Excess Lipid Availability Increases Mitochondrial Fatty Acid Oxidative Capacity in Muscle

Abstract

A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including 14 C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, ␤-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks ؉23%, P < 0.05, and 20 weeks ؉29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks ؉49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1␣, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.

High-Fat Diet–Induced Mitochondrial Biogenesis Is Regulated by Mitochondrial-Derived Reactive Oxygen Species Activation of CaMKII

“…We first examined the phosphorylation state of CaMKII in a chronic model of obesity, namely obese Zucker rats, which are known to have higher levels of skeletal muscle mitochondrial content (2,20). We have confirmed these findings because mtDNA was increased (P , 0.05) approximately twofold in obese animals (Fig.…”

“…However, high-fat feeding has been shown to induce insulin resistance while increasing mitochondrial content (2,3), divorcing this proposed causal relationship. Nevertheless, a reduction in mitochondrial content could exacerbate the phenotype of insulin resistance (4), whereas the increase in mitochondrial content observed at the initiation of a high-fat diet is likely beneficial because genetic approaches that modestly increase mitochondrial content improve insulin signaling in insulin resistant animals (5).…”

Gastric inhibitory polypeptide receptor antagonist, SKL‐14959, suppressed body weight gain on diet‐induced obesity mice

“…From the viewpoint of energy consumption, the SKL‐14959‐treated group did not significantly enhance β‐HAD activity in the liver and the muscle (Figure 2D–2F) nor significantly up‐regulate the relative gene expression of PPAR‐alpha ( ppara ) in the liver and the adipose tissue, UCP‐2 ( ucp2 ) and hormone sensitive lipase ( Lipe ) in the adipose tissue compared with the HFD control group (Figure 4A and 4B). It might be because GLP‐1 made up for the effect 31; alternatively, raised β‐HAD activity in the HFD control group compared with the LFD group was already reached maximal effectiveness, so that further combustible effects of SKL‐14959 were not observed 32. These results suggested that SKL‐14959 might not have direct action or have only a subtle effect of lipolysis.…”

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

“…Moreover, control mice fed HFD had lower VO 2 than control mice fed STD. These data suggest that in Ames dwarf mice oxygen consumption is not affected by HFD feeding, possibly reflecting that an increase in respiration is linked to an increase in fatty acid oxidation (Garcia‐Roves et al ., 2007; Turner et al ., 2007). …”