Metabolic flexibility and carnitine flux: The role of carnitine acyltransferase in glucose homeostasis

Abstract

Skeletal muscle is the major site of glucose disposal, accounting for 80% of glucose catabolism under insulin-stimulated conditions in healthy subjects. In type 2 diabetes mellitus patients, muscular glucose uptake is decreased; therefore, skeletal muscle can be a major therapeutic target for the daily control of hyperglycemia and improvement in insulin sensitivity. To develop therapeutic approaches to insulin resistance, numerous researchers have shown its underlying mechanisms, and there is a great deal of evidence that abnormalities in muscular mitochondrial function can lead to the accumulation of toxic lipid metabolites and induce insulin resistance (the lipotoxicity paradigm). Furthermore, increasing evidence indicates that metabolic inflexibility leads to muscular insulin resistance. Indeed, Muoio et al.1 recently described a molecular mechanism by which metabolic inflexibility causes insulin resistance in skeletal muscle, and showed the efficacy of carnitine supplementation therapy in patients with insulin resistance and metabolic inflexibility. Mitochondrial dysfunction in skeletal muscle is considered central to the development of insulin resistance and type 2 diabetes mellitus. Many studies show that decreased muscular lipid oxidation capacity results in the accumulation of toxic lipid intermediates, such as diacylglycerol, acyl-coenzyme A (acyl-CoA) and ceramides, and activates atypical protein kinase C isoforms. This is followed by serine phosphorylation of insulin receptor substrates and, eventually, impaired insulin signaling. According to these findings, researchers postulated the lipotoxicity hypothesis, which suggests that decreased mitochondrial function in the prediabetic state leads to the accumulation of toxic fatty metabolites, thereby contributing to the development of insulin resistance. Kelley and Mandarino2 originally defined metabolic flexibility as the capacity to switch from predominant lipid oxidation and high rates of fatty acid uptake during fasting conditions to the suppression of lipid oxidation, and increased glucose uptake, oxidation and storage under insulin-stimulation. In contrast, metabolic inflexibility observed in type 2 diabetes mellitus patients is characterized by an inability of the organism to shift mitochondrial energy sources promptly in response to changes in nutrient availability. However, the causal relationship between metabolic inflexibility and muscular insulin resistance remains unclear. Carnitine is considered a key molecule associated with the mechanism of metabolic flexibility. Although carnitine is best known for its role in the import of long-chain fatty acids (acyl groups) into the mitochondrial matrix for subsequent β-oxidation, it is also necessary for the mitochondrial efflux of acyl groups in cases where substrate oxidation exceeds energy demands. Importantly, free carnitine is decreased in skeletal muscles of obese rats, whereas dietary L-carnitine supplementation rescues metabolic flexibility. Therefore, deficient carnitine-dependent efflux systems might be one of the mechanisms underlying metabolic inflexibility. To test this hypothesis, Muoio et al.1 generated muscle-specific carnitine acyltransferase (CrAT)-knockout (CrATM−/−) mice. CrAT is a carnitine-dependent acyltransferase enzyme that catalyzes the reversible conversion of short-chain acyl-CoA (mainly acetyl-CoA) and carnitine to free CoA and short-chain acylcarnitine (mainly acetylcarnitine). Unlike acyl-CoA, these metabolites can cross mitochondrial and cellular membranes with ease. CrAT resides principally in the mitochondrial matrix, where it regulates the flux of acetyl-CoA. In normal skeletal muscle, CrAT converts excessive acetyl-CoA to acetylcarnitine and promotes its mitochondrial and cellular efflux (Figure 1a). However, in CrAT-deficient muscle, acetyl-CoA was not converted to its permeable form and was not excreted from mitochondria or cells. This led to the overaccumulation of acetyl-CoA, which exerted an allosteric inhibiting effect on pyruvate dehydrogenase (PDH), a rate-limiting enzyme for pyruvate entry into the tricarboxylic acid cycle, and subsequently impaired glucose utilization (Figure 1b). In addition, CrATM−/− mice showed glucose intolerance, insulin resistance and metabolic inflexibility. It is noteworthy that insulin-stimulated phosphorylation of Akt in skeletal muscle did not differ between wild-type and CrATM−/− mice, suggesting that glucose intolerance in CrATM−/− mice is not a result of lack of insulin sensitivity in skeletal muscle and might be a result of attenuation of glucose oxidation capacity through PDH inhibition. Taken together, CrAT inhibits mitochondrial acetyl-CoA overload by regulating the efflux of acetyl-CoA, thus maintaining PDH activity in skeletal muscle. Through these molecular mechanisms, muscular CrAT plays an important role in whole-body glucose tolerance. Muoio et al.1 also showed the accumulation of medium- and long-chain acylca