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 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.
Department of Clinical Biochemistry, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. sr441@medschl.cam.ac.uk
Sergio
S
Rodriguez-Cuenca
Stefania
S
Carobbio
Vidya R
VR
Velagapudi
Nuria
N
Barbarroja
Jose Maria
JM
Moreno-Navarrete
Francisco Jose
FJ
Tinahones
Jose Manuel
JM
Fernandez-Real
Matej
M
Orešic
Antonio
A
Vidal-Puig
D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics; D051379:Mice; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D002395:Catecholamines; D020738:Leptin; D047495:PPAR gamma; D017868:Cyclic AMP-Dependent Protein Kinases