Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss

Abstract

A number of biochemical defects have been identified in glucose metabolism within skeletal muscle in obesity, and positive effects of weight loss on insulin resistance are also well established. Less is known about the capacity of skeletal muscle for the metabolism of fatty acids in obesity-related insulin resistance and of the effects of weight loss, though it is evident that muscle contains increased triglyceride. The current study was therefore undertaken to profile markers of human skeletal muscle for fatty acid metabolism in relation to obesity, in relation to the phenotype of insulin-resistant glucose metabolism, and to examine the effects of weight loss. Fifty-five men and women, lean and obese, with normal glucose tolerance underwent percutaneous biopsy of vastus lateralis skeletal muscle for determination of HADH, CPT, heparin-releasable (Hr) and tissue-extractable (Ext) LPL, CS, COX, PFK, and GAPDH enzyme activities, and content of cytosolic and plasma membrane FABP. Insulin sensitivity was measured using the euglycemic clamp method. DEXA was used to measure FM and FFM. In skeletal muscle of obese individuals, CPT, CS, and COX activities were lower while, conversely, they had a higher or similar content of FABP(C) and FABP(PM) than in lean individuals. Hr and Ext LPL activities were similar in both groups. In multivariate and simple regression analyses, there were significant correlations between insulin resistance and several markers of FA metabolism, notably, CPT and FABP(PM). These data suggest that in obesity-related insulin resistance, the metabolic capacity of skeletal muscle appears to be organized toward fat esterification rather than oxidation and that dietary-induced weight loss does not correct this disposition.

Upregulation of peroxisome proliferator-activated receptor gamma coactivator gene (PGC1A) during weight loss is related to insulin sensitivity but not to energy expenditure

“…This is in agreement with previously reported findings [18,36] after moderate weight loss, demonstrating that even massive weight reduction is without effect on CPT1 expression. In contrast to physical exercise-mediated PGC1A upregulation, PGC1A upregulation due to weight reduction was not associated with an increase of CPT1 expression.…”

“…Their downregulation, after weight reduction, has been proposed as a possible reason for limited weight loss and/or relapse to obesity [18,23]. Skeletal muscle is a major contributor to overall energy expenditure.…”

“…A defect in CPT1 has been observed in muscle of obese persons [17], persisting after weight loss [18]. Defective lipid oxidation, resulting from impaired CPT1 activity, could lead to excessive intramyocellular triacylglycerol accumulation and, ultimately, to insulin resistance [17].…”

“…Defective lipid oxidation, resulting from impaired CPT1 activity, could lead to excessive intramyocellular triacylglycerol accumulation and, ultimately, to insulin resistance [17]. Furthermore, after weight loss, a low lipid oxidation rate could favour relapse to obesity [18].…”

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

“…However, the role of mitochondria in the pathogenesis of insulin resistance and diabetes is still unclear. In vastus lateralis muscles from obese insulin-resistant patients after weight loss, no increase in oxidative enzyme activities was reported, in spite of an improvement of insulin sensitivity [42]. In addition, Toledo and collaborators [37] have reported that weight loss, without physical exercise, in obese patients ameliorates insulin sensitivity with no effects on muscle mitochondrial capacity.…”