Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model.
10.3803/EnM.2014.29.3.336
- Author:
Seok Joo PARK
1
;
Yoon Hee CHUNG
;
Jeong Hyun LEE
;
Duy Khanh DANG
;
Yunsung NAM
;
Ji Hoon JEONG
;
Yong Sun KIM
;
Toshitaka NABESHIMA
;
Eun Joo SHIN
;
Hyoung Chun KIM
Author Information
1. Neuropsychopharmacology and Toxicology Program, Kangwon National University College of Pharmacy, Chunchon, Korea. or shinej@kangwon.ac.kr, kimhc@kangwon.ac.kr
- Publication Type:Original Article
- Keywords:
klotho gene;
Cognitive dysfunction;
GH-releaser diet;
Receptor, IGF type 1
- MeSH:
Aging*;
Animals;
Caspase 3;
Diet*;
Gene Expression;
Growth Hormone;
Hippocampus;
Insulin-Like Growth Factor I;
Memory;
Mice*;
Oxidative Stress;
Phosphotransferases;
Receptor, IGF Type 1
- From:Endocrinology and Metabolism
2014;29(3):336-348
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND: It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). METHODS: In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice. RESULTS: The GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3beta (p-GSK3beta), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist. CONCLUSION: The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.
