Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell metabolism, 2016-06, Vol.23 (6), p.1154-1166

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Insulin autonomously regulates hepatic lipid synthesis in vivo•Activation of mTORC1 is not sufficient to induce lipogenesis in the absence of Akt•Inhibition of Foxo1 and activation of mTORC1 are sufficient to drive lipogenesis•Foxo1 controls adipocyte lipolysis to nonautonomously regulate glucose production During diabetes, both gluconeogenesis and lipogenesis occur in the liver. Titchenell et al. (2016) 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.