Dongquan Huang1, Jie Gao1, Chong Li1, Caihong Nong1, Wenting Huang1, Xifen Zheng1, Sirou Li1, Yongzheng Peng2,3. 1. Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China. 2. Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China. yzpeng1981@126.com. 3. Department of Transfusion Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China. yzpeng1981@126.com.
Abstract
BACKGROUND: Olanzapine (OLZ) is one of the most effective atypical antipsychotics but is associated with severe metabolic side effects, in which the gut microbiota plays an important role. Akkermansia muciniphila (A. muciniphila; Akk), a Gram-negative anaerobic bacterium in the intestine, can potentially improve metabolic syndrome. OBJECTIVE: This study investigated the effect and underlying mechanisms of an A. muciniphila subtype (A. muciniphilasub; Akksub) on OLZ-induced metabolic dysfunction in lean and obese mice. METHODS: C57BL/6 female mice were fed a high-fat diet to induce obesity or normal chow for 8 weeks before OLZ treatment for 16 weeks. During the treatment period, mice in each group were orally administrated A. muciniphilasub. Weight gain, glucose and lipid metabolism, and inflammation were evaluated. RESULTS: A. muciniphilasub decreased OLZ-related weight gain only at week 16 in lean mice and significantly alleviated OLZ-induced hyperglycemia irrespective of diet. This was accompanied by reduced levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)-key enzymes in hepatic gluconeogenesis-and OLZ-associated insulin resistance. Moreover, OLZ-induced increases in serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were improved by A. muciniphilasub in both obese and lean mice. OLZ did not increase serum lipid levels or hepatic fat accumulation. CONCLUSIONS: A. muciniphilasub improves OLZ-related hyperglycemia via regulation of G6Pase and PEPCK levels and insulin resistance. Moreover, A. muciniphilasub alleviates systemic inflammation caused by OLZ. A. muciniphilasub is a promising probiotic treatment for OLZ-induced metabolic dysfunction.
BACKGROUND:Olanzapine (OLZ) is one of the most effective atypical antipsychotics but is associated with severe metabolic side effects, in which the gut microbiota plays an important role. Akkermansia muciniphila (A. muciniphila; Akk), a Gram-negative anaerobic bacterium in the intestine, can potentially improve metabolic syndrome. OBJECTIVE: This study investigated the effect and underlying mechanisms of an A. muciniphila subtype (A. muciniphilasub; Akksub) on OLZ-induced metabolic dysfunction in lean and obesemice. METHODS: C57BL/6 female mice were fed a high-fat diet to induce obesity or normal chow for 8 weeks before OLZ treatment for 16 weeks. During the treatment period, mice in each group were orally administrated A. muciniphilasub. Weight gain, glucose and lipid metabolism, and inflammation were evaluated. RESULTS: A. muciniphilasub decreased OLZ-related weight gain only at week 16 in lean mice and significantly alleviated OLZ-induced hyperglycemia irrespective of diet. This was accompanied by reduced levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)-key enzymes in hepatic gluconeogenesis-and OLZ-associated insulin resistance. Moreover, OLZ-induced increases in serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were improved by A. muciniphilasub in both obese and lean mice. OLZ did not increase serum lipid levels or hepatic fat accumulation. CONCLUSIONS: A. muciniphilasub improves OLZ-related hyperglycemia via regulation of G6Pase and PEPCK levels and insulin resistance. Moreover, A. muciniphilasub alleviates systemic inflammation caused by OLZ. A. muciniphilasub is a promising probiotic treatment for OLZ-induced metabolic dysfunction.
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