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

AbstractOptimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ 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 PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ 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 PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) 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 PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans. SUPPLEMENTAL MATERIALSupplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06154-11. ACKNOWLEDGMENTSWe thank Erik Schoenmakers (Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom) for providing us with the pgl4 vector and for his excellent technical advice and Andrew Whittle (Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom) for his useful comments and suggestions. We also thank Janice Carter, Dan Hart, and Helen Westby for the excellent husbandry of the PPARγ-P465L mutant colony.This work was funded by Diabetes UK, an MRC Programme grant, MITIN (Integration of the System Models of Mitochondrial Function and Insulin Signaling and its Application in the Study of Complex Diseases), and the Cambridge NIHR Biomedical Research Centre (A.V.-P.); FP6 HEPADIP (A.V.-P. and M.O.); the Human Frontier Science Programme (M.O.); Junta de Andalucia (P08-CTS-04369) and the Fondo de Investigacion Sanitaria (PS09/00997) (F.J.T.); and the Ministerio de Educacion y Ciencia (SAF2008-02073) and the Instituto de Salud Carlos III-CIBERobn (J.M.F.-R.).S. R.-C. and S.C. performed the ex vivo experiments in mice (RNA and protein expression analysis and lipolysis, EMSA, ChIP, and luciferase assays) and collected and analyzed the data. V.R.V. and M.O. developed analytical platforms and performed and analyzed lipidomic experiments. N.B., J.M.M.-N., F.J.T., and J.M.F.-R. held and characterized the human cohorts, performed experiments and collected gene expression data from adipose depots, and analyzed the data. S.R.-C., S.C., and A.V.-P. designed the experiments. S.R.-C., S.C., N.B., J.M.M.-N., F.J.T., J.M.F.-R., V.R.V., M.O., and A.V.-P. discussed the manuscript. S.R.-C., S.C., and A.V.-P. coordinated and directed the project. S.R.-C. and A.V.-P. developed the hypothesis and wrote the manuscript.We declare that we have no conflict of interest.