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KMID : 0356620140290030336
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Journal of Korean Society of Endocrinology
2014 Volume.29 No. 3 p.336 ~ p.348
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Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model
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Park Seok-Joo
Chung Yoon-Hee
Lee Jeong-Hyun
Dang Duy Khanh
Nam Yun-Sung
Jeong Ji-Hoon
Kim Yong-Sun
Nabeshima Toshitaka
Shin Eun-Joo
Kim Hyoung-Chun
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Abstract
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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 kinase3β (p-GSK3β), 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.
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KEYWORD
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klotho gene, Cognitive dysfunction, GH-releaser diet, Receptor, IGF type 1
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