogenèse : ACLP et DIPA. La caractérisation d une troisième protéine, TSC-22, déjà connue pour participer à la mise en place du développement, est en cours. Celle-ci semble jouer un rôle essentiel lors de l adipogenèse, notamment dans la régulation des phases prolifératives. Un dernier aspect du tissu adipeux a également été abordé au cours de cette thèse. Le tissu adipeux a longtemps été considéré comme un simple tissu de stockage des réserves graisseuses dont les débordements contribueraient à aggraver les pathologies liées à l obésité. Nous avons démontré que l adipocyte sécrète PTX3, une protéine de l inflammation, en réponse aux signaux pro-inflammatoires. Cette étude fournit donc une nouvelle corrélation entre l obésité et ses complications et un état inflammatoire chronique.NICE-BU Sciences (060882101) / SudocSudocFranceF

La teneur en acides gras polyinsaturés du lait maternel : un marqueur biologique fiable du niveau de consommation des populations

Polyunsaturated fatty acids (PUFA) are nutritionally important constituents of breast milk to support normal growth, immune function and central nervous system development of newborn infants. Both linoleic acid (18:2 n-6; LA) and alpha-linolenic acid (18:3 n-3 ; ALA), the essential fatty acids, precursors of n-6 and n-3 long-chain PUFA. LA and LNA contents in human milk reflect differences in dietary fats consumed by the mothers, including those consumed during several months (long term impact). The composition of breast milk from this point of view is a reliable biological marker of the level of habitual consumption of PUFAs in different populations. An increase of LA content for the 1950-1990 period, without any change of LNA content, has been reported in breast milk of women living in western countries, reflecting changes in LA intake by the mother