Akt-dependent phosphorylation of hepatic FoxO1 is compartmentalized on a WD40/ProF scaffold and is selectively inhibited by aPKC in early phases of diet-induced obesity.
Initiating mechanisms that impair gluconeogenic enzymes and spare lipogenic enzymes in diet-induced obesity (DIO) are obscure. Here, we examined insulin signaling to Akt and atypical protein kinase C (aPKC) in liver and muscle and hepatic enzyme expression in mice consuming a moderate high-fat (HF) diet. In HF diet-fed mice, resting/basal and insulin-stimulated Akt and aPKC activities were diminished in muscle, but in liver, these activities were elevated basally and were increased by insulin to normal levels. Despite elevated hepatic Akt activity, FoxO1 phosphorylation, which diminishes gluconeogenesis, was impaired; in contrast, Akt-dependent phosphorylation of glycogenic GSK3β and lipogenic mTOR was elevated. Diminished Akt-dependent FoxO1 phosphorylation was associated with reduced Akt activity associated with scaffold protein WD40/Propeller/FYVE (WD40/ProF), which reportedly facilitates FoxO1 phosphorylation. In contrast, aPKC activity associated with WD40/ProF was increased. Moreover, inhibition of hepatic aPKC reduced its association with WD40/ProF, restored WD40/ProF-associated Akt activity, restored FoxO1 phosphorylation, and corrected excessive expression of hepatic gluconeogenic and lipogenic enzymes. Additionally, Akt and aPKC activities in muscle improved, as did glucose intolerance, weight gain, hepatosteatosis, and hyperlipidemia. We conclude that Akt-dependent FoxO1 phosphorylation occurs on the WD/Propeller/FYVE scaffold in liver and is selectively inhibited in early DIO by diet-induced increases in activity of cocompartmentalized aPKC.
Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, FLDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.
Mini P
MP
Sajan
Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, FLDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.
Mildred E
ME
Acevedo-Duncan
Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, FLDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.
Mary L
ML
Standaert
Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, FLDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.
Robert A
RA
Ivey
Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, FLDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.
Mackenzie
M
Lee
Medical and Research Services, James A. Haley Veterans Medical Center; Tampa, FLDivision of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL rfarese@health.usf.edu.
Robert V
RV
Farese
D000821:Animal Feed; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002518:Ceramides / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal; D009765:Obesity / Q000139:chemically induced*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D002518:Ceramides; C574715:FGD5 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C514055:ProF protein, mouse; D047428:Protein Kinase Inhibitors; C065576:ceramide 1-phosphate; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C115015:PKC-3 protein; D011493:Protein Kinase C