Enhancement of Muscle Mitochondrial Oxidative Capacity and Alterations in Insulin Action Are Lipid Species Dependent: Potent Tissue-Specific Effects of Medium-Chain Fatty Acids

OBJECTIVE

Medium-chain fatty acids (MCFAs) have been reported to be less obesogenic than long-chain fatty acids (LCFAs); however, relatively little is known regarding their effect on insulin action. Here, we examined the tissue-specific effects of MCFAs on lipid metabolism and insulin action.

RESEARCH DESIGN AND METHODS

C57BL6/J mice and Wistar rats were fed either a low-fat control diet or high-fat diets rich in MCFAs or LCFAs for 4–5 weeks, and markers of mitochondrial oxidative capacity, lipid levels, and insulin action were measured.

RESULTS

Mice fed the MCFA diet displayed reduced adiposity and better glucose tolerance than LCFA-fed animals. In skeletal muscle, triglyceride levels were increased by the LCFA diet (77%, P < 0.01) but remained at low-fat diet control levels in the MCFA-fed animals. The LCFA diet increased (20–50%, P < 0.05) markers of mitochondrial metabolism in muscle compared with low-fat diet–fed controls; however; the increase in oxidative capacity was substantially greater in MCFA-fed animals (50–140% versus low-fat–fed controls, P < 0.01). The MCFA diet induced a greater accumulation of liver triglycerides than the LCFA diet, likely due to an upregulation of several lipogenic enzymes. In rats, isocaloric feeding of MCFA or LCFA high-fat diets induced hepatic insulin resistance to a similar degree; however, insulin action was preserved at the level of low-fat diet–fed controls in muscle and adipose from MCFA-fed animals.

CONCLUSIONS

MCFAs reduce adiposity and preserve insulin action in muscle and adipose, despite inducing steatosis and insulin resistance in the liver. Dietary supplementation with MCFAs may therefore be beneficial for preventing obesity and peripheral insulin resistance.Insulin resistance, defined as an impaired ability of insulin to regulate carbohydrate and lipid metabolism in target tissues, is one of the major metabolic defects of obesity and type 2 diabetes. It is closely linked with excess lipid deposition in nonadipose tissues, particularly skeletal muscle and liver, and several mechanisms have been proposed describing how lipid metabolites antagonize insulin action (1,2). Although the precise factors that cause inappropriate lipid accumulation are still not completely resolved, a number of studies have suggested that reduced mitochondrial capacity for lipid oxidation, particularly in skeletal muscle, may lead to partitioning of fatty acids into lipid storage pathways and a subsequent deterioration in insulin sensitivity (1,3).Given the close link between lipid accumulation and reduced insulin action, one of the primary experimental paradigms for investigating the etiology of insulin resistance is high-fat feeding (e.g., 45–60% of calories) in rodents. Many studies have demonstrated that consumption of a diet high in long-chain fatty acids (LCFAs) induces widespread insulin resistance in muscle, liver, and adipose tissue of both rats and mice (4–7). Under these conditions of excess LCFA availability, however, we (8) and others (9) have demonstrated that mitochondrial content and fatty acid oxidative capacity are actually increased in muscle, suggesting that there is a compensatory response to increase fatty acid utilization pathways, which is insufficient to prevent lipid overload and insulin resistance. Indeed, we have recently shown that acute overexpression of carnitine palmitoyltransferase (CPT)-1 in muscle increases fatty acid oxidative capacity above that induced by high-fat feeding alone, and this partially protects against lipid-induced insulin resistance (10).While high-fat diets containing most classes of LCFAs (e.g., saturated, monounsaturated, and omega-6) lead to obesity and insulin resistance (4,6,11), an interesting group of fatty acids that have been suggested to have antiobesity potential are medium-chain (C8–12) fatty acids (MCFAs) (12,13). Studies in humans and rodents have shown that MCFAs induce higher energy expenditure and fatty acid oxidation compared with LCFAs, and this is associated with lower adipose mass (14–17). Compared with LCFAs, however, less is known regarding the effect of MCFAs on insulin sensitivity. In rats, high-fat diets rich in MCFAs have been reported to be less deleterious for glucose and insulin tolerance compared with LCFAs (11,18,19). A limited number of studies in humans have also suggested that MCFAs may not have detrimental effects on insulin action (20,21). Whether specific tissues are involved in the favorable effects of MCFAs on insulin action is currently unclear, particularly as several studies have shown that MCFAs induce hepatic steatosis (11,17), which would be expected to have a negative impact on insulin sensitivity in this tissue. Therefore, our aim in this study was to investigate the tissue-specific effects of high-fat diets containing MCFAs on lipid metabolism and insulin action.