In normal-weight adults, white adipose tissue (WAT) represents 10 to 29% of body weight but this mass increases in obesity. Western dietary habits and a sedentary lifestyle have produced a worldwide epidemic of obesity. Thus, it is imperative to understand the cellular origin of obesity to generate effective strategies for treating or preventing metabolic disorders. Increased adipose tissue mass may result from cellular hyperplasia and/or hypertrophy of existing adipocytes. Hyperplasia implies that new adipocytes are produced from the differentiation of progenitor cells and/or by the proliferation of existing fat cells. Recently, a discreet population of adipocyte progenitor cells (APCs) was identified in the stromal-vascular fraction (SVF) of WAT. Deletion of insulin receptor substrate 2 (IRS2) in mice impairs pancreatic beta cell development and expansion. Additionally, female Irs2 null are insulin resistant and develop moderate obesity. Thus, our working hypothesis is that insulin/IRS signals may determine the number of APCs by regulating their development and proliferation. To gain further insight into the molecular mechanisms that control APC number and proliferation, we have pursued the following specific aims: 1) quantify and characterize APCs in visceral (VIS) and subcutaneous (SC) WAT in Irs2-/- and wild-type (WT) control mice, and 2) evaluate the relationship between inflammation and number of APCs. Female Irs2 null mice had more adipose tissue in both VIS and SC depots than WT mice. Histological analysis revealed that adipocyte size and density were similar between the two groups, suggesting that the observed differences in WAT mass is due to increased cell number rather than hypertrophy. Using a FACS-based strategy, we isolated APCs from SVF of WAT depots. We observed that VIS of female Irs2 null mice has increased hematopoietic cells and also APCs. Moreover, when cultured, SC progenitors isolated from Irs2-deficient mice displayed an increased mitogenic rate. Estimation of doubling-time revealed that cultures of APCs from Irs2-/- SC proliferate faster than APS from WT SC (doubling-time Irs2-/- SC: 0.66 days vs doubling-time WT SC: 1.04 days). Collectively, our data suggest that Irs2-deficiency is associated with increased APCs, thereby revealing IRS2 as a potential target for anti-obesity strategies.
2013-05-27
