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Ovariectomy Impaired Hepatic Glucose and Lipid Homeostasis and Altered the Gut Microbiota in Mice With Different Diets.

ABSTRACT: The lower incidence of metabolic diseases of women than men and the increasing morbidity of metabolic disorders of menopausal women indicated that hormones produced by ovaries may affect homeostasis of glucose and lipid metabolism, but the underlying mechanisms remain unclear. To explore the functions of ovaries on regulating glucose and lipid metabolism in females, 8 weeks old C57BL/6 mice were preformed ovariectomy and administrated with normal food diet (NFD) or high fat diet (HFD). Six weeks after ovariectomy, blood biochemical indexes were tested and the morphology and histology of livers were checked. The expression levels of genes related to glucose and lipid metabolism in liver were detected through transcriptome analysis, qPCR and western blot assays. 16S rDNA sequence was conducted to analyze the gut microbiota of mice with ovariectomy and different diets. The serum total cholesterol (TC) was significantly increased in ovariectomized (OVX) mice fed with NFD (OVXN), and serum low density lipoprotein-cholesterol (LDL-C) was significantly increased in both OVXN mice and OVX mice fed with HFD (OVXH). The excessive glycogen storage was found in livers of 37.5% mice from OVXN group, and lipid accumulation was detected in livers of the other 62.5% OVXN mice. The OVXN group was further divided into OVXN-Gly and OVXN-TG subgroups depending on histological results of the liver. Lipid drops in livers of OVXH mice were more and larger than other groups. The expression level of genes related with lipogenesis was significantly increased and the expression level of genes related with β-oxidation was significantly downregulated in the liver of OVXN mice. Ovariectomy also caused the dysbiosis of intestinal flora of OVXN and OVXH mice. These results demonstrated that hormones generated by ovaries played important roles in regulating hepatic glucose and lipid metabolism and communicating with the gut microbiota in females.

SUBMITTER: Lei Z

PROVIDER: S-EPMC8278766 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIncreasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and α-glucosidase inhibitor in modulating the gut microbiota.Methods16S-rDNA sequencing was performed to analyse the effects of DPP-4i and acarbose on the gut microbiota in mice fed a high-fat diet (HFD). Fecal microbiota transplantation (FMT) from type 2 diabetes patients to germ-free mice was performed to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics was also analysed by untargeted and targeted GC-MS systems.FindingsAlthough DPP-4i and α-glucosidase inhibitor both altered the gut microbial composition, only the microbiome modulation of DPP-4i contributed to its hypoglycemic effect. Specifically, the changes of 68.6% genera induced by HFD were rescued by DPP-4i. FMT showed that the DPP-4i-altered microbiome improved glucose tolerance in colonized mice, while acarbose did not. Moreover, DPP-4i increased the abundance of Bacteroidetes, and also promoted a functional shift in the gut microbiome, especially increasing the production of succinate.InterpretationOur findings demonstrate an important effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and an additional benefit of it. Furthermore, modulating the microbial composition, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. FUND: This work was supported by grants from the National Natural Science Foundation of China (No. 81700757, No. 81471039, No. 81700714 and No. 81770434), the National Key R&D Program of China (No. 2017YFC1309602, No. 2016YFC1101100, No. 2017YFD0500503 and No. 2017YFD0501001), and the Natural Science Foundation of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518).

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Ovariectomy Impaired Hepatic Glucose and Lipid Homeostasis and Altered the Gut Microbiota in Mice With Different Diets.

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