Adipose stem cells niche in obesity

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Obesity continues to escalate as a significant public health problem and as the leading preventable cause of death. One third of adult population in US is obese (CDC's BRFSS, 2015). Alarmingly, 78% of the veteran population is obese, a notably higher percent compared to general population. With over 9.2 million beneficiaries, the cost of obesity and its related diseases exceeds $1.7 billion annually for the VA (18). With this significant rising epidemic, obesity has become one of the major health risk factor that contributes to the development of severe conditions such as cardiovascular diseases, diabetes mellitus, stroke and certain cancers. Genetic, environmental, behavioral, and socioeconomic factors cause excess weight gain and obesity. Adipose tissue is an important endocrine regulator of energy homeostasis and glucose metabolism. New adipocytes are required for storage of excess energy (intake>expenditure) in the white adipocyte tissue and this is accomplished via adipose stem cells' adipogenesis process. Using human adipose stem cells (ASC) from lean and obese patients, it was showed that adipogenesis is dysregulated in obesity and mature adipocytes in obese subjects show distinctive phenotype compared to lean subjects(5, 6). Obesity is accompanied with chronic low grade inflammation which initiates insulin resistance and metabolic syndrome(7, 8). It was demonstrated that obesity changes the adipose stem cell niche. However, the impact of this phenomenon and importance of ASC niche in obesity has not been investigated mechanistically. Hence, a screening study was undertaken to identify genes whose expression is altered in obese ASC such that it renders adipocytes susceptible to increased inflammation. Data showed increase of Protein Kinase C deltaI (PKCδI) -an important kinase in cellular differentiation, proliferation and apoptosis. The data indicated that PKCδI promotes inflammation in obese adipocytes. Based on these observations, the goal is to elucidate the role of PKCδI in adipose stem cells in obesity. Aim 1: Determine the role of PKCδI in promoting inflammation in obesity: Obesity associated inflammation contributes to insulin resistance and metabolic syndrome. Data showed that PKCδI is increased in obesity and PKCδI knockdown inhibits inflammation in obese ASC. Systematic analysis of inflammatory genes with gain and loss of PKCδI will be performed. Aim 2: Determine the regulation of PKCδI expression in obese ASC. Using ASC, the data shows that NEAT1, a long noncoding RNA, regulates PKCδI expression. The molecular mechanisms underlying regulation of PKCδI expression by NEAT1 will be determined using RNA binding assays and loss/gain of function studies in ASC. Aim 3: Develop and validate a novel, specific PKCδI inhibitor in obesity in vivo. PKCδI is increased in obese adipocytes and it mediates inflammation which culminates in insulin resistance in obesity. Silencing PKCδI decreases apoptosis and inflammation in obese adipocytes. The pharmacokinetics and pharmacodynamics of a novel PKCδI specific inhibitor will be evaluated in vivo in an obese mouse model. Obesity is the leading preventable cause of death. Overweight and obesity per se are not fatal; however obesity is the predominant condition that promotes diseases such as cardiovascular disease, diabetes mellitus and insulin resistance, and cancer which have high mortality rates(9). PKCδI is an important mediator of inflammation in obesity which significantly contributes to obesity- associated co-morbidities. The drug discovery arm has developed a novel, specific PKCδI inhibitor which will lead to an advanced therapeutic strategy for management of obesity related morbidities.