Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPAR gamma on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPAR gamma mouse as a model of dysfunctional PPAR gamma that recapitulates the human ppar gamma mutation (P467L). We demonstrated that defective PPAR gamma impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPAR gamma-dependent regulatory node of the lipolytic response. Specifically, defective PPAR gamma is associated with decreased basal expression of prkaca (PKAcat alpha) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPAR gamma is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans.