Insulin resistance is a common complication of obesity and an important risk factor for diabetes and other metabolic complications. In the present study, we found that moderate weight loss increases both liver and skeletal muscle insulin sensitivity in obese adolescents. Our subjects had normal oral glucose tolerance and fasting plasma glucose concentrations. Therefore, the improvement in insulin sensitivity was not detectable by routine blood tests and required a sophisticated assessment of insulin action by evaluating glucose kinetics during basal conditions and experimentally induced hyperinsulinemia. These results demonstrate that moderate (~8%) weight loss has important beneficial metabolic effects in obese adolescents who do not have obvious evidence of metabolic abnormalities after evaluation by a standard medical examination.
In the present study, we recruited obese adolescents who had normal glucose tolerance and used the hyperinsulinemic– euglycemic clamp technique to identify subtle changes in tissue-specific insulin action. The improvement in insulin sensitivity observed after weight loss is consistent with the results from previous studies conducted in obese adults who also had normal oral glucose tolerance (11
). An earlier study conducted in obese prepubertal and peri-pubertal children demonstrated that ~7% reduction in body weight, induced by 14 days of severe calorie restriction, also increased insulin-mediated whole-body glucose disposal (35
). The mechanisms responsible for the improvement in insulin sensitivity caused by weight loss are not entirely clear. The accumulation of IHTG is a major determinant of hepatic and skeletal muscle insulin resistance in both adolescents (9
) and adults (23
). Therefore, the reduction in IHTG content after weight loss could have contributed to the improvement in insulin action in our obese adolescents.
Weight loss caused >60% reduction in IHTG content, which was much greater than the relative decrease in total body fat, abdominal subcutaneous fat, and intra-abdominal fat masses. In addition, the relative decrease in IHTG was directly related to baseline content. These findings are consistent with observations made previously after modest weight loss in adult subjects (36
). We have recently found that IHTG content responds rapidly to calorie restriction; 48 h of a low-calorie diet resulted in ~25% reduction in IHTG and only a small 1.5% reduction in body weight (10
). The mechanism(s) responsible for IHTG depletion after weight loss is not known but must involve a change in the balance between IHTG formation (i.e., hepatic FFA uptake and de novo
lipogenesis) and removal (fatty acid oxidation and very low-density lipoprotein–triglyceride secretion). Our findings imply that a decrease in basal FFA delivery to the liver is not critical for weight loss–induced decrease in IHTG content because plasma FFA concentrations did not change. However, data from a recent study that evaluated hepatic fatty acid uptake by using positron emission tomography found that moderate weight loss (~11% of initial body weight) in obese adults reduced both IHTG content and hepatic FFA uptake from the circulation, even though plasma FFA concentrations did not change (11
). Therefore, it is possible that factors that regulate tissue FFA uptake from plasma influence ectopic triglyceride accumulation, independently of plasma FFA concentrations.
In conclusion, the results from this study demonstrate that moderate diet-induced weight loss reduces IHTG content and improves insulin sensitivity in both the liver and skeletal muscle in obese adolescents. Moreover, the improvement in insulin-mediated glucose metabolism occurred even though subjects had normal glucose tolerance at baseline.