White adipose tissue (WAT) expansion occurs by adipocyte hypertrophy or recruitment and differentiation of adipocyte progenitors (hyperplasia) in a depot-dependent manner. Growth of subcutaneous (SUB) WAT is believed to occur by hyperplasia while visceral (VIS) WAT growth is predominantly by hypertrophy. The hypertrophic growth of VIS WAT is associated with insulin resistance, type 2 diabetes and cardiovascular disease. The mechanisms underlying the hypertrophic growth of VIS WAT at adulthood is uncompletely understood. We have recently uncovered the existence of a heterogeneous population of adipose progenitors (APs) unique to VIS WAT of mice that exhibit distinct adipogenic and secretory capacity. We named these cells VIS low and VIS high APs based on their low or high expression of CD34. These cells are functionally distinct based on their transcriptional profiling. Indeed, VIS low but not VIS high APs express higher levels of peroxisome proliferator-activated receptor gamma (PPARg;) and fatty acid binding protein (FABP4) and differentiate well in response to hormonal stimulation. Most, importantly, VIS high but not VIS low APs proliferate faster and their proportion correlate positively with hypertrophic growth of VIS WAT and the degree of insulin resistance in mice. Furthermore, VIS high APs exert an inhibitory effect on adipogenic differentiation of both VIS low and SUB APs in vitro. The aim of this proposal is to provide mechanistic insights into the development of hypertrophic VIS obesity through the functional characterization of these newly identified progenitors. The following specific aims will be tested: Aim1: will identify novel secreted protein(s)/factor(s) by VIS high APs that inhibit adipogenic differentiation of VIS low and SUB APs in vitro and Aim 2: will determine if similar AP populations (VIS low and VIS high) exist in VIS fat of humans, if they exhibit a distinct adipogenic capacity and whether their proportions vary with hypertrophic obesity. The proposed study is innovative, highly significant and aligns with the American Heart Association mission because it is aimed to decipher the cellular and molecular mechanisms involved in the pathogenesis of VIS obesity, an important risk factor for the development of cardiovascular disease.
|Effective start/end date||07/01/2016 → 06/30/2018|