Alterations in Skeletal Muscle Fatty Acid Handling Predisposes Middle-Aged Mice to Diet-Induced Insulin Resistance

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 6; pp. 1366 - 1375
• Main Authors: KOONEN, Debby P. Y, SUNG, Miranda M. Y, FEBBRAIO, Maria, DYCK, Jason R. B, KAO, Cindy K. C, DOLINSKY, Vernon W, KOVES, Timothy R, ILKAYEVA, Olga, JACOBS, René L, VANCE, Dennis E, LIGHT, Peter E, MUOIO, Deborah M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2010
• Subjects: Aging; Aging (Biology); Aging - physiology; Animal Feed; Animals; Baby boomers; Basal Metabolism; Biological and medical sciences; Calorimetry, Indirect; CD36 Antigens - deficiency; CD36 Antigens - genetics; CD36 Antigens - physiology; Chromatography; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Health aspects; Insulin resistance; Insulin Resistance - physiology; Lipids; Medical sciences; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle age; Muscle, Skeletal - growth & development; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Muscles; Musculoskeletal system; Obesity - genetics; Obesity - prevention & control; Older people; Original; Oxidation; Physiological aspects; Research design; Risk factors; Skeletal muscle; Striated muscle. Tendons; Triglycerides; Type 2 diabetes; Vertebrates: osteoarticular system, musculoskeletal system; United States; Endocrinopathy; Diabetes mellitus; Rodentia; Lipids; Metabolic diseases; Striated muscle; Fatty acids; Feeding; Target tissue resistance; Vertebrata; Mammalia; Diet; Mouse; Animal; Insulin resistance
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1142

Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance. Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages. Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance-a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice. Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet.