Paracrine effects of leptin in regulating visceral fat expansion

Project summary: Visceral adiposity is a major risk factor for the development of metabolic syndrome. A better understanding of visceral fat expansion in the progression of obesity may provide new strategies to treat obesity and its associated metabolic disorders. Visceral fat expansion requires the dedicated coordination between mature adipocytes and precursor cells. Recent advances using single cell sequencing have revealed the heterogeneity of visceral fat depots and identified two major precursor populations in PDGFRb+ stromal cells – adipogenic progenitor cells (APCs) and fibro- inflammatory progenitors (FIPs) – which contribute to visceral fat expansion during obesity. However, the main regulators that determine the fate of these two populations are largely unknown. Recently, we found that gene expression of leptin (lep) in visceral fat is much higher than it is in subcutaneous and brown fat. In response to acute high-fat diet (HFD) exposure (1 day), we found a rapid increase in lep gene expression in visceral fat depots, but not in subcutaneous and brown fat depots. This increase in lep gene expression in visceral fat is paired with a rapid expansion of APCs and FIPs, suggesting a regulatory role for leptin. In addition, during the progression to obesity, high leptin derived from visceral adipocytes creates a unique “hyperleptinemia” micro-environment, which promotes the expansion of FIPs and leads to adipose tissue hypertrophy and inflammation. Therefore, we hypothesize that leptin from visceral fat is a significant regulatory element of the detrimental effects of visceral adiposity and controls visceral fat expansion by regulating precursor cells-FIPs and APCs. In this proposal, we will take advantage of novel and well-established mouse models, paired with biochemical techniques to uncover the paracrine effects of leptin in the regulation of visceral fat expansion, with three specific Aims: Aim 1 is to determine whether visceral- derived leptin contributes to the detrimental effects of visceral adiposity; Aim 2 is to assess the paracrine effects of leptin in regulating the fate of FIPs and APCs; Aim 3 is to investigate the effect of CXCL14 in mediating visceral fat healthy expansion. Combined, these studies will provide new insights into paracrine effects of leptin in regulating the fate of FIPs and APCs, leading to an unhealthy visceral fat expansion and developing visceral adiposity. In addition, this study will offer an entirely novel means to combat against visceral adiposity by targeting on leptin/CXCL14 axis.