Abstract
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.
Highlights
Obesity has reached epidemic proportions globally, with more than one billion adults overweight and at least 300 million of them clinically obese
We have reported the characterization of mesenchymal stem cells from human adipose tissue of young male and female donors [termed human multipotent adipose-derived stem cells] which exhibit at a clonal level a normal karyotype, selfrenewal ability, the absence of tumorigenicity (Rodriguez et al, 2004, 2005a; Zaragosi et al, 2006; Elabd et al, 2007; Fontaine et al, 2008), and are able to convert into functional brown-like adipocytes (Elabd et al, 2009)
uncoupling protein 1 (UCP1), 2, AND 3 EXPRESSION DURING HMADS CELL DIFFERENTIATION We showed previously that human multipotent adipose-derived stem cells (hMADS) cells were able to differentiate into white and brown adipocytes depending on the length of activation of PPARγ by rosiglitazone (Elabd et al, 2009)
Summary
Obesity has reached epidemic proportions globally, with more than one billion adults overweight and at least 300 million of them clinically obese. In contrast to WAT, brown adipose tissue (BAT) is specialized in adaptive thermogenesis in which the uncoupling protein 1 (UCP1) plays a key role (Golozoubova et al, 2006). Recent data show that active BAT is present as discrete and small depots in healthy adult individuals (Nedergaard et al, 2007; Cypess et al, 2009; Saito et al, 2009; Van Marken Lichtenbelt et al, 2009; Virtanen et al, 2009; Zingaretti et al, 2009) and represents a new target to fight obesity (Fruhbeck et al, 2009; Whittle et al, 2011)
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