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

N Kunath, A Kumar, M Dozier-Sharpe, D Allison, T Van Groen, I Kadish
2015 Pharmacopsychiatry  
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
more » ... is. 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 longterm 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. Ever since the discovery of ghrelin as a ligand of the growth hormone secretagogue receptor in 1999 1 , our understanding of the versatile role of ghrelin in mammals has constantly expanded. The characterization of ghrelin has spanned its actions as an orexigenic hormone leading to weight gain and adiposity in rodents 2,3 , to the stimulation of appetite in humans 4 , its impacts on cognitive processes in rodents 5,6 and humans 7-9 , and its role as a neuroprotective agent in neurodegenerative diseases 10-14 . Ghrelin's involvement in glucose metabolism became apparent very early 15,16 , with evidence for a differential role of des-acyl ghrelin 17,18 . Recently, many groups have focused on the interactions of ghrelin with the insulin system in humans 9, 19 . Antagonizing the insulinostatic ghrelin system has repeatedly been suggested as a novel mechanism by which to improve glucose homeostasis in humans. However, to our knowledge, none of the studies of the interactions of ghrelin with glucose homeostasis have addressed the long-term impact of ghrelin administration on a mammal. Our group showed previously that administration of a ghrelin agonist leads to improved cognition and improved markers of pathology in an Alzheimer's disease mouse model, even in the absence of caloric restriction 12 . The pathophysiological correlations between Alzheimer's disease, impaired glucose metabolism, and diabetes are well established 20-22 , and elevated serum glucose levels have been shown to be an independent risk factor for dementia in humans 23 . In the present study, therefore, we aimed to investigate the long-term effects of a ghrelin agonist given for 4 months on Alzheimer's disease pathology, cognition, and metabolism in the same mouse model fed a high-glycemic index (GI) diet as a constant
doi:10.1055/s-0035-1557966 fatcat:e5evr6kyu5hpjips4s4w65v3hu