Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss

Abstract

The current study was undertaken to investigate fatty acid metabolism by skeletal muscle to examine potential mechanisms that could lead to increased muscle triglyceride in obesity. Sixteen lean and 40 obese research volunteers had leg balance measurement of glucose and free fatty acid (FFA) uptake (fractional extraction of [9,10 (3)H]oleate) and indirect calorimetry across the leg to determine substrate oxidation during fasting and insulin-stimulated conditions. Muscle obtained by percutaneous biopsy had lower carnitine palmitoyl transferase (CPT) activity and oxidative enzyme activity in obesity (P < 0.05). During fasting conditions, obese subjects had an elevated leg respiratory quotient (RQ, 0.83 +/- 0.02 vs. 0.90 +/- 0.01; P < 0.01) and reduced fat oxidation but similar FFA uptake across the leg. During insulin infusions, fat oxidation by leg tissues was suppressed in lean but not obese subjects; rates of FFA uptake were similar. Fasting values for leg RQ correlated with insulin sensitivity (r = -0.57, P < 0.001). Thirty-two of the obese subjects were restudied after weight loss (WL, -14.0 +/- 0.9 kg); insulin sensitivity and insulin suppression of fat oxidation improved (P < 0.01), but fasting leg RQ (0.90 +/- 0.02 vs. 0.90 +/- 0.02, pre-WL vs. post-WL) and muscle CPT activity did not change. The findings suggest that triglyceride accumulation in skeletal muscle in obesity derives from reduced capacity for fat oxidation and that inflexibility in regulating fat oxidation, more than fatty acid uptake, is related to insulin resistance.

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

“…In parallel, impairment of muscle or plasma NEFA oxidation in obesity and type 2 diabetes have been reported by different groups [4][5][6]. The observation that in obese women [5] and type 2 diabetic patients [7] the impairment of fat oxidation was not reversed by considerable body weight reduction and that it was also detected in individuals with impaired glucose tolerance [8] would support the hypothesis of a primary genetic defect. An impairment of fasting lipid oxidation in association with insulin resistance and IMCL accumulation may also be seen as a secondary consequence of metabolic disturbances [9].…”

Mathematical modelling of hepatic lipid metabolism

“…k gi 2.632 × 10 7 mmol −1 Approximated using data from Kelley and Kraegen simultaneously [30,35] See kg k gl 0.9277l/min Liver to blood glucose scalar In combination with k gl2 this confers steady state concentrations of liver (8mmol/l) to blood (5mmol/l).…”

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

“…Two points, however, should be considered: first, the studies in which both mRNA expression and activity were measured demonstrate that in general these two parameters consistently vary [39]. Second, and even more convincingly, the only study investigating CPT1 activity and energy expenditure, both at the muscle level, failed to find any relationship between CPT1 activity and energy expenditure, even when the latter is measured locally [40].…”