Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
The forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 --> PI3K --> Akt --> Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.
Dong
Xiaocheng C
XC
Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Karp Family Research Laboratories, 300 Longwood Avenue, Harvard Medical School, Boston, MA 02115, USA.
Copps
Kyle D
KD
Guo
Shaodong
S
Li
Yedan
Y
Kollipara
Ramya
R
DePinho
Ronald A
RA
White
Morris F
MF
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D000818:Animals; D004702:Endocrine Glands / Q000502:physiology*; D005502:Food; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006128:Growth; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency; D015398:Signal Transduction; D000071161:Forkhead Box Protein O1
D048868:Adaptor Proteins, Signal Transducing; D051858:Forkhead Transcription Factors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1