FunctionalPlasticityofAdipose-DerivedStromalCells During Development of Obesity

Obesityisamajorriskfactorforanumberofchronicdiseases,includingdiabetes,cardiovasculardiseases, andcancer.Expansionof theadiposemassrequiresadipocyteprecursorcells thatoriginatefrom multipotent adipose-derived stromal cells (ASCs),which in turn also participate in repair activities. ASC function might decline in a disease milieu, but it remains unclear whether ASC function varies during the developmentofobesity.Wetestedthehypothesisthatmicroenvironmentalinflammatorychangesduring development of metabolic disorders in obesity affect ASC function. Domestic pigs were fed with an atherogenic(n=7)ornormal(n=7)dietfor16weeks.Abdominaladiposetissuebiopsieswerecollected after 8, 12, and 16 weeks of diet for ASC isolation and immunohistochemistry of in situ ASCs and tumor necrosis factor-a (TNF-a). Longitudinal changes in proliferation, differentiation, and anti-inflammatory functions of ASCs were assessed. At 16 weeks, upregulated TNF-a expression in adipose tissue from obese pigs was accompanied by increased numbers of adipocyte progenitors (CD24 + /CD34 + )i n adipose tissue and enlarged adipocyte size. In vitro, ASCs from obese pigs showed enhanced adipogenic and osteogenicpropensity,whichwasabolishedbyanti-TNF-atreatment,whereasleanASCstreatedwith TNF-ashowedenhancedadipogenesis.Furthermore,obeseASCsshowedincreasedsenescencecompared with lean ASCs, whereas their immunomodulatory capacity was preserved. Adipose tissue inflammation promotes an increase in resident adipocyte progenitors and upregulated TNF-a enhances ASC adipogenesis.Thus,adiposetissueanti-inflammatorystrategiesmightbeanoveltargettoattenuateobesityandits complications. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:893–900