@article{7a7ce1736e0f47f0bfc58a58bd4953a9,
title = "Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production",
abstract = "During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed {"}selective insulin resistance{"} to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic insulin signaling is likely to be intact in insulin-resistant states. Moreover, cell-nonautonomous suppression of HGP by insulin depends on a reduction of adipocyte lipolysis and serum FFAs but is independent of vagal efferents or glucagon signaling. These data are consistent with a model in which, during T2DM, intact liver insulin signaling drives enhanced lipogenesis while excess circulating FFAs become a dominant inducer of nonsuppressible HGP.",
author = "Titchenell, {Paul M.} and Quinn, {William J.} and Mingjian Lu and Qingwei Chu and Wenyun Lu and Changhong Li and Helen Chen and Monks, {Bobby R.} and Julia Chen and Rabinowitz, {Joshua D.} and Birnbaum, {Morris J.}",
note = "Funding Information: The authors would like to thank Domenico Accili (Columbia University) for sharing the Foxo1 loxP/loxP mice, Gary Schwartz (Albert Einstein College of Medicine) for instruction in vagotomy, and Mitch Lazar for careful reading of the manuscript. Deuterium-labeled palmitate levels were measured by the Stable Isotope Tracer Kinetic Service Center in the University of Pennsylvania. The Viral Vector Core of the University of Pennsylvania and the Metabolomics Core at Princeton supported by the University of Pennsylvania Diabetes Research Center (NIH DK19525) provided viruses and metabolite measurements. This work was supported by U.S. National Institutes of Health grant R01 DK056886 (M.J.B.), NRSA individual postdoctoral fellowship F32 DK101175 (P.M.T.), and the Samuel Chiaffa Memorial Fund (P.M.T). M.J.B. is an employee of Pfizer, Inc. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = jun,
day = "14",
doi = "10.1016/j.cmet.2016.04.022",
language = "English (US)",
volume = "23",
pages = "1154--1166",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}