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Calorie restriction initiated at a young age activates the Akt/PKC zeta/lambda-Glut4 pathway in rat white adipose tissue in an insulin-independent manner.

ABSTRACT: Calorie restriction (CR) may exert an anti-aging effect through a metabolic adaptation to limited energy intake. The present study investigated the effect of CR on insulin signaling in response to glucose load in the epididymal adipose tissue of male F344 rats at 7 and 22 months of age. Young and middle-aged rats were fed ad libitum (AL) or 30% CR diets for 4 months, underwent glucose tolerance tests and were sacrificed 15 min after an intraperitoneal glucose or saline injection to evaluate glucose-stimulated insulin response and subsequent activation of insulin signaling molecules in the adipose tissue. In the 7- and 22- month AL groups, glucose administration increased serum insulin levels and also increased phosphorylated (p) levels of the insulin receptor (IR), v-akt murine thymoma viral oncogene homolog (Akt), protein kinase C (PKC) zeta/lambda and the membrane fraction of glucose transporter 4 (mGlut4). In contrast, in the 7-month CR group, p-Akt, p-PKC zeta/lambda and mGlut4 levels were upregulated without glucose stimulation; the glucose load augmented the p-IR level but there was no additional activation of the downstream molecules. In the 22-month CR group, these unexpected findings were not observed. In summary, basal levels of insulin signaling molecules such as p-Akt, p-PKC zeta/lambda, and mGlut4 were significantly increased with a low insulin response in the 7-month CR group. The present results suggest the presence of an age-specific insulin-independent mechanism that is induced by CR to regulate energy metabolism in white adipose tissue.

SUBMITTER: Park S

PROVIDER: S-EPMC2585642 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Calorie restriction initiated at a young age activates the Akt/PKC zeta/lambda-Glut4 pathway in rat white adipose tissue in an insulin-independent manner.

Park Seongjoon S Komatsu Toshimitsu T Hayashi Hiroko H Yamaza Haruyoshi H Chiba Takuya T Higami Yoshikazu Y Kuramoto Kazunao K Shimokawa Isao I

Age (Dordrecht, Netherlands) 20080903 4

Calorie restriction (CR) may exert an anti-aging effect through a metabolic adaptation to limited energy intake. The present study investigated the effect of CR on insulin signaling in response to glucose load in the epididymal adipose tissue of male F344 rats at 7 and 22 months of age. Young and middle-aged rats were fed ad libitum (AL) or 30% CR diets for 4 months, underwent glucose tolerance tests and were sacrificed 15 min after an intraperitoneal glucose or saline injection to evaluate gluc ...[more]

PMID: 19424853

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Project description:BackgroundMitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is expressed in all cancer types examined and in neuroprogenitor cells. The gene is upregulated by amino acid limitation and ER-stress in an ATF4-dependent manner, and its activity modulates the PEP/Ca2+ signaling axis, providing clear arguments for a functional relationship with metabolic adaptations for cell survival. Despite its potential relevance to cancer metabolism, the mechanisms responsible for its pro-survival activity have not been completely elucidated.Methods[U-13C]glutamine and [U-13C]glucose labeling of glycolytic and TCA cycle intermediates and their anabolic end-products was evaluated quantitatively using LC/MS and GC/MS in conditions of abundant glucose and glucose limitation in loss-of-function (shRNA) and gain-of-function (lentiviral constitutive overexpression) HeLa cervix carcinoma cell models. Cell viability was assessed in conjunction with various glucose concentrations and in xenografts in vivo.ResultsPEPCK-M levels linearly correlated with [U-13C]glutamine label abundance in most glycolytic and TCA cycle intermediate pools under nutritional stress. In particular, serine, glycine, and proline metabolism, and the anabolic potential of the cell, were sensitive to PEPCK-M activity. Therefore, cell viability defects could be rescued by supplementing with an excess of those amino acids. PEPCK-M silenced or inhibited cells in the presence of abundant glucose showed limited growth secondary to TCA cycle blockade and increased ROS. In limiting glucose conditions, downregulation of PKC-ζ tumor suppressor has been shown to enhance survival. Consistently, HeLa cells also sustained a survival advantage when PKC-ζ tumor suppressor was downregulated using shRNA, but this advantage was abolished in the absence of PEPCK-M, as its inhibition restores cell growth to control levels. The relationship between these two pathways is also highlighted by the anti-correlation observed between PEPCK-M and PKC-ζ protein levels in all clones tested, suggesting co-regulation in the absence of glucose. Finally, PEPCK-M loss negatively impacted on anchorage-independent colony formation and xenograft growth in vivo.ConclusionsAll in all, our data suggest that PEPCK-M might participate in the mechanisms to regulate proteostasis in the anabolic and stalling phases of tumor growth. We provide molecular clues into the clinical relevance of PEPCK-M as a mechanism of evasion of cancer cells in conditions of nutrient stress.

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Dataset Information

Calorie restriction initiated at a young age activates the Akt/PKC zeta/lambda-Glut4 pathway in rat white adipose tissue in an insulin-independent manner.

Publications

Calorie restriction initiated at a young age activates the Akt/PKC zeta/lambda-Glut4 pathway in rat white adipose tissue in an insulin-independent manner.

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