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

Paul M. Titchenell, William J. Quinn, Mingjian Lu, Qingwei Chu, Wenyun Lu, Changhong Li, Helen Chen, Bobby R. Monks, Julia Chen, Joshua D. Rabinowitz, Morris J. Birnbaum

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1154-1166
Number of pages13
JournalCell Metabolism
Volume23
Issue number6
DOIs
StatePublished - Jun 14 2016

Fingerprint

Lipogenesis
Hepatocytes
Insulin
Glucose
Liver
Lipolysis
Glucagon
Adipocytes
Type 2 Diabetes Mellitus
Insulin Resistance
Lipids
Serum

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology

Cite this

Titchenell, Paul M. ; Quinn, William J. ; Lu, Mingjian ; Chu, Qingwei ; Lu, Wenyun ; Li, Changhong ; Chen, Helen ; Monks, Bobby R. ; Chen, Julia ; Rabinowitz, Joshua D. ; Birnbaum, Morris J. / Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production. In: Cell Metabolism. 2016 ; Vol. 23, No. 6. pp. 1154-1166.
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Titchenell, PM, Quinn, WJ, Lu, M, Chu, Q, Lu, W, Li, C, Chen, H, Monks, BR, Chen, J, Rabinowitz, JD & Birnbaum, MJ 2016, 'Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production', Cell Metabolism, vol. 23, no. 6, pp. 1154-1166. https://doi.org/10.1016/j.cmet.2016.04.022

Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production. / Titchenell, Paul M.; Quinn, William J.; Lu, Mingjian; Chu, Qingwei; Lu, Wenyun; Li, Changhong; Chen, Helen; Monks, Bobby R.; Chen, Julia; Rabinowitz, Joshua D.; Birnbaum, Morris J.

In: Cell Metabolism, Vol. 23, No. 6, 14.06.2016, p. 1154-1166.

Research output: Contribution to journalArticle

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