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

Sergio Rodriguez-Cuenca, Stefania Carobbio, Vidya Velagapudi, Nuria Barbarroja, Jose Maria Moreno-Navarrete, Francisco Jose Tinahones, Jose Manuel Fernandez-Real, Matej Orešič, Antonio Vidal-Puig

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Abstract

Optimal 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.
Original languageEnglish
Pages (from-to)1555-1565
JournalMolecular and Cellular Biology
Volume32
Issue number8
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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Rodriguez-Cuenca, S., Carobbio, S., Velagapudi, V., Barbarroja, N., Moreno-Navarrete, J. M., Tinahones, F. J., Fernandez-Real, J. M., Orešič, M., & Vidal-Puig, A. (2012). Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility. Molecular and Cellular Biology, 32(8), 1555-1565. https://doi.org/10.1128/MCB.06154-11