Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor

Abstract

Metabolic flexibility of skeletal muscle, that is, the preference for fat oxidation (FOx) during fasting and for carbohydrate oxidation in response to insulin, is decreased during insulin resistance. The aim of this study was to test the hypothesis that the capacity of myotubes to oxidize fat in vitro reflects the donor's metabolic characteristics. Insulin sensitivity (IS) and metabolic flexibility of 16 healthy, young male subjects was determined by euglycemic hyperinsulinemic clamp. Muscle samples were obtained from vastus lateralis, cultured, and differentiated into myotubes. In human myotubes in vitro, we measured suppressibility (glucose suppression of FOx) and adaptability (an increase in FOx in the presence of high palmitate concentration). We termed these dynamic changes in FOx metabolic switching. In vivo, metabolic flexibility was positively correlated with IS and maximal oxygen uptake and inversely correlated with percent body fat. In vitro suppressibility was inversely correlated with IS and metabolic flexibility and positively correlated with body fat and fasting FFA levels. Adaptability was negatively associated with percent body fat and fasting insulin and positively correlated with IS and metabolic flexibility. The interindividual variability in metabolic phenotypes was preserved in human myotubes separated from their neuroendocrine environment, which supports the hypothesis that metabolic switching is an intrinsic property of skeletal muscle. IntroductionObesity and type 2 diabetes are characterized by an increase in body fat, a decrease in insulin-stimulated glucose disposal, and disturbances of oxidative metabolism. Skeletal muscle, the organ responsible for the majority of insulin-stimulated glucose uptake, has a decreased oxidative capacity in obesity and diabetes (1-3) and after weight loss (4-7). Furthermore, Zurlo (8) and others (9-11) showed that decreased fat oxidation (FOx) (represented by a higher respiratory quotient [RQ], the ratio of CO 2 produced to O 2 consumed) is a predictor of weight gain, which suggests the importance of early defects in FOx for future development of obesity and diabetes. Defects in skeletal muscle oxidative capacity and fat metabolism are highly correlated with insulin sensitivity (IS) (1,5,12) and are believed to contribute to the pathogenesis of insulin resistance (13,14).A high-fat diet (HFD) challenges the oxidative machinery of skeletal muscle. Substantial variability exists in the ability of individuals to adapt to HFD by increasing FOx (15). An imbalance between fat intake and FOx results in a positive fat balance (15). Decreased adaptation to HFD has been observed in restrained eaters (16), formerly obese (17, 18) and obese individuals (19), and individuals with a family history of obesity (20). The latter study points toward a possible genetic basis for reduced FOx. Attenuated adaptation to HFD might represent yet another feature of "metabolic inflexibility," the impaired ability of skeletal muscle to switch from carbohydrate to fat oxidation during...

Metabolic Flexibility in Response to Glucose Is Not Impaired in People With Type 2 Diabetes After Controlling for Glucose Disposal Rate

“…Such phenomenon is analogous to the thermic effect of a meal, which is proportional to the energy content of the meal (10). The high correlation between insulin-stimulated glucose disposal rate and metabolic flexibility to glucose supports this idea (2,11).…”

Are cultured human myotubes far from home?

“…In myotubes established from young healthy subjects, the capacity to increase lipid oxidation in response to increased fatty acid availability in vitro (adaptability) was positively related to insulin sensitivity in vivo (Ukropcova, et al, 2005). In a recent study, we observed that intracellular lipid oxidation and adaptability were reduced in myotubes established from T2D individuals (Corpeleijn, et al, 2010).…”

“…Myotubes retain the characteristics of the donor, which indicates that metabolic switching is an intrinsic characteristic of skeletal muscle (Gaster, 2007b, Ukropcova, et al, 2005. This suggests that defects in metabolic switching might be one of the primary events in the development of obesity and insulin resistance.…”

Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles

“…An increase in UCP3 expression in skeletal muscle of male mice could diminish the ability to switch between glucose and fat oxidation. Indeed, the competition between glucose and fat oxidation resulting in metabolic inflexibility may occur within the mitochondria [40]. This inflexibility could be associated with deteriorated glucose tolerance.…”