Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance

Objective: Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity.Hypothesis: We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content.Design: Thirty-four healthy obese subjects (body mass index, 33.7 +/- 8.0 kg/m(2)) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [18(F)] fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [18(F)] fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy.Results: Subjects lost weight (11.2 +/- 2.9 kg; P <0.0001). Liver volume decreased by 11% (P <0.002), which was partly explained by decreased liver fat content (P <0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P <0.003) and correlated with the decrement in liver fat content (r = 0.54; P <0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P <0.04), andhepatic insulin resistance by 40% (P <0.05).Conclusions: The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance. (J Clin Endocrinol Metab 94: 50-55, 2009)