Effects of the activation of three major hepatic Akt substrates on glucose metabolism in male mice

Gota Sakai, Ikuo Inoue, Tokuko Suzuki, Takashi Sumita, Kouichi Inukai, Shigehiro Katayama, Takuya Awata, Tetsuya Yamada, Tomoichiro Asano, Hideki Katagiri, Mitsuhiko Noda, Akira Shimada, Hiraku Ono

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Insulin suppresses glucose output from the liver via Akt activation; however, which substrate of Akt plays the major role in transducing this effect is unclear. We tested the postnatal expression of Aktunresponsive, constitutively active mutants of three major Akt substrates widely considered to regulate glucose metabolism [i.e., FoxO1, PGC1a, and glycogen synthase kinase-3b (GSK3b)] using adenoviral gene delivery to the mouse liver. We performed physiological hyperinsulinemiceuglycemic clamp studies using these mice under awake and nonrestrained conditions with blood sampling via an arterial catheter. Hepatic expression of constitutively active FoxO1 induced significant hepatic and systemic insulin resistance. However, neither the expression of constitutively active PGC1a nor that of GSK3b significantly changed insulin sensitivity. Simultaneous expression of all three mutants together induced no further insulin resistance compared with that of the FoxO1 mutant. The glycogen content in the liver was significantly reduced by constitutively active GSK3b expression. In cultured hepatocytes, constitutively active PGC1a induced markedly stronger transcriptional enhancement of gluconeogenic key enzymes than did constitutively active FoxO1. From these results, we conclude that FoxO1 has the most prominent role in transducing insulin's effect downstream from Akt to suppress hepatic glucose output, involving mechanisms independent of the transcriptional regulation of key gluconeogenic enzymes.

Original languageEnglish
Pages (from-to)2659-2671
Number of pages13
Issue number8
Publication statusPublished - 2017 Aug 1

ASJC Scopus subject areas

  • Endocrinology


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