Dataset Information

AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks.

ABSTRACT: During hibernation, mammalian cells are exposed to severe environmental stressors such as low temperature, lowered O2 supply, and glucose deficiency. The cellular metabolic rate is markedly reduced for adapting to these conditions. AMP-activated protein kinase (AMPK) senses the cellular energy status and regulates metabolism. Therefore, we examined AMPK signaling in several brain regions and peripheral tissues in hibernating chipmunk. Eukaryotic elongation factor 2 (eEF2) is a downstream target of AMPK. Phosphorylation of eEF2, indicating its inactivation, is enhanced in the cerebral cortex of hibernating chipmunks. The study indicated that the sequential regulation of AMPK-mammalian target of rapamycin complex 1-eEF2 signaling was altered and protein synthesis ability was reduced in the cerebral cortex of hibernating chipmunks.

SUBMITTER: Yamada S

PROVIDER: S-EPMC6695389 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks.

Yamada Shintaro S Kamata Taito T Nawa Hiroyuki H Sekijima Tsuneo T Takei Nobuyuki N

Scientific reports 20190815 1

During hibernation, mammalian cells are exposed to severe environmental stressors such as low temperature, lowered O<sub>2</sub> supply, and glucose deficiency. The cellular metabolic rate is markedly reduced for adapting to these conditions. AMP-activated protein kinase (AMPK) senses the cellular energy status and regulates metabolism. Therefore, we examined AMPK signaling in several brain regions and peripheral tissues in hibernating chipmunk. Eukaryotic elongation factor 2 (eEF2) is a downstr ...[more]

PMID: 31417118

Similar Datasets

Project description:BACKGROUND: In phenylketonuria (PKU), elevated blood phenylalanine (Phe) concentrations are considered to impair transport of large neutral amino acids (LNAAs) from blood to brain. This impairment is believed to underlie cognitive deficits in PKU via different mechanisms, including reduced cerebral protein synthesis. In this study, we investigated the hypothesis that impaired LNAA influx relates to reduced cerebral protein synthesis. METHODS: Using positron emission tomography, L-[1-11C]-tyrosine (11C-Tyr) brain influx and incorporation into cerebral protein were studied in 16 PKU patients (median age 24, range 16 - 47 years), most of whom were early and continuously treated. Data were analyzed by regression analyses, using either 11C-Tyr brain influx or 11C-Tyr cerebral protein incorporation as outcome variable. Predictor variables were baseline plasma Phe concentration, Phe tolerance, age, and 11C-Tyr brain efflux. For the modelling of cerebral protein incorporation, 11C-Tyr brain influx was added as a predictor variable. RESULTS: 11C-Tyr brain influx was inversely associated with plasma Phe concentrations (median 512, range 233 - 1362 ?mol/L; delta adjusted R2=0.571, p=0.013). In addition, 11C-Tyr brain influx was positively associated with 11C-Tyr brain efflux (delta adjusted R2=0.098, p=0.041). Cerebral protein incorporation was positively associated with 11C-Tyr brain influx (adjusted R2=0.567, p<0.001). All additional associations between predictor and outcome variables were statistically nonsignificant. CONCLUSIONS: Our data favour the hypothesis that an elevated concentration of Phe in blood reduces cerebral protein synthesis by impairing LNAA transport from blood to brain. Considering the importance of cerebral protein synthesis for adequate brain development and functioning, our results support the notion that PKU treatment be continued in adulthood. Future studies investigating the effects of impaired LNAA transport on cerebral protein synthesis in more detail are indicated.

Project description:BACKGROUND:Glaucoma is a chronic degenerative disease for which inflammation is considered to play a pivotal role in the pathogenesis and progression. In this study, we examined the impact of a ketogenic diet on the inflammation evident in glaucoma as a follow-up to a recent set of experiments in which we determined that a ketogenic diet protected retinal ganglion cell structure and function. METHODS:Both sexes of DBA/2J (D2) mice were placed on a ketogenic diet (keto) or standard rodent chow (untreated) for 8 weeks beginning at 9 months of age. DBA/2J-Gpnmb+ (D2G) mice were also used as a non-pathological genetic control for the D2 mice. Retina and optic nerve (ON) tissues were micro-dissected and used for the analysis of microglia activation, expression of pro- and anti-inflammatory molecules, and lactate- or ketone-mediated anti-inflammatory signaling. Data were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, western blot, and capillary tube-based electrophoresis techniques. RESULTS:Microglia activation was observed in D2 retina and ON as documented by intense microglial-specific Iba1 immunolabeling of rounded-up and enlarged microglia. Ketogenic diet treatment reduced Iba1 expression and the activated microglial phenotype. We detected low energy-induced AMP-activated protein kinase (AMPK) phosphorylation in D2 retina and ON that triggered NF-?B p65 signaling through its nuclear translocation. NF-?B induced pro-inflammatory TNF-?, IL-6, and NOS2 expression in D2 retina and ON. However, treatment with the ketogenic diet reduced AMPK phosphorylation, NF-?B p65 nuclear translocation, and expression of pro-inflammatory molecules. The ketogenic diet also induced expression of anti-inflammatory agents Il-4 and Arginase-1 in D2 retina and ON. Increased expression of hydroxycarboxylic acid receptor 1 (HCAR1) after ketogenic diet treatment was observed. HCAR1 stimulation by lactate or ketones from the ketogenic diet reduced inflammasome formation, as shown by reduced mRNA and protein expression of NLRP3 and IL-1?. We also detected increased levels of Arrestin ?-2 protein, an adapter protein required for HCAR1 signaling. CONCLUSION:Our data demonstrate that the AMPK activation apparent in the glaucomatous retina and ON triggers NF-?B signaling and consequently induces a pro-inflammatory response. The ketogenic diet resolves energy demand and ameliorates the inflammation by inhibition of AMPK activation and stimulation of HCAR1-ARRB2 signaling that inhibits NLRP3 inflammasome-mediated inflammation. Thus, these findings depict a neuroprotective mechanism of the ketogenic diet in controlling inflammation and suggest potential therapeutic targets for inflammatory neurodegenerative diseases, including glaucoma.

Dataset Information

AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks.

Publications

AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets