Postnatal overfeeding induces gut microbiota disturbances and impairs GPR43/FIAF/LPL pathway in the rat model of PCOS

Abstract

Women with polycystic ovary syndrome (PCOS) has high incidence of metabolic dysfunction-associated steatotic liver disease (MASLD). The development of PCOS-associated MASLD is accelerated by prepubertal obesity, therefore, we analyzed the impact of postnatal overfeeding-induced obesity on the gut microbiota and hepatic lipid metabolism in the PCOS rat model. Wistar rats were divided into 4 groups, where treatment with 5α-dihydrotestosterone (5α-DHT) stimulated hyperandrogenemia (DHT groups), whereas litter size reduction induced early postnatal overfeeding and obesity (SL groups). The fecal microbiota composition and diversity was analyzed by 16S rRNA sequencing. The bacterial metabolites level was measured by mass spectrometry. Hematoxylin-eosin staining, Western blots, and qRT-PCR were used to analyze hepatic lipid metabolism. Our results show that postnatal overfeeding shifted the microbiota composition towards obesity-associated genera, while hyperandrogenemia led to reduced β-diversity and increased abundance of androgen-regulated genera. Interaction of treatments reduced α- and β-diversity and decreased the abundance of beneficial butyrate-producing genera Roseburia, Oscillospira, and Ruminococcus and butyric acid plasma level. Shift in microbiota composition and activity was accompanied by decreased expression of G-protein coupled receptor (GPR) 43, fasting-induced adipocyte factor (FIAF) and increased expression of lipoprotein lipase (LPL). In accordance with altered GPR43 and FIAF/LPL pathway, increased expression of lipogenic transcription factors was observed in SL-DHT animals, but this did not result in hepatic lipid deposition. Our results demonstrated that postnatal overfeeding contributes to decreased richness and changes in gut microbiota composition in the PCOS animal model that is associated with impaired hepatic lipid metabolism, which may accelerate development of MASLD.

Keywords: Adiposity; Metabolic dysfunction-associated steatotic liver disease; Microbiota; Polycystic ovary syndrome; Prepubertal obesity.