Dietary protein deprivation upregulates insulin signaling and inhibits gluconeogenesis in rat liver.
This study was undertaken to elucidate the effects of dietary protein deprivation on glucose metabolism and hepatic insulin signaling in rats. The results of glucose and pyruvate tolerance tests in rats fed with a 12% casein diet (12C) and a protein-free diet (PF) indicated that protein deprivation enhanced clearance of blood glucose and suppressed gluconeogenesis. Correspondingly, the mRNA level of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme, was suppressed by dietary protein deprivation. In PF-fed rats, total tyrosine phosphorylation of insulin receptor (IR) in the liver induced by insulin injection was enhanced compared with 12C pair-fed rats due to an increase in IR protein level. In addition, protein deprivation caused an increase in protein levels of IR substrate 1 (IRS1) and IRS2, leading to the marked enhancement of insulin-induced tyrosine phosphorylation of IRS2 and its binding to the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K). Based on these results, we conclude that protein deprivation suppresses gluconeogenesis by a mechanism primarily mediated by the enhancement of the insulin signals through the IR/IRS/PI3K/mammalian target of rapamycin complex 1 pathway in the liver. Taken together with our previous report, these findings suggest that tissue-specific potentiation of insulin action in the liver and the skeletal muscle plays important roles in maintaining glucose homeostasis even when energy usage is reduced by dietary protein deprivation.
Toyoshima
Yuka
Y
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Tokita
Reiko
R
Ohne
Yoichiro
Y
Hakuno
Fumihiko
F
Noguchi
Tadashi
T
Minami
Shiro
S
Kato
Hisanori
H
Takahashi
Shin-Ichiro
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D004044:Dietary Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D004734:Energy Metabolism; D005943:Gluconeogenesis; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011488:Protein Deficiency / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation
D001786:Blood Glucose; D004044:Dietary Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; C546845:mTOR protein, rat; D058539:Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases