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

OBJECTIVE

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.

RESEARCH DESIGN AND METHODS

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.

RESULTS

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.

CONCLUSION

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.Over the past few decades, type 2 diabetes has increased in prevalence largely as a result of the obesity epidemic (1). Although it is widely accepted that skeletal muscle insulin resistance is a major determinant in both the onset and progression of type 2 diabetes (2), the exact cause of decreased insulin action in skeletal muscle is not known (3). That said, it is generally believed that skeletal muscle insulin resistance develops secondary to impaired mitochondrial fatty acid oxidation (4,5). However, several other studies have shown that lipid accumulation is not associated with skeletal muscle insulin resistance (6–8) or overall mitochondrial dysfunction (9–13). Consistent with this, a growing body of evidence has suggested that the cause of skeletal muscle insulin resistance may not result from impaired fatty acid oxidation but might actually result from excessive skeletal muscle mitochondrial fatty acid oxidation and ensuing mitochondrial stress (12,14). While it is not known which of these two processes are most relevant in the pathogenesis of skeletal muscle insulin resistance, it is clear that excessive entry of fatty acids into the skeletal muscle plays a central role in diet-induced insulin resistance.Because advanced age is a significant risk factor in the etiology of type 2 diabetes (15,16), the accompanying loss of mitochondrial function observed with normal aging has been proposed to contribute to the increased risk of type 2 diabetes in the elderly population (17). However, a clear understanding of the physiological changes that occur during the onset of middle age and the influence that this may have on the development of insulin resistance is currently lacking. This is particularly important given that the baby boomer generation, the largest population group in the Western world, is currently classified as middle-aged (18) as well as the fact that the prevalence of type 2 diabetes in the Western world is expected to increase dramatically over the next 5–10 years (16,18). The study herein was designed to investigate how middle age impacts whole-body glucose utilization, fatty acid handling, and triglyceride accumulation within skeletal muscle as well as the susceptibility of middle-aged mice to the development of diet-induced insulin resistance.