Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production

Cell Metab. 2016 Jun 14;23(6):1154-1166. doi: 10.1016/j.cmet.2016.04.022. Epub 2016 May 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Diet
  • Efferent Pathways / drug effects
  • Efferent Pathways / metabolism
  • Fatty Acids, Nonesterified / metabolism
  • Forkhead Box Protein O1 / metabolism
  • Gene Deletion
  • Gene Expression Regulation / drug effects
  • Glucagon / metabolism
  • Glucokinase / metabolism
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics
  • Glucose / biosynthesis*
  • Glucose Tolerance Test
  • Heparin / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Resistance
  • Lipogenesis* / drug effects
  • Lipogenesis* / genetics
  • Liver / drug effects
  • Liver / innervation
  • Liver / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Postprandial Period / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiology

Substances

  • Fatty Acids, Nonesterified
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Insulin
  • Multiprotein Complexes
  • Heparin
  • Glucagon
  • TOR Serine-Threonine Kinases
  • Glucokinase
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Glucose