Metabolic Inflexibility Associated with Obesity

Healthy skeletal muscle adapts to differing concentrations of plasma substrates (carbohydrates and fats) and hormones (primarily insulin). When a substrate is in oversupply, healthy skeletal muscle is able to adjust and activate processes that are necessary for appropriate oxidation or storage. Accordingly, healthy muscle is also able to adjust substrate utilization in response to hormonal changes. This process has been termed metabolic flexibility and constantly occurs in daily life when conditions move from fasting to fed to fasting again. This term was coined by Kelley and colleagues55 following a study (previously mentioned) in which they measured differences in substrate utilization during basal- and insulin-stimulated conditions across the leg in obese and nonobese subjects. During fasting conditions, obese individuals had significantly higher rates of carbohydrate oxidation and decreased fat oxidation, which fit the hypothesis for reduced oxidative capacity in obese skeletal muscle. When moving from basal to euglycemic/hyperinsulinemic conditions, the nonobese subjects increased rates of carbohydrate oxidation and decreased fat oxidation, indicating an appropriate response to an increase of plasma glucose and insulin. This adaptation or flexibility did not occur in obese individuals. Figure 5.2 demonstrates rates of fat and carbohydrate oxidation as measured in the study by basal insulin basal insulin

Carbohydrate Oxidation

Fat Oxidation

FIGURE 5.2 Metabolic flexibility in A Obese and ■ Lean-NonObese subjects during basal and insulin-stimulated conditions. Data derived from Kelley et al., Am. J. Physiol., 277, 1999.

Kelley et al.55 Therefore, the obese subjects displayed metabolic inflexibility, as their skeletal muscle was unable to adapt to changes in their nutritional environment.

Measures of muscle metabolism from our laboratory and others may provide insight into the metabolic inflexibility found with obesity. Lean skeletal muscle has higher basal- and insulin-stimulated glucose uptake than muscle from obese, and this could affect the ability of obese individuals to increase carbohydrate reliance during postabsorptive conditions. Preliminary data from our laboratory suggests another possible mechanism51. We have measured rates of fatty-acid uptake under basal- and insulin-stimulated conditions in skeletal muscle from lean and obese. Uptake values in obese muscle were twofold and threefold greater under basal- and insulin-stimulated conditions, respectively, compared to nonobese. Fatty-acid uptake was increased (twofold) in response to insulin in obese muscle, while this did not occur in lean muscle. This is interesting, as obesity is associated with an opposite response of insulin upon glucose uptake. Therefore, it is possible that altered rates of glucose and fatty-acid uptake affect cellular substrate availability and influence substrate reliance directly or through signaling events.

A clear association can be linked between metabolic inflexibility and a defect in lipid oxidation measured with obesity. In normal conditions, an increase in dietary fat or plasma lipids is met with adaptations that increase lipid metabolism in skeletal muscle. In rodent studies, in which plasma fatty-acids levels are significantly increased (fasting, high-fat feedings, streptozotocin-induced diabetes) there is an equivalent increase in the expression and activity of lipid-metabolizing enzymes in skeletal muscle, including malonyl-CoA decarboxylase, CPT-1, P-HAD, pyruvate dehydrogenase kinase 4, and FAT/CD36.72108 In healthy, nonobese humans, five days of a high-fat diet increased lipid oxidation (measured by RQ) during submaximal exercise and increased genes important for fat oxidation, including FAT/CD36, FABPpm, P-HAD, and CPT-1.18 In another study, nonobese subjects increased total daily fat oxidation (measured in indirect calorimetry chamber) after seven days of a high-fat diet.96 These data demonstrate that nonobese individuals can increase lipid oxidation when needed. Conversely, it appears that obese individuals lack an ability to increase lipid oxidation following dietary manipulation. Astrup et al.5 compared lipid oxidation between previously obese and lean women following three days of a high fat-diet (50 percent fat). Lean women adjusted rates of fat oxidation to the diet. However, previously obese (post weight loss) women could not increase fat oxidation, resulting in positive fat balance and storage.

As previously mentioned, the CPT-1-malonyl-CoA interaction in skeletal muscle probably plays a role in metabolic flexibility. Plasma insulin and glucose dictate malonyl-CoA content in muscle. Therefore, the altered substrate utilization associated with obesity could be related to a dysregulation of muscle malonyl-CoA content. Preceding enzymatic dysregulation, the response of gene expression to changes in the nutritional environment may be malfunctioning in skeletal muscle of obese subjects. Peroxisome proliferators-activated receptors (PPARs) are the first genetic sensors known to respond to changes in lipids.32 PPARs are activated by changes in dietary fat and metabolic derivatives, and then enact their response by changing the expression of proteins regulating fat metabolism. The PPAR-a receptor has been shown to enhance skeletal-muscle lipid oxidation. Therefore, a defect in the PPAR-a response to lipids is a possible candidate for the reductions in lipid oxidation and the lack of metabolic flexibility in skeletal muscle from obese subjects.

In conclusion, our in vitro skeletal-muscle studies show that obese skeletal muscle possesses defective rates of lipid oxidation. This leads to another question: Is defective lipid oxidation the "chicken" or the "egg" of obesity? Do preobese individuals possess muscle that is defective in metabolizing fat, or does this occur after the onset of obesity? We believe that defective lipid oxidation in skeletal muscle plays a likely role in the onset of obesity based on the following factors: 1) genetic work involving families and twins demonstrates that genetic factors at least predispose individuals to obesity,69 and that part of these genetic factors are related to energy expenditure, and, assumedly, defective lipid metabolism; 2) a short-term, prospective study in Pima Indians demonstrated that elevated RQ values were correlated with increased weight gain over four years103; 3) a study from our lab has shown that women who were previously extremely obese but had lost approximately 100 lbs (gastric-bypass surgery) had significantly lower rates of fat utilization during exercise compared with healthy women matched for BMI42; 4) recently, we have performed primary-cell cultures of muscle from lean and obese individuals, and we see the same defect in rates of lipid oxidation in cultured obese muscle that are measured in vitro,9 demonstrating a distinct phenotype that is unaltered when removing muscle from its environment; and 5) finally, in transgenic animal models where rates of lipid oxidation are elevated, animals are resistant to high-fat diets and do not gain weight, demonstrating that an increased metabolic capacity can withstand overfeeding.1 These studies provide evidence that a disturbance in muscle-lipid metabolism may lead to obesity. Currently, scientists are examining the effect of exercise and pharmacological treatments upon lipid metabolism in skeletal muscle. These studies will provide insight into the prevention of obesity and its related comorbidities.

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