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Published in: Diabetologia 11/2006

01-11-2006 | Article

Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids

Authors: B. Brunmair, K. Staniek, J. Dörig, Z. Szöcs, K. Stadlbauer, V. Marian, F. Gras, C. Anderwald, H. Nohl, W. Waldhäusl, C. Fürnsinn

Published in: Diabetologia | Issue 11/2006

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Abstract

Aims/hypothesis

GW501516, an agonist of peroxisome proliferator-activated receptor-δ (PPAR-δ), increases lipid combustion and exerts antidiabetic action in animals, effects which are attributed mainly to direct effects on skeletal muscle. We explored such actions further in isolated rat skeletal muscle.

Materials and methods

Specimens of rat skeletal muscle were pretreated with GW501516 (0.01–30 μmol/l) for 0.5, 4 or 24 h and rates of fuel metabolism were then measured. In addition, effects on mitochondrial function were determined in isolated rat liver mitochondria.

Results

At concentrations between 0.01 and 1 μmol/l, GW501516 dose-dependently increased fatty acid oxidation but reduced glucose utilisation in isolated muscle. Thus after 24 h of preincubation with 1 μmol/l GW501516, palmitate oxidation increased by +46±10%, and the following decreased as specified: glucose oxidation −46±8%, glycogen synthesis −42±6%, lactate release −20±2%, glucose transport −15±6% (all p<0.05). Reduction of glucose utilisation persisted independently of insulin stimulation or muscle fibre type, but depended on fatty acid availability (the effect on glucose transport in the absence of fatty acids was an increase of 30±9%, p<0.01), suggesting a role for the glucose–fatty acid cycle. At higher concentrations, GW501516 uncoupled oxidative phosphorylation by direct action on isolated mitochondria.

Conclusions/interpretation

GW501516-induced activation of PPAR-δ reduces glucose utilisation by skeletal muscle through a switch in mitochondrial substrate preference from carbohydrate to lipid. High concentrations of GW501516 induce mitochondrial uncoupling independently of PPAR-δ.
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Metadata
Title
Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids
Authors
B. Brunmair
K. Staniek
J. Dörig
Z. Szöcs
K. Stadlbauer
V. Marian
F. Gras
C. Anderwald
H. Nohl
W. Waldhäusl
C. Fürnsinn
Publication date
01-11-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0357-6

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