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Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer's disease mouse model.

ABSTRACT: The orexigenic hormone ghrelin, a potential antagonist of the insulin system, ensures sufficient serum glucose in times of fasting. In the race for new therapeutics for diabetes, one focus of study has been antagonizing the ghrelin system in order to improve glucose tolerance. We provide evidence for a differential role of a ghrelin agonist on glucose homeostasis in an Alzheimer's disease mouse model fed a high-glycemic index diet as a constant challenge for glucose homeostasis. The ghrelin agonist impaired glucose tolerance immediately after administration but not in the long term. At the same time, the ghrelin agonist improved spatial learning in the mice, raised their activity levels, and reduced their body weight and fat mass. Immunoassay results showed a beneficial impact of long-term treatment on insulin signaling pathways in hippocampal tissue. The present results suggest that ghrelin might improve cognition in Alzheimer's disease via a central nervous system mechanism involving insulin signaling.

SUBMITTER: Kunath N

PROVIDER: S-EPMC4473679 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer's disease mouse model.

Kunath Nicolas N van Groen Thomas T Allison David B DB Kumar Ashish A Dozier-Sharpe Monique M Kadish Inga I

Scientific reports 20150619

The orexigenic hormone ghrelin, a potential antagonist of the insulin system, ensures sufficient serum glucose in times of fasting. In the race for new therapeutics for diabetes, one focus of study has been antagonizing the ghrelin system in order to improve glucose tolerance. We provide evidence for a differential role of a ghrelin agonist on glucose homeostasis in an Alzheimer's disease mouse model fed a high-glycemic index diet as a constant challenge for glucose homeostasis. The ghrelin agon ...[more]

PMID: 26090621

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Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging associated frailty may preclude physical activity. AMP-activated protein kinase (AMPK) is a transcriptional regulator important for muscle physiology. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (2-month-old), aged (23-month-old) C57Bl/6 mice, and transgenic mice with muscle-specific mutated AMPK alpha-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3 to 14 days and tested in the Morris water maze, rotarod and open field. Improved water maze performance and motor function was observed, albeit at longer duration of administration, in aged (14 days AICAR) than young (3 days AICAR) mice. In the AMPKDN mice, the compound did not enhance behavior, providing support for a muscle mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus genes relevant to neuronal development and plasticity were enriched. Altogether, endurance related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. Key words: Skeletal Muscle, Brain, Exercise, AMPK, Learning and Memory, Morris water maze 23-month old female C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were housed under standard conditions, 3 mice per cage, with food and water ad libitum. Mice were injected intraperitoneally with 5-Aminoimidazole-4-carboxamide-1-a-D-ribofuranoside (AICAR, Toronto Research Chemicals Inc., Canada) dissolved in saline, 500 mg/kg/day for 3 (ACR3), 7 (ACR7) or 14 (ACR14) days or saline vehicle, for 3 (CTR) days. Thirty-three days after the final injection animals were deeply anesthetized with isofluorane and perfused transcardially with 0.9% NaCl solution. The gastrocnemius muscle and Hippocampus were quickly removed, frozen on dry ice and stored at M-bM-^HM-^R80 M-BM-0C for RNA isolation and microarray analysis.

Dataset Information

Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer's disease mouse model.

Publications

Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer's disease mouse model.

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