High-fat diets cause insulin resistance despite an increase in muscle mitochondria

Abstract

It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)delta by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR gamma coactivator 1alpha (PGC-1alpha) protein expression. Similarly, overexpression of PPARdelta results in a large increase in PGC-1alpha protein in the absence of any increase in PGC-1alpha mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPARdelta, which mediates a posttranscriptional increase in PGC-1alpha. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.

Fig. 1.

A high-fat diet induces an increase in skeletal muscle mitochondria. Western blot analysis of mitochondrial proteins from triceps muscles of rats fed the flax seed oil/olive oil diet. Values are mean ± SE for 6–10 muscles. *, P < 0.05, high fat versus chow. C, control; F, high fat; COX1, cytochrome oxidase subunit 1; COX4, cytochrome oxidase subunit 4; ALAs, aminolevulinate synthase.

Fig. 2.

High-fat diet induces an increase in mitochondrial DNA copy number. Mitochondrial DNA copy number was evaluated in triceps muscles by determining the ratio of cytochrome b DNA to 18S DNA. Values are means ± SE for four rats per group. *, P < 0.05.

Fig. 3.

A high-fat diet induces a gradual increase in muscle mitochondria. Time course of the increase in mitochondrial enzyme proteins in response to the high-fat, lard/corn oil diet. Values are means ± SE for four to eight muscles per group. *, P < 0.05 versus other groups. Values are means ± SE for four muscles per group. COX1, cytochrome oxidase subunit 1; ALAs, aminolevulinate synthase.

Fig. 4.

A high-fat diet induces a gradual increase in PGC-1α protein. Time course of the increase in PGC-1α protein in epitrochlearis muscles of rats fed the lard/corn oil diet. C, control; F, high fat. Values are means ± SE for four to eight muscles per group.

Fig. 5.

Overexpression of PPARδ in muscle results in an increase in PGC-1α protein. (A) PPARδ protein in tibialis anterior muscles in which PPARδ (P) was overexpressed by electric pulse field gene transfer. *, P < 0.05. (B) PGC-1α protein expression is increased in muscles overexpressing PPARδ. *, P < 0.05. Values are means ± SE for four muscles per group. C, control.