Effects of the Activation of Three Major Hepatic Akt Substrates on Glucose Metabolism in Male Mice

Endocrinology
Gota SakaiHiraku Ono

Abstract

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 Akt-unresponsive, constitutively active mutants of three major Akt substrates widely considered to regulate glucose metabolism [i.e., FoxO1, PGC1α, and glycogen synthase kinase-3β (GSK3β)] using adenoviral gene delivery to the mouse liver. We performed physiological hyperinsulinemic-euglycemic 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 PGC1α nor that of GSK3β 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 GSK3β expression. In cultured hepatocytes, constitutively active PGC1α induced markedly stronger transcriptional enhancement of gluconeogenic key enzymes than did constitutively activ...Continue Reading

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Citations

Mar 17, 2019·International Journal of Molecular Sciences·Hiraku Ono
Aug 26, 2017·Endocrinology·Greg C Smith, Nigel Turner
Jan 1, 2020·Antioxidants & Redox Signaling·Leonard Clinton D'SouzaSubash Chandra Gupta

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