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This Article Full Text Full Text (PDF) All Versions of this Article: 293/2/R642    most recent 00133.2007v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dube, J. J. Articles by O'Doherty, R. M. Search for Related Content PubMed PubMed Citation Articles by Dube, J. J. Articles by O'Doherty, R. M.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

Leptin, skeletal muscle lipids, and lipid-induced insulin resistance

Departments of ¹Medicine and ²Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania; and ³Department of Human Health and Nutritional Science, University of Guelph, Ontario, Canada

Submitted 23 February 2007 ; accepted in final form 8 May 2007

Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (15%), and increased SkM Akt (30%) and glycogen synthase kinase 3 (52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; 61%), elevated ceramides (50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity (25%) and increased SkM DAG (33%) and ceramide (60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase C (PKC), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKC and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by HL.

insulin sensitivity; PKC; Akt; diacylglycerol; ceramide; triglyceride