Improved insulin sensitivity after weight loss and exercise training is mediated by a reduction in plasma fatty acid mobilization, not enhanced oxidative capacity.

Obesity is characterized by excessive rates of plasma fatty acid mobilization and uptake, which play a key role in mediating insulin resistance. While weight loss via diet-only or a diet + exercise program clearly improves insulin sensitivity, the precise mechanisms modulating this improvement are not completely understood. The purpose of the present study was to determine the role of the reduced fatty acid mobilization and uptake after weight loss in obese women who were randomly assigned to lifestyle interventions of either weight loss without exercise (WL) (n = 7) or a weight loss + exercise program (WL + EX) (n = 10). Before and after losing 12% of their body weight, we measured insulin sensitivity (S(I)), systemic fatty acid rate of appearance (Ra) and disappearance (Rd), oxidative capacity, and markers for pro-inflammatory pathways in skeletal muscle. Fatty acid Ra and Rd were reduced by 30% after both interventions (P < 0.05). While oxidative capacity increased 25% in WL + EX (compared with no increase after WL), the improvement in S(I) was identical in both groups (60%; P < 0.05), and skeletal muscle pro-inflammatory pathways were reduced (P < 0.05) similarly in both groups. When we artificially increased fatty acid mobilization after weight loss to pre-weight-loss levels via an overnight lipid infusion, the improvement in S(I) was almost completely reversed. Importantly, WL + EX did not protect against this lipid-induced reversal in S(I) despite a significant increase in resting whole-body fat oxidation and a marked increase in skeletal muscle oxidative capacity. In conclusion, reduced fatty acid mobilization and uptake appears to be a primary mediator of improved insulin sensitivity after weight loss. Moreover, enhancing fatty acid oxidative capacity via exercise training is not sufficient to prevent the insulin resistance caused by high fatty acid mobilization, such as that found in obesity.

Reducing dietary fat from a meal increases the bioavailability of exogenous carbohydrate without altering plasma glucose concentration.

The primary goal of this study was to determine the acute glycemic and endocrine responses to the reduction of fat content from a meal. On three separate occasions, nine overweight subjects (body mass index = 30 +/- 1 kg/m(2); 5 men, 4 women) consumed 1) a control meal ( approximately 800 kcal; 100 g of carbohydrate, 31 g of fat, and 30 g of protein), 2) a low-fat meal ( approximately 530 kcal; 100 g of carbohydrate, 1 g of fat, and 30 g of protein), or 3) a low-fat meal plus lipid infusion [same meal as low-fat meal, but the total energy provided was the same as control (800 kcal), with the "missing" fat ( approximately 30 g) provided via an intravenous lipid infusion]. All three meals contained [(13)C]glucose (3 mg/kg body wt) to assess the bioavailability of ingested glucose. During the 5-h period after each meal, we measured the recovery of [(13)C]glucose in plasma, plasma glucose, and insulin concentrations. We also measured plasma concentration of the gastrointestinal peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)). The recovery of the ingested [(13)C]glucose in the hour after ingestion was greater (P < 0.05) after the low-fat than after the control meal [area under the curve (AUC): 1,206 +/- 252 and 687 +/- 161 microM.h, respectively]. However, removing dietary fat from the meal did not affect the plasma concentration of glucose or insulin. Importantly, [(13)C]glucose recovery was not different during the low-fat and lipid infusion trials (AUC: 1,206 +/- 252 and 1,134 +/- 247 microM.h, respectively), indicating that the accelerated delivery of exogenous glucose found after removing fat from the meal is due exclusively to the reduction of fat in the gastrointestinal tract. In parallel with these findings, the reduction in fat calories from the meal reduced plasma concentration of GIP, GLP-1, and PYY(3-36). In summary, these data suggest that removing fat from the diet expedited exogenous glucose delivery into the systemic circulation and reduced the concentration of key gastrointestinal peptides, yet maintained plasma glucose concentration at control levels.