Saturated- and n-6 Polyunsaturated-Fat Diets Each Induce Ceramide Accumulation in Mouse Skeletal Muscle: Reversal and Improvement of Glucose Tolerance by Lipid Metabolism Inhibitors

• Published in: Endocrinology (Philadelphia) Vol. 151; no. 9; pp. 4187 - 4196
• Main Authors: Frangioudakis, G, Garrard, J, Raddatz, K, Nadler, J. L, Mitchell, T. W, Schmitz-Peiffer, C
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.09.2010; The Endocrine Society
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Body Weight - drug effects; Cell Line; Ceramide; Ceramides - metabolism; Dietary Fats - administration & dosage; Dietary Fats - pharmacology; Diets; Fatty acids; Fatty Acids - administration & dosage; Fatty Acids - pharmacology; Fatty Acids, Monounsaturated - pharmacology; Fatty Acids, Unsaturated - administration & dosage; Fatty Acids, Unsaturated - pharmacology; Fundamental and applied biological sciences. Psychology; Glucose Intolerance - blood; Glucose Intolerance - prevention & control; Glucose tolerance; Homeostasis; Immunoblotting; Immunosuppressive Agents - pharmacology; Insulin; Insulin - blood; Linoleic Acid - pharmacology; Lipid metabolism; Lipid Metabolism - drug effects; Male; Mass spectroscopy; Mice; Mice, Inbred C57BL; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Myotubes; Oxidoreductases - metabolism; Palmitates - pharmacology; Palmitic acid; Pentoxifylline - analogs & derivatives; Pentoxifylline - pharmacology; phosphatidic acid; Phosphatidic Acids - metabolism; Skeletal muscle; Striated muscle. Tendons; Triglycerides - metabolism; Vertebrates: endocrinology; Vertebrates: osteoarticular system, musculoskeletal system; Rodentia; Sphingolipid; Tolerance; Lipids; Glucose; Striated muscle; Metabolism; Feeding; Vertebrata; Mammalia; Diet; Mouse; Animal; Ceramide
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0250

Lipid-induced insulin resistance is associated with intracellular accumulation of inhibitory intermediates depending on the prevalent fatty acid (FA) species. In cultured myotubes, ceramide and phosphatidic acid (PA) mediate the effects of the saturated FA palmitate and the unsaturated FA linoleate, respectively. We hypothesized that myriocin (MYR), an inhibitor of de novo ceramide synthesis, would protect against glucose intolerance in saturated fat-fed mice, while lisofylline (LSF), a functional inhibitor of PA synthesis, would protect unsaturated fat-fed mice. Mice were fed diets enriched in saturated fat, n-6 polyunsaturated fat, or chow for 6 wk. Saline, LSF (25 mg/kg · d), or MYR (0.3 mg/kg · d) were administered by mini-pumps in the final 4 wk. Glucose homeostasis was examined by glucose tolerance test. Muscle ceramide and PA were analyzed by mass spectrometry. Expression of LASS isoforms (ceramide synthases) was evaluated by immunoblotting. Both saturated and polyunsaturated fat diets increased muscle ceramide and induced glucose intolerance. MYR and LSF reduced ceramide levels in saturated and unsaturated fat-fed mice. Both inhibitors also improved glucose tolerance in unsaturated fat-fed mice, but only LSF was effective in saturated fat-fed mice. The discrepancy between ceramide and glucose tolerance suggests these improvements may not be related directly to changes in muscle ceramide and may involve other insulin-responsive tissues. Changes in the expression of LASS1 were, however, inversely correlated with alterations in glucose tolerance. The demonstration that LSF can ameliorate glucose intolerance in vivo independent of the dietary FA type indicates it may be a novel intervention for the treatment of insulin resistance. Ceramide accumulation occurs in muscle of fat-fed mice, independent of the predominant fat source; modulation of ceramide synthase enzyme expression is associated with improved glucose tolerance by myriocin and lisofylline.