This Article Full Text Full Text (PDF) All Versions of this Article: 147/5/2077    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watt, M. J. Articles by Febbraio, M. A. Search for Related Content PubMed PubMed Citation Articles by Watt, M. J. Articles by Febbraio, M. A.

Ciliary Neurotrophic Factor Prevents Acute Lipid-Induced Insulin Resistance by Attenuating Ceramide Accumulation and Phosphorylation of c-Jun N-Terminal Kinase in Peripheral Tissues

Cellular and Molecular Metabolism Laboratory (M.J.W., G.I.L., M.A.F.), School of Medical Sciences, RMIT University, Bundoora, Victoria 3083, Australia; and Department of Medicine (A.H.), University of California, San Diego, La Jolla, California 92093

Address all correspondence and requests for reprints to: Matthew J. Watt, Ph.D., St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia. E-mail: mwatt{at}svi.edu.au.

Ciliary neurotrophic factor (CNTF) is a member of the gp130 receptor cytokine family recently identified as an antiobesity 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 pretreatment (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 (insulin-stimulated glucose disposal rate) and liver (hepatic glucose production) insulin sensitivity by 30 and 45%, respectively. CNTF pretreatment completely prevented the lipid-mediated reduction in insulin-stimulated glucose disposal rate and the blunted suppression of hepatic glucose production by insulin. Although lipid infusion increased triacylglycerol and ceramide accumulation and phosphorylation of mixed linage kinase 3 and c-Jun N-terminal kinase 1 in skeletal muscle, CNTF pretreatment prevented these lipid-induced effects. Alterations in hepatic and muscle insulin signal transduction as well as phosphorylation of c-Jun N-terminal kinase 1/2 paralleled alterations in insulin sensitivity. These data support the use of CNTF as a potential therapeutic means to combat lipid-induced insulin resistance.

This article has been cited by other articles:

				W. L. Holland and S. A. Summers Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism Endocr. Rev., June 1, 2008; 29(4): 381 - 402. [Abstract] [Full Text] [PDF]

				M. J. Watt, B. J. W. van Denderen, L. A. Castelli, C. R. Bruce, A. J. Hoy, E. W. Kraegen, L. Macaulay, and B. E. Kemp Adipose Triglyceride Lipase Regulation of Skeletal Muscle Lipid Metabolism and Insulin Responsiveness Mol. Endocrinol., May 1, 2008; 22(5): 1200 - 1212. [Abstract] [Full Text] [PDF]

				J. Chung, A.-K. Nguyen, D. C. Henstridge, A. G. Holmes, M. H. S. Chan, J. L. Mesa, G. I. Lancaster, R. J. Southgate, C. R. Bruce, S. J. Duffy, et al. HSP72 protects against obesity-induced insulin resistance PNAS, February 5, 2008; 105(5): 1739 - 1744. [Abstract] [Full Text] [PDF]

				C. Moro, S. Bajpeyi, and S. R. Smith Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E203 - E213. [Abstract] [Full Text] [PDF]

				G. R. Steinberg, B. E. Kemp, and M. J. Watt Adipocyte triglyceride lipase expression in human obesity Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E958 - E964. [Abstract] [Full Text] [PDF]

				C. Escartin, K. Pierre, A. Colin, E. Brouillet, T. Delzescaux, M. Guillermier, M. Dhenain, N. Deglon, P. Hantraye, L. Pellerin, et al. Activation of Astrocytes by CNTF Induces Metabolic Plasticity and Increases Resistance to Metabolic Insults J. Neurosci., July 4, 2007; 27(27): 7094 - 7104. [Abstract] [Full Text] [PDF]

				F. J. Spargo, S. L. McGee, N. Dzamko, M. J. Watt, B. E. Kemp, S. L. Britton, L. G. Koch, M. Hargreaves, and J. A. Hawley Dysregulation of muscle lipid metabolism in rats selectively bred for low aerobic running capacity Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1631 - E1636. [Abstract] [Full Text] [PDF]

				N. Sharma, I. C. Okere, M. K. Duda, D. J. Chess, K. M. O'Shea, and W. C. Stanley Potential impact of carbohydrate and fat intake on pathological left ventricular hypertrophy Cardiovasc Res, January 15, 2007; 73(2): 257 - 268. [Abstract] [Full Text] [PDF]

				A. L. Carey, G. R. Steinberg, S. L. Macaulay, W. G. Thomas, A. G. Holmes, G. Ramm, O. Prelovsek, C. Hohnen-Behrens, M. J. Watt, D. E. James, et al. Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase. Diabetes, October 1, 2006; 55(10): 2688 - 2697. [Abstract] [Full Text] [PDF]

				R. Janoschek, L. Plum, L. Koch, H. Munzberg, S. Diano, M. Shanabrough, W. Muller, T. L. Horvath, and J. C. Bruning gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor PNAS, July 11, 2006; 103(28): 10707 - 10712. [Abstract] [Full Text] [PDF]

				D. J. Dyck Ciliary Neural Trophic Factor: Mimicking Leptin's Effects in Skeletal Muscle? Endocrinology, May 1, 2006; 147(5): 2075 - 2076. [Full Text] [PDF]