Hepatocyte Insulin Signaling is Required for Feeding-Induced Lipogenesis but Dispensable for the Suppression of Glucose Production

Summary

Insulin-resistant syndromes such as type II diabetes mellitus (T2DM) involve disrupted temporal coordination of hepatic metabolism such that synthesis and secretion of lipid and glucose are inappropriately engaged concurrently. Here we test the hypothesis that a combination of direct and indirect actions of insulin on liver can lead to the metabolic phenotype exhibited in T2DM without a defect in proximal hepatic insulin signaling. First, we show that the insulin-dependent inhibition of Foxo1 and activation of mTorc1 by Akt is both necessary and sufficient for the induction of lipogenesis and the lipogenic gene program. In marked contrast, insulin, acting in vivo independent of hepatocyte insulin signaling can suppress glucose production by reducing serum free fatty acids. These studies support the hypothesis that under conditions of obesity and diabetes, intact hepatic insulin signaling can maintain lipogenesis while excess circulating FFAs become a dominant positive regulator of HGP.

eTOC Paragraph

During diabetes, both gluconeogenesis and lipogenesis occur in the liver. Titchenell et al address the issue of selective insulin resistance to show that direct liver insulin signaling is required for lipogenesis, while liver insulin signaling only indirectly suppresses glucose production by reducing serum free fatty acids coming from adipocytes.