The Mechanism Of Akkermansia Muciniphila Subtype Alleviating Olanzapine-induced Glucose Metabolism Disorder By Regulating AMPK Signaling Pathway

Olanzapine(OLZ)is one of the first-class atypical antipsychotic drugs for the treatment of schizophrenia and other mental disorders.But olanzapine can easily cause severe metabolic abnormalities,such as weight gain,hyperglycemia and dyslipidemia,which increase the risk of cardiovascular disease.Many Studies have shown that olanzapine intervention can cause changes in intestinal flora.Akkermansia muciniphila(A.muciniphila/Akk)is one of the most important symbiotic bacteria in mammalian intestinal flora that can degrade mucin and regulate blood glucose homeostasis.Studies have confirmed that the Akk subtype independently isolated by our research group can reduce the expression of key enzymes phosphoenolpyruvate carboxykinase(PEPCK)and glucose-6-phosphatase(G6Pase)in gluconeogenesis,thereby improving olanzapine-induced hyperglycemia,but its mechanism has not been further studied.AMP-activated protein kinase(AMPK)is an important inhibitor of gluconeogenesis.The activation of AMPK in the liver inhibits the expression of PEPCK and G6Pase.Thus,the intention of this study is to investigate whether the Akk subtype can improve the side effects of olanzapine-induced glucose metabolism disorders by regulating the AMPK signaling pathway and its related mechanisms.1 Objectives1.1 To explore the improvement effect of Akk subtype on abnormal glucose and lipid metabolism induced by olanzapine in mice;1.2 To explore the mechanism of Akk subtype in alleviating olanzapine-induced glucose metabolism disorder by regulating AMPK signaling pathway.2 Methods50 six-week-old C57BL/6 female mice were randomly divided into 5 groups,including a VEH+PBS+PBS group,OLZ+PBS+PBS group,OLZ+PBS+3-MPA group,OLZ+Akk+PBS group and OLZ+Akk+3-MPA group,respectively.All were fed with high fat diet.The body weight and food intake of the mice were measured and recorded weekly.The whole animal experiment lasted 16 weeks.After mice were sacrificed,serum,liver and epididymal white fat tissue were collected and analyzed.3 Results3.1 Akk subtype treatment can improve olanzapine-induced hyperglycemia and insulin resistance in mice.3.2 Akk subtype treatment can improve olanzapine-induced abnormal gluconeogenesis and abnormal glycogen synthesis in mice by regulating AMPK signaling pathway.3.3 Akk subtype treatment can improve olanzapine-induced abnormal lipid metabolism in mice.4 ConclusionWe found that Akk subtype treatment can improve olanzapine-induced high fasting blood glucose,abnormal glucose tolerance and insulin resistance in mice,but the role of Akk subtype in regulating body weight and food intake in mice is not obvious.Akk subtype treatment inhibits gluconeogenesis and promotes glycogen synthesis by activating AMPK signaling pathway,thereby improving olanzapine-induced abnormal gluconeogenesis and abnormal glycogen synthesis in mice.Olanzapine has no significant effect on lipid metabolism and hepatic steatosis in mice fed a high-fat diet,but Akk subtype treatment can improve dyslipidemia and hepatic steatosis to some extent.In addition,Akk subtype treatment can improve the abnormal adipogenesis induced by olanzapine in mice.Supplementing or regulating the abundance of Akk subtypes may become a new strategy for clinical treatment of olanzapine-induced metabolic side effects.