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

摘要: Skeletal muscle is the major site of glucose disposal, accounting for 80% catabolism under insulin‐stimulated conditions in healthy subjects. In type 2 diabetes mellitus patients, muscular uptake decreased; therefore, skeletal can be a therapeutic target daily control hyperglycemia and improvement insulin sensitivity. To develop approaches to resistance, numerous researchers have shown its underlying mechanisms, there great deal evidence that abnormalities mitochondrial function lead accumulation toxic lipid metabolites induce resistance (the lipotoxicity paradigm). Furthermore, increasing indicates metabolic inflexibility leads resistance. Indeed, Muoio et al.1 recently described molecular mechanism by which causes muscle, showed efficacy carnitine supplementation therapy patients with inflexibility. Mitochondrial dysfunction considered central development mellitus. Many studies show decreased oxidation capacity results intermediates, such as diacylglycerol, acyl‐coenzyme A (acyl‐CoA) ceramides, activates atypical protein kinase C isoforms. This followed serine phosphorylation receptor substrates and, eventually, impaired signaling. According these findings, postulated hypothesis, suggests prediabetic state fatty metabolites, thereby contributing resistance. Kelley Mandarino2 originally defined flexibility switch from predominant high rates acid during fasting suppression oxidation, increased uptake, storage insulin‐stimulation. contrast, observed characterized an inability organism shift energy sources promptly response changes nutrient availability. However, causal relationship between remains unclear. Carnitine key molecule associated flexibility. Although best known role import long‐chain acids (acyl groups) into matrix subsequent β‐oxidation, it also necessary efflux acyl groups cases where substrate exceeds demands. Importantly, free muscles obese rats, whereas dietary L‐carnitine rescues Therefore, deficient carnitine‐dependent systems might one mechanisms inflexibility. To test this generated muscle‐specific acyltransferase (CrAT)‐knockout (CrATM−/−) mice. CrAT enzyme catalyzes reversible conversion short‐chain acyl‐CoA (mainly acetyl‐CoA) CoA acylcarnitine acetylcarnitine). Unlike acyl‐CoA, cross cellular membranes ease. resides principally matrix, regulates flux acetyl‐CoA. normal converts excessive acetyl‐CoA acetylcarnitine promotes (Figure 1a). CrAT‐deficient was not converted permeable form excreted mitochondria or cells. led overaccumulation acetyl‐CoA, exerted allosteric inhibiting effect on pyruvate dehydrogenase (PDH), rate‐limiting entry tricarboxylic cycle, subsequently utilization (Figure 1b). addition, CrATM−/− mice intolerance, inflexibility. It noteworthy Akt did differ wild‐type mice, suggesting intolerance result lack sensitivity attenuation through PDH inhibition. Taken together, inhibits overload regulating thus maintaining activity muscle. Through plays important whole‐body tolerance. Figure 1 The roles (CrAT) mitochondria. (a) physiological conditions, acetyl‐coenzyme (Ac‐CoA) acetylcarnitine, out ... Muoio medium‐ acylcarnitines resembled metabolite profile assayed diabetic rodents. pronounced mRNA expression insulin‐resistant patients. As aforementioned, levels are rats. pathological condition similar those indicating metabolism treatment resistance. The antidiabetic potential long‐term has been tested rigidly controlled human studies. clinical study et al.1, 6 months serum concentrations, plasma levels, homeostasis model assessment (HOMA‐IR) index. Muscle increased, partially ameliorated supplementation. These data provided first firm prompting experts carry larger more studies. Notably, cause several addressed conflicting suggest does always type 2 For example, flavoprotein apoptosis‐inducing factor (Aifm1)‐knockout transcription (Tfam)‐knockout tolerance despite oxidative capacity. Differences terminology at least explain contradictory conclusions, term used interchangeably describe alterations content, other inadequacies. Recently, systematic define parameters proposed review article Nature Reviews Endocrinology3 (Table 1). light criteria, although maximal loss submaximal suggested respiratory exchange ratio vivo isolated limiting conditions. activity, plasticity coupling were measured study. relevant remain unclear. Table 1 Definition classification function In recent published Medicine, Kim et al.4 reported intriguing relates autophagy‐knockout (Atg7 knockout) (one definitions dysfunction), they diet‐induced obesity amelioration activating 4‐dependent induction fibroblast growth (FGF) 21. observations autophagy FGF21 expression, affects metabolism. Like study, cell‐non‐autonomous signal released stress termed ‘mitokine’5. Given mitokine paradigm, Aifm knockout Tfam reflect circulating FGF21. action observed. production will subject future investigations.