Endogenous peroxisome proliferator-activated receptor-gamma augments fatty acid uptake in oxidative muscle.
In the setting of insulin resistance, agonists of peroxisome proliferator-activated receptor (PPAR)-gamma restore insulin action in muscle and promote lipid redistribution. Mice with muscle-specific knockout of PPARgamma (MuPPARgammaKO) develop excess adiposity, despite reduced food intake and normal glucose disposal in muscle. To understand the relation between muscle PPARgamma and lipid accumulation, we studied the fuel energetics of MuPPARgammaKO mice. Compared with controls, MuPPARgammaKO mice exhibited significantly increased ambulatory activity, muscle mitochondrial uncoupling, and respiratory quotient. Fitting with this latter finding, MuPPARgammaKO animals compared with control siblings exhibited a 25% reduction in the uptake of the fatty acid tracer 2-bromo-palmitate (P < 0.05) and a 13% increase in serum nonesterified fatty acids (P = 0.05). These abnormalities were associated with no change in AMP kinase (AMPK) phosphorylation, AMPK activity, or phosphorylation of acetyl-CoA carboxylase in muscle and occurred despite increased expression of fatty acid transport protein 1. Palmitate oxidation was not significantly altered in MuPPARgammaKO mice despite the increased expression of several genes promoting lipid oxidation. These data demonstrate that PPARgamma, even in the absence of exogenous activators, is required for normal rates of fatty acid uptake in oxidative skeletal muscle via mechanisms independent of AMPK and fatty acid transport protein 1. Thus, when PPARgamma activity in muscle is absent or reduced, there will be decreased fatty acid disposal leading to diminished energy utilization and ultimately adiposity.
Norris
Andrew W
AW
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. andrew-norris@uiowa.edu
Hirshman
Michael F
MF
Yao
Jianrong
J
Jessen
Niels
N
Musi
Nicolas
N
Chen
Lihong
L
Sivitz
William I
WI
Goodyear
Laurie J
LJ
Kahn
C Ronald
CR
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D004036:Diet, Atherogenic; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009928:Organ Specificity / Q000235:genetics; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D047495:PPAR gamma; C493569:Slc27a1 protein, mouse; D000263:Adenylate Kinase