Foxo1 integrates insulin signaling with mitochondrial function in the liver.
Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes. Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD(+)/NADH ratio and ATP production. Although peroxisome proliferator-activated receptor-gamma coactivator-1alpha (Ppargc-1alpha) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD(+)/NADH ratio, reduced Ppargc-1alpha acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.
Cheng
Zhiyong
Z
Harvard Medical School, Boston, Massachusetts, USA.
Guo
Shaodong
S
Copps
Kyle
K
Dong
Xiaochen
X
Kollipara
Ramya
R
Rodgers
Joseph T
JT
Depinho
Ronald A
RA
Puigserver
Pere
P
White
Morris F
MF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000648:ultrastructure*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009243:NAD / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
D045222:Electron Transport Chain Complex Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009243:NAD; D000255:Adenosine Triphosphate; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse