Increased Efficiency of Fatty Acid Uptake Contributes to Lipid Accumulation in Skeletal Muscle of High Fat-Fed Insulin-Resistant Rats

Abstract

In humans and animal models, increased lipid content of skeletal muscle is strongly associated with insulin resistance. However, it is unclear whether this accumulation is due to increased uptake or reduced utilization of fatty acids (FAs). We used 3 H-R-bromopalmitate tracer to assess the contribution of tissue-specific changes in FA uptake to the lipid accumulation observed in tissues of insulin-resistant, high fat-fed rats (HFF) compared with control rats (CON) fed a standard diet. To study FA metabolism under different metabolic states, tracer was infused under basal conditions, during hyperinsulinemic-euglycemic clamp (low FA availability) or during the infusion of intralipid and heparin (high FA availability). FA clearance was significantly increased in the red gastrocnemius muscle of HFF under conditions of low (HFF ‫؍‬ 10.4 ؎ 1.1; CON ‫؍‬ 7.4 ؎ 0.5 ml ⅐ min ؊1 ⅐ 100 g ؊1 ; P < 0.05), basal (HFF ‫؍‬ 8.3 ؎ 1.4; CON ‫؍‬ 4.5 ؎ 0.7 ml ⅐ min ؊1 ⅐ 100 g ؊1 ; P < 0.01), and high (HFF ‫؍‬ 7.0 ؎ 0.8; CON ‫؍‬ 4.3 ؎ 0.5 ml ⅐ min ؊1 ⅐ 100 g ؊1 ; P < 0.05) FA levels. This indicates an adaptation by muscle for more efficient uptake of lipid. Associated with the enhanced efficiency of FA uptake, we observed increases in CD36/FA translocase mRNA expression (P < 0.01) and acyl-CoA synthetase activity (P < 0.02) in the same muscle. FA clearance into white adipose tissue was also increased in HFF when circulating FA were elevated, but there was little effect of the high-fat diet on hepatic FA uptake. In conclusion, insulin resistance induced by feeding rats a high-fat diet is associated with tissue-specific adaptations that enhance utilization of increased dietary lipid but could also contribute to the accumulation of intramuscular lipid with a detrimental effect on insulin action.

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

“…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].…”

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

“…Evidence for both has been published: skeletal muscle from high fat fed normal rats display an increased efficiency of FFA uptake that could be explained by increased level of mRNA coding for the fatty acid transporter CD36 and for acyl CoA synthase. 34 In contrast, studies on muscle biopsies from patients with type 2 diabetes show impaired mitochondrial oxidative capacity and size. 35 Very recently, similar impairment of mitochondrial activity has been demonstrated in insulin-resistant offspring of patients with type 2 diabetes, suggesting that an inherited defect in mitochondrial oxidative phosphorylation could be a cause of lipid accumulation.…”

Increased susceptibility to oxidative damage in post-diabetic human myotubes

“…Along these lines, it has been proposed that the overflow of triacylglycerol metabolites in skeletal muscle mitochondria leads to an uncoupling of the tricarboxylic acid cycle and the electron transport chain (ETC), resulting in an accumulation of incompletely oxidised long-chain fatty acids [10]. These may thus be diverted from the tricarboxylic acid cycle into other lipid metabolites such as ceramides, diacylglycerol and/or acylcarnitines, which in turn can interfere with the insulin signalling pathway [10,11], as discussed in reviews [12][13][14]. Indeed, decreased mitochondrial content and impaired oxidative capacity are correlated with insulin resistance and associated with obesity [15][16][17][18], but effects can be mitigated by weight loss and physical activity [19,20].…”