SREBP-1c coordinately regulates transcription of key enzymes involved

in lipogenesis.31 Moreover, insulin resistance in rodents and in human subjects changes the disposition of ingested carbohydrate away from skeletal muscle glycogen synthesis towards hepatic de novo lipogenesis.32 Thus, the beneficial effects of hypocaloric diets on IHL fat could be mediated in part through improved peripheral insulin resistance. Yet, whereas insulin-resistant subjects tended Epacadostat to lose more IHL compared with insulin-sensitive subjects, we did not observe a relevant interaction between insulin sensitivity and the response to macronutrient composition of the diet. We obtained similar results when we stratified our subjects for glucose tolerance. A recent clinical study in obese insulin-resistance subjects reported similar reductions in body weight and IHL after 11 weeks on a hypocaloric diet with either high or low carbohydrate content. However, the low carbohydrate diet was superior in improving hepatic insulin sensitivity.15 In our subjects an OGTT-derived index of hepatic insulin

resistance, which has to be interpreted with caution, showed no significant interaction between macronutrient composition and improvements in hepatic insulin sensitivity during the 6-month intervention. Approximately half of our subjects had an IHL content >5.6%, a value reported as “the upper limit of normal” for IHL find protocol with an increased risk of hepatic steatosis.33 Subjects exceeding this cutoff showed an ≈7-fold greater absolute reduction in IHL compared with subjects with Glycogen branching enzyme normal IHL content. Remarkably, subjects with normal and with elevated IHL content showed similar improvements in glucose metabolism,

even though the absolute reduction in IHL was much greater in the latter group. The observation may suggest that the improvement in glucose metabolism with dietary weight loss is not directly related to the quantity of mobilized IHL. The dynamics of fat mobilization may be more important in this regard. Possibly other mechanisms, such as reductions in abdominal visceral or subcutaneous adipose tissue, mediated the beneficial effect of dietary weight loss on glucose metabolism.34 Indeed, subjects with normal and with elevated IHL showed similar reductions in abdominal visceral adipose tissue. We observed larger reductions in total- and LDL-cholesterol in the reduced fat compared with the reduced carbohydrate group. Yet triglycerides, HDL-cholesterol, and measures of insulin resistance responded similarly or improved more with reduced carbohydrate diets.20 Similar to another dietary intervention study,29 circulating total and high molecular weight adiponectin tended to increase more with reduced carbohydrate diet. These findings fuel the concern that macronutrient composition of hypocaloric diets could adversely affect cardiovascular and metabolic risk.