Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction

Pere Puigserver, James Rhee, Jerry Donovan, Christopher J. Walkey, J. Cliff Yoon, Francesco Oriente, Yukari Kitamura, Jennifer Altomonte, Hengjiang Dong, Domenico Accili and Bruce M. Spiegelman ()
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Pere Puigserver: Harvard Medical School
James Rhee: Harvard Medical School
Jerry Donovan: Harvard Medical School
Christopher J. Walkey: Harvard Medical School
J. Cliff Yoon: Harvard Medical School
Francesco Oriente: College of Physicians & Surgeons of Columbia University
Yukari Kitamura: College of Physicians & Surgeons of Columbia University
Jennifer Altomonte: Mount Sinai School of Medicine
Hengjiang Dong: Mount Sinai School of Medicine
Domenico Accili: College of Physicians & Surgeons of Columbia University
Bruce M. Spiegelman: Harvard Medical School

Nature, 2003, vol. 423, issue 6939, 550-555

Abstract: Abstract Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis1,2,3. Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-γ co-activator 1 (PGC-1α; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear. Using wild-type and mutant alleles of FOXO1, here we show that PGC-1α binds and co-activates FOXO1 in a manner inhibited by Akt-mediated phosphorylation. Furthermore, FOXO1 function is required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PGC-1α. Insulin suppresses gluconeogenesis stimulated by PGC-1α but co-expression of a mutant allele of FOXO1 insensitive to insulin completely reverses this suppression in hepatocytes or transgenic mice. We conclude that FOXO1 and PGC-1α interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis.

Date: 2003
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DOI: 10.1038/nature01667

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