High-fat diets rich in medium- versus long-chain fatty acids induce distinct patterns of tissue specific insulin resistance

Abstract

Excess dietary long-chain fatty acid (LCFA) intake results in ectopic lipid accumulation and insulin resistance. Since medium-chain fatty acids (MCFA) are preferentially oxidized over LCFA, we hypothesized that diets rich in MCFA result in a lower ectopic lipid accumulation and insulin resistance compared to diets rich in LCFA. Feeding mice high-fat (HF) (45% kcal fat) diets for 8 weeks rich in triacylglycerols composed of MCFA (HFMCT) or LCFA (HFLCT) revealed a lower body weight gain in the HFMCT-fed mice. Indirect calorimetry revealed higher fat oxidation on HFMCT compared to HFLCT (0.011.0±0.0007 vs. 0.0096±0.0015 kcal/g body weight per hour, P<.05). In line with this, neutral lipid immunohistochemistry revealed significantly lower lipid storage in skeletal muscle (0.05±0.08 vs. 0.30±0.23 area%, P <.05) and in liver (0.9±0.4 vs. 6.4±0.8 area%, P<.05) after HFMCT vs. HFLCT, while ectopic fat storage in low fat (LF) was very low. Hyperinsulinemic euglycemic clamps revealed that the HFMCT and HFLCT resulted in severe whole body insulin resistance (glucose infusion rate: 53.1±6.8, 50.8±15.3 vs. 124.6±25.4 μmol min(-1) kg(-1), P<.001 in HFMCT, HFLCT and LF-fed mice, respectively). However, under hyperinsulinemic conditions, HFMCT revealed a lower endogenous glucose output (22.6±8.0 vs. 34.7±8.5 μmol min(-1) kg(-1), P<.05) and a lower peripheral glucose disappearance (75.7±7.8 vs. 93.4±12.4 μmol min(-1) kg(-1), P<.03) compared to HFLCT-fed mice. In conclusion, both HF diets induced whole body insulin resistance compared to LF. However, the HFMCT gained less weight, had less ectopic lipid accumulation, while peripheral insulin resistance was more pronounced compared to HFLCT. This suggests that HF-diets rich in medium- versus long-chain triacylglycerols induce insulin resistance via distinct mechanisms.

Effect of GPR84 deletion on obesity and diabetes development in mice fed long chain or medium chain fatty acid rich diets

“…1). This corroborates previous findings that the outcome of weight gain in rodents depends on the fatty acid composition of the diet, and that MCFA are non-obesogenic compared to LCFA diets [5,29,30]. In our study, there were no differences in body mass that could be attributed to GPR84 expression or deletion.…”

Long- and Medium-Chain Fatty Acids Induce Insulin Resistance to a Similar Extent in Humans Despite Marked Differences in Muscle Fat Accumulation

“…In contrast to our study (10), however, this study also showed that mice fed the high-fat MCFA diet, in contrast to the high-fat LCFA diet, maintained a normal whole-body glucose tolerance as well as normal insulin-stimulated muscle glucose uptake, as assessed by a hyperinsulinemic-euglycemic clamp (11). Furthermore, these findings associated with increased markers of mitochondrial metabolism in skeletal muscle tissue (11).…”

“…This may result in blunted lipid-induced insulin resistance upon MCFA administration. Indeed, we have recently shown that consumption of a high-fat diet rich in medium-chain triacylglycerols (MCT), as opposed to long-chain triacylglycerols (LCT), does not lead to ectopic fat accumulation in skeletal muscle and liver of both rats and mice (9,10). However, we were unable to show beneficial effects of the reduction in intramyocellular lipid levels upon high-fat MCT feeding in mice with respect to insulin-stimulated glucose uptake in the peripheral organs (primarily accounted for by skeletal muscle) (10).…”

Contrasting metabolic effects of medium- versus long-chain fatty acids in skeletal muscle

“…In contrast, diets rich in MCFAs, when used at an equal-caloric level, do not induce the same degree of detrimental effects on metabolic health; despite a similar increase in dietary fat intake as with the LCFA diet (4)(5)(6)(7)(8). These favorable effects have been partially ascribed to the physical properties of MCFAs, because this class of FAs is more readily funneled into oxidative pathways, which could lead to increased energy expenditure and less fat deposition in adipose and other tissues compared with LCFAs ( 26 ). The tissue that is likely to be responsible for many of the benefi cial effects of MCFAs on whole-body glucose homeostasis is skeletal muscle, where previous studies from our group have shown that a MCFA-rich diet leads to a substantially greater increase in palmitoyl carnitine as substrates.…”

“…In the current cohort of animals, we similarly observed that hepatic lipid accumulation was increased after LCFA feeding, and to an even greater extent after MCFA feeding (data not shown). While excess hepatic lipid can have deleterious metabolic effects, it should be noted that many studies in rodents and humans have reported no adverse effects of MCFAs on liver lipid levels ( 4,26,33,34 ). These disparate fi ndings on liver lipid accumulation between studies indicates that differences in methodological factors may also be important, such as the exact composition and fat content of the MCFA-enriched diets, as well as the composition of the other macronutrients in the diet.…”