Research On The Mechanism And Pharmacological Treatment Of Cognitive Impairment Caused By Obesity

PART ? NEURONAL ABLATION OF GHS-R GENERATES MEMORY ENHANCEMENT AND IMPROVES DEPRESSIVE-LIKE BEHAVIOR IN DIETINDUCED OBESITY THROUGH MITIGATING NEUROINFLAMMATIONObjectiveThe ghrelin receptor,named growth hormone secretagogue receptor?GHS-R?,is highly expressed in the brain.Obesity is associate with a high prevalence of central nervous system?CNS?diseases.Our previous study showed neuronal GHS-R deletion almost completely prevents diet-induced obesity,here we hypothesis that whether neuronal deletion of GHS-R mitigates mood symptoms and cognitive dysfunctions in diet-induced obesity?DIO?.MethodsAge-matched male Ghsr ^f/f?WT?and Syn1-Cre;Ghsr ^f/f?neuronal specific KO?mice were fed either regular diet?RD?or high-fat diet?HFD?.Forced swimming test?FST?was performed to determine depressive-like behavior.Both Morris water maze?MWM?and novel object recognition test?NORT?were used to evaluate learning and memory.Hall marks of relevant signaling pathways were determined.Inflammatory cytokines along with related-impact factors in the cortex and hippocampus were measured to determine the inflammation state under DIO with or without GHS-R expression in neuron.ResultsIn comparison with Ghsr ^f/f mice,Syn1-Cre;Ghsr ^f/f mice under DIO showed significantly less immobility time during the forced swimming test;Syn1-Cre;Ghsr ^f/f mice under DIO in Morris water maze task showed a trend of reduced escape latency in terms of time and distance but failed to show statistic significant during the training section,and during the probe test,these mice spent less time for the first time to find the platform location and spent more time in the target quadrant where the platform was located.Then,in the cortex and hippocampus,GFAP-labeled astrocytes increased in Syn1-Cre;Ghsr ^f/f mice;In addition,neuronal deletion of GHS-R altered AMPK-mTOR-autophagy signaling pathway;The inflammatory cytokines significantly decreased under DIO in Syn1-Cre;Ghsr ^f/f mice.ConclusionsWe reported for the first time that under DIO neuron-specific GHS-R deletion improved depressive like state and enhanced cognitive function by attenuating neuro-inflammation.Important to note,increased astrocytes in Syn1-Cre;Ghsr ^f/f mice may serve as functional barrier to help to control the inflammation;Neuron-specific GHS-R deletion altered AMPK-mTOR-autophagy signaling pathway independent of diet factor;More importantly,deletion of neuron GHS-R significantly resulted in reduced pro-inflammatory cytokines along with related regulators.This study provides a new insight of the GHS-R plays a promising role linking nutrient sensing and CNS behaviors.PART ? HUPERZINE A AMELIORATES THE IMPAIRMENT OF OBESITY-RELATED COGNITIVE PERFORMANCE INVOLVING NEURONAL INSULIN SIGNALING PATHWAYS IN MICEObjective Huperzine A?HupA?,a Lycopodium alkaloid originally extracted from the Chinese club moss Huperzia serrata,is a specific,selective and reversible inhibitor of ACh E,which is one of the main drugs clinically for Alzheimer's disease?AD?.Obesity,type 2 diabetes?T2D?and AD share several common pathophysiological features such as chronic inflammation,brain insulin signaling impairment and cognitive dysfunction.Here,we explored whether HupA improves metabolic and cognitive dysfunctions in high fat diet?HFD?induced obese mice or genetic obese ob/ob mice.Methods Age-matched male C57 BL/6 mice were randomly divided into HFD and regular diet?LFD?.HFD and ob/ob mice were administrated HupA at doses of 0.1 and 0.3 mg/kg/day for three months.Body weight was monitored and glucose tolerance test?GTT?were performed.Novel object recognition test and Morris water maze were performed.Enzyme-linked immunosorbent assay?ELISA?was used to measure insulin levels in the cortex and western blotting was used to investigate changes in neuronal insulin signaling and BACE1 expression in the cortex and hippocampus.Results HupA had no significant effect on body weight and glucose homeostasis in obese mice.Novel object recognition test showed that low dose HupA significantly improved the short-term learning memory of dietinduced obese mice.Morris water maze test showed that low-dose HupA significantly improved spatial learning and memory in diet-induced obese mice.The insulin levels in the cortex were significantly higher than those in the control groups,and the low-dose groups showed the highest insulin.The BACE1 expression in cortex and hippocampus in the high-dose HupA group was significantly lower than that in the control group.The level of pAkt in cortex and hippocampus of the HupA administration group was significantly higher than that in the control groups.Conclusions Our results have demonstrated for the first time that HupA protects against obesity-associated cognitive impairment in HFD mice,but not in ob/ob mice.Although HupA had no effect on body weight and peripheral glucose metabolism,it significantly enhanced the activity of neuronal insulin signaling pathway,which contributes to its improvement on cognitive dysfunctions associated with T2 DM.The novel findings in this study provide important information for the potential new application of HupA in addition to its classical treatment of AD.