Previous studies examining the effect of different fatty acids on insulin action have reported improved glucose tolerance and insulin tolerance in rodents fed high-fat diets rich in MCFAs compared with LCFAs (11
). Our current study reveals the tissues responsible for the favorable effect of MCFAs on whole-body glucose metabolism, as well as a mechanistic basis for these effects. We have made the intriguing observation that insulin action in skeletal muscle and adipose tissue is preserved at the level of low-fat–fed controls when animals consume a high-fat diet rich in MCFAs. In muscle, the lack of induction of insulin resistance with MCFA high-fat feeding is associated with a substantial increase in mitochondrial oxidative capacity, which is sufficient to prevent lipid accumulation in this tissue. However, the liver of MCFA-fed animals accumulated greater amounts of triglycerides, likely due to upregulation of lipogenic pathways, and as such, hepatic insulin action was reduced after MCFA high-fat feeding.
It is likely that our findings have clinical relevance, as several studies have suggested that MCFAs may be beneficial for insulin action in humans. Eckel et al. (20
) showed in a small (n
= 3) cohort of subjects with type 2 diabetes that acute treatment with MCFAs (40% fat for 5 days) resulted in a beneficial effect on insulin-stimulated glucose disposal, without consistent effects on insulin-mediated suppression of HGO. Furthermore, a 3-month trial in patients with type 2 diabetes reported improved homeostatic model assessment of insulin resistance in subjects consuming MCFAs compared with LCFAs (21
). The above human studies and those in rodents (11
) indicate that MCFAs do not induce insulin resistance to the same degree as LCFAs; however, they have provided limited information regarding the tissue-specific effects of MCFAs on insulin action in vivo and/or a mechanism for any observed beneficial effects. Our current study clearly shows that MCFAs do not induce insulin resistance in either muscle and adipose tissue, and given the fact that muscle is the major tissue for insulin-stimulated glucose disposal (25
), the reported favorable effects of MCFAs on whole-body glucose metabolism (11
) are probably related to changes in insulin action in muscle. It is worth noting, however, that the daily caloric intake in MCFA-fed mice was ~25% higher than in low-fat–fed controls, and whether with more prolonged high-fat feeding this elevated energy intake would eventually lead to some metabolic dysfunction in muscle and adipose tissue remains to be determined.
The strong association between lipid accumulation and insulin resistance is well documented (1
), and our findings that MCFAs do not induce lipid accumulation in muscle and concurrently preserve insulin action in this tissue strongly support the above link. We and others have reported that under conditions of increased lipid availability, either through high-fat feeding (with LCFAs), acute lipid infusions, or muscle-specific overexpression of lipoprotein lipase, mitochondrial content and fatty acid oxidative capacity are upregulated in muscle (8
). Such a response likely represents an attempt of the muscle to cope with additional fatty acid substrates; however, the fact that lipids still accumulate in muscle in animals under these conditions suggests that the compensatory upregulation of oxidative pathways is unable to deal with the elevated uptake of LCFAs that is observed with such manipulations (26
). In comparison with LCFAs, however, we have shown that MCFAs induce a substantially greater upregulation of mitochondrial oxidative capacity in muscle, and this appears to be at a sufficient level to prevent the deleterious effects of lipid oversupply on insulin action in this tissue.
The underlying molecular mechanism by which MCFAs induce a more potent upregulation of mitochondrial biogenesis in muscle than LCFAs is currently unclear. We observed a substantial accumulation of MCFAs in the neutral lipid fraction of muscle from MCFA-fed animals, and one major pathway through which fatty acids influence substrate metabolism in muscle is via activation of PPAR, particularly PPARδ. These transcription factors, when activated by fatty acids or other ligands, control genes involved in oxidative and fatty acid metabolism (29
). Several studies (30
) have shown, however, that MCFAs have low binding affinity for PPARs, suggesting that a direct effect of MCFAs on PPAR-dependent transcription is unlikely responsible for the increase in mitochondrial biogenesis. PPARs can also be activated via interaction with the transcriptional coactivator PGC-1α, which is considered a master controller of mitochondrial biogenesis in muscle. We observed similar upregulation of PGC-1α content in muscle with both the MCFA and LCFA diets. However, posttranslational modification (e.g., acetylation) of PGC-1α is known to regulate its activity (32
), and whether MCFAs specifically affect this pathway or influence the activity of other transcription factors is currently unknown.
In addition to oxidative metabolism, there are a number of other pathways that influence lipid deposition in tissues, including lipid uptake from the circulation and, for tissues such as the liver, the rate of de novo lipogenesis. With regard to these factors, MCFAs differ from LCFAs in a number of important ways. MCFAs are more readily absorbed into the bloodstream, and, therefore, a greater proportion of these fatty acids reach the liver through the portal vein (33
). MCFAs can also enter the mitochondrion for oxidation via CPT-1–independent mechanisms (34
). These unusual physical properties are thought to largely explain the increase in energy expenditure and decreased adiposity observed with MCFA-rich diets (i.e., due to enhanced hepatic fatty acid oxidation), particularly in the postprandial period (13
). Our novel finding of a very potent upregulation of mitochondrial content in muscle by MCFAs suggests that enhanced flux of substrates through oxidative metabolism in muscle may also contribute to MCFA-induced changes in energy expenditure and adiposity, as well as improved muscle insulin action (current study and 13
The other tissue in which MCFAs were less deleterious than LCFAs for insulin action was adipose tissue. Small adipocytes are more insulin-sensitive than large adipocytes (35
), and previous studies (16
) have demonstrated that adipocyte size is reduced with MCFA diets, potentially due to a reduction in adipogenic gene expression (18
). It is likely that the preserved insulin sensitivity we observed in adipose following MCFA high-fat feeding is simply a consequence of reduced adipocyte size, although given the fact that MCFAs accumulate significantly in adipose tissue following MCFA high-fat feeding (current study and 18
), we cannot rule out a more direct effect of MCFAs on adipocyte function that may be beneficial for insulin action. Furthermore, as adipose tissue secretes a number of adipokines that affect carbohydrate and lipid metabolism in other tissues, it remains to be determined if MCFA-induced changes in adipokine profile (19
) partly contribute to the changes in mitochondrial content and insulin action observed in skeletal muscle with the MCFA high-fat diet.
Despite the favorable effects of MCFAs on muscle and adipose metabolism, another important finding was that MCFAs robustly induced insulin resistance in liver and caused a greater degree of hepatic steatosis than LCFAs in both mice and rats. This elevation in liver triglyceride levels did not appear to be due to a decreased capacity for lipid oxidation, as we observed generally similar levels of mitochondrial enzyme activity and protein expression in the different dietary groups. As mentioned above, the entry of MCFAs into mitochondria is less dependent on CPT-1 than LCFAs, and a consequence of accelerated β-oxidation is an excess production of acetyl-CoA. Much of this acetyl-CoA is converted into ketone bodies, which have been reported to be elevated in MCFA-fed animals (17
). Acetyl-CoA is also a substrate for de novo lipogenesis, and, in line with other reports (39
), we observed a substantial upregulation of lipogenic enzymes in liver from the MCFA-fed mice, presumably to deal with the excess acetyl-CoA, and this is likely a major contributor to the increased triglyceride levels in these animals. Consistent with this, we only observed a small proportion of MCFAs in the neutral lipid fraction of liver from MCFA-fed animals, suggesting metabolism of these fatty acids through lipogenic pathways.
There is controversy in the literature regarding the effects of MCFAs on liver triglycerides. In rodents, a number of studies (11
) have reported increased liver triglyceride levels with MCFA feeding, while others (16
) show no difference between high-fat diets containing MCFAs or LCFAs. Interestingly, one recent study (41
) in rats suggested that liver triglyceride content is significantly lower with a diet containing only MCFAs compared with LCFAs, but this effect was diminished in the presence of LCFAs. In humans, a number of studies have reported that MCFAs do not have adverse effects on liver lipid levels (42
); however, inconsistent findings have been reported regarding the effect of MCFA on circulating lipid parameters (21
). It is possible that methodological differences may underlie many of these seemingly disparate findings, such as the dietary fat content and composition, the length of dietary intervention, and the composition of other constituents of the diet (e.g., carbohydrates and protein).
In summary, our study shows that high-fat diets containing MCFAs have divergent effects on tissue-specific insulin sensitivity, inducing insulin resistance to a similar degree as LCFAs in liver while preserving insulin action at the level of low-fat–fed controls in muscle and adipose tissue. The preservation of muscle insulin action by MCFAs is associated with a potent stimulation of mitochondrial biogenesis, which appears to be sufficient to prevent lipid accumulation in this tissue. Given that the total amount of dietary fat used in the current studies is relatively high (i.e., 45–60% of energy), it will be important to determine in future studies the amount of dietary MCFAs (both in absolute terms and relative to dietary LCFAs) required for beneficial effects on energy metabolism and insulin action and whether this amount of dietary MCFAs avoids liver lipid accumulation. In this regard, some human studies (21
) have reported positive effects on energy expenditure and body composition with relatively low dietary doses of MCFAs. Additionally, as some antidiabetes therapies (e.g., metformin) are known to exert the majority of their insulin-sensitizing effects via their actions in the liver (48
), it will be of interest to determine whether MCFA supplementation in conjunction with such agents results in beneficial effects on insulin action in multiple insulin target tissues.