| Prevalence of obesity and obesity-associated metabolic problems has become a major economic and medical burden worldwide.Obesity is a major risk factor for many chronic diseases,including diabetes,fatty livers and cancer.By 2030,nearly 60% of the world's adult population might be either overweight or obese.White adipose tissues(WATs),the major type of adipose tissues,function as a storage depot of lipid.WAT is also an endocrine organ secreting adipokines which plays a key role in pathogenesis of obesity and its complications.In obese individuals,the adipose tissue constitutes almost half the body weight,making it the largest endocrine organ in humans.Even minor metabolic changes in such a large secretory organ have the potential to affect broadly the entire body.Therefore,a better understanding of adipose tissue biology is crucial to design targeted novel interventions which can attenuate obesity and minimize its deleterious effects.Expansion of the adipose mass has been shown to be related to adipogenic differentiation of adipose-derived stem cells(ASCs).Adipose stem cells(ASCs)are an important adipose resident population,which maintain adipose tissue homeostasis through regulating the quantity of mature adipocytes.Over the past decades,ASCs have been used in clinical therapy protocols in a broad range of diseases due to their potent immunomodulatory properties and their intrinsic ability to differentiate into multiple cell lineages,such as adipocytes,osteoblasts,chondrocytes,and neurons.ASCs,under defined conditions in vitro,can differentiate into adipocytes depending on the presence of particular cytokines,(e.g.,isobutylmethylxanthin,indomethacin,and dexamethasone).It has been shown that such adipogenic factors can activate transcription factors C/EBPs,which were critical for adipogenesis,the process whereby undifferentiated progenitor cells differentiate into fat cells.However,the underlying mechanism of this effect has yet to be elucidated.Osteopontin(OPN),an arginine-glycine-aspartate-containing glycoprotein,is known as a soluble protein that is present in most body fluids.As an important inflammatory cytokine originally identified in osteoblasts,OPN has multi-roles on bone remodeling,cell migration,immune regulation and tumor metastasis.OPN can be secreted to the extracellular space acting autocrinely and paracrinely within tissues.Recently,it has been reported that OPN regulates the differentiation of MSC through its interactions with integrins,expressed cell surface receptors.MSCs are a subset of CD34-fibroblast-like progenitor cells and can be derived and propagated in vitro from different organs and tissues,such as bone marrow,embryos,adipose tissue.ASCs are the mesenchymal stem cells derived from adipose tissues.We found that osteopontin(OPN)is downregulated in ASCs and adipose tissue of obese mice and human beings because of methylation on its promoter,indicating that OPN may affect the development of obesity.Silencing of OPN in wild type ASCs promotes adipogenic differentiation,while re-expression of OPN reduced the rate of adipogenic differentiation in OPN-/-ASCs.The role of extracellular OPN in ASCs differentiation was further demonstrated by supplementation and neutralization of OPN.Additionally,OPN suppresses adipogenic differentiation in ASCs through the C/EBPs pathways.Consistent with these in vitro results,by intravenous injection of OPN-expressing adenovirus to the mice,we found OPN can delay the development of obesity and inhibit the increase of blood glucose.Therefore,our study demonstrates a important role for OPN in regulating the development of obesity,indicating OPN might be a novel target to attenuate obesity and its complications. |
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