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Submitted on August 23, 2005
Accepted on December 23, 2005
Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, RMIT University, Bundoora, Victoria, 3083, Australia.; University of California, San Diego, Department of Medicine, La Jolla, California, USA, 92093-0673
* To whom correspondence should be addressed. E-mail: matthew.watt{at}rmit.edu.au.
Ciliary neurotrophic factor (CNTF) is a member of the gp130 receptor cytokine family recently identified as an anti-obesity agent in rodents and humans by mechanisms that remain unclear. We investigated the impact of acute CNTF treatment on insulin action in the presence of lipid oversupply. To avoid confounding effects of long term high-fat feeding or genetic manipulation on whole body insulin sensitivity, we performed a 2 h Intralipid infusion (20% heparinized Intralipid) with or without recombinant CNTF pre-treatment (Axokine 0.3 mg/kg), followed by a 2 h hyperinsulinemic-euglycemic clamp (12 mU/kg/min) in fasted, male Wistar rats. Acute Intralipid infusion increased plasma free fatty acid levels from 1.0 ± 0.1 to 2.5 ± 0.3 mM, which subsequently caused reductions in skeletal muscle (IS-GDR) and liver (HGP) insulin sensitivity by 30% and 45%, respectively. CNTF pre-treatment completely prevented the lipid mediated reduction in IS-GDR and the blunted suppression of HGP by insulin. While lipid infusion increased triacylglycerol and ceramide accumulation and phosphorylation of MLK3 and JNK1 in skeletal muscle, CNTF pre-treatment prevented these lipid induced effects. Alterations in hepatic and muscle insulin signal transduction as well as phosphorylation of JNK1/2 paralleled alterations in insulin sensitivity. These data support the use of CNTF as a potential therapeutic means to combat lipid-induced insulin resistance.
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