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.

Authors

Affiliations

¹ Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
² Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
³ Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: birnbaum@mail.med.upenn.edu.

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.

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
Glucokinase
Mechanistic Target of Rapamycin Complex 1
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Glucose

Abstract

MeSH terms

Substances

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