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)␦ by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR ␥ coactivator 1␣ (PGC-1␣) protein expression. Similarly, overexpression of PPAR␦ results in a large increase in PGC-1␣ protein in the absence of any increase in PGC-1␣ mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPAR␦, which mediates a posttranscriptional increase in PGC-1␣. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.I t has been hypothesized that insulin resistance in patients with impaired or diabetic glucose tolerance is mediated by a deficiency of mitochondria in skeletal muscle (1, 2). The mechanism by which a decrease in mitochondria is proposed to cause insulin resistance is accumulation of intramyocellular lipids caused by a decrease in the capacity to oxidize fat (2). This hypothesis is based on the finding that type 2 diabetics and insulin-resistant individuals with impaired glucose tolerance have Ϸ30% less mitochondria in their muscles than insulinsensitive control subjects (3-7). In support of this concept, recent studies have reported that raising serum free fatty acids (FFA) by a high-fat diet in humans (8), or by feeding mice or rats high-fat diets (8-10), results in decreases in skeletal muscle peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) mRNA (8-10) and the mRNA levels of various mitochondrial constituents (8). In contrast, a number of earlier studies provided evidence that high-fat diets induce increases in mitochondrial marker enzymes (11-14), and Turner et al. (15) recently reported that a high-fat diet resulted in increases in mitochondrial biogenesis and fatty acid oxidative capacity in skeletal muscle of mice.We have found that raising serum FFA in rats by feeding them a high-fat diet and giving them daily heparin injections results in an increase in muscle mitochondria (16). The initial purpose of the present study was to determine whether the more modest increase in FFA induced by a high-fat diet also results in increased mitochondrial biogenesis with an increase in the capacity of muscle to oxidize fat. We found that a high-fat diet does induce an increase in muscle mitochondria. This finding made it possible to evaluate whether a high-fat diet causes muscle insulin resistance despite increases in mitochondria and fat oxidative capacity.Overexpression of peroxisome proliferator-activated receptor (PPAR)␦ i...

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

“…Muscle mitochondrial markers Previous studies have found that AMPK regulates mitochondrial biogenesis [24,25] and that high-fat feeding increases mitochondrial oxidative capacity [14,15]. To estimate mitochondrial content, we measured levels of mitochondrial marker proteins in gastrocnemius muscle (Fig.…”

“…In humans, skeletal muscle fatty acid oxidation is reduced with obesity [8] and type 2 diabetes [9], an effect associated with reduced mitochondrial capacity in some [10][11][12], but not all studies [13]. However, in animal models of obesity and insulin resistance skeletal muscle mitochondrial capacity is increased [14,15], suggesting that despite increases in mitochondrial capacity, the oxidative rate of muscle is unable to fully compensate for increases in fatty acid delivery and uptake [16,17]. In accordance with this idea, increased protein levels of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting factor involved in mitochondrial uptake of long-chain carnitine acyl-CoAs, protects muscle from lipid accumulation and insulin resistance [18], whereas chronic inhibition of CPT-1 exacerbates obesityrelated insulin resistance [19].…”

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…PGC-1α targeting of subsarcolemmal mitochondria may be an attempt to efficiently remove, via β-oxidation, fatty acids as soon as they cross the sarcolemma, thus minimising their intramuscular accumulation. However, the relationship between skeletal muscle fatty acid oxidation and intramuscular lipid accumulation is not necessarily a simple reciprocal one [14,50], as has been widely thought.…”

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

“…However, despite the large number of studies suggesting a role for mitochondrial dysfunction in the development of insulin resistance, there are also an increasing number of reports showing a disconnection between these two variables. For example, we and others have shown that high-fat feeding enhances mitochondrial oxidative capacity in skeletal muscle, even though lipid accumulates and insulin resistance develops in this tissue [4,5]. Furthermore, mice with genetically induced mitochondrial dysfunction in skeletal muscle are not insulin resistant, even when challenged with a high-fat diet (HFD) [6,7].…”