Endocrine Abstracts

JOINT1046

Background & Aims: In women with polycystic ovary syndrome (PCOS), the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is high. The development of PCOS-associated MASLD is accelerated by prepubertal obesity, but the extent to which early-life weight gain exacerbates the metabolic features of PCOS is still under debate. To clarify this, we analyzed the impact of overfeeding in early postnatal period on metabolic features, gut microbiota profile and hepatic lipid metabolism in the rat model of PCOS.

Methods: Wistar rats were divided into 4 groups, in which treatment with 5α-dihydrotestosterone (5α-DHT) was used to mimic hyperandrogenemia, whereas litter size reduction was used to induce early postnatal overfeeding and prepubertal obesity. The composition of the intestinal bacterial community was determined by 16S rDNA sequencing. The level of short chain fatty acids was measured by mass spectrometry. Hematoxylin-eosin-stained sections, Western blots, and qRT-PCR were used to analyze hepatic lipid metabolism.

Results: Only postnatally overfed DHT-treated rats developed prominent obesity and glucose intolerance, which was not associated with altered Firmicutes/Bacteroidetes ratio. Postnatal overfeeding shifted the microbiota composition towards obesity-associated genera, while hyperandrogenemia led to reduced β-diversity and an increased abundance of androgen-regulated genera. Interaction of treatments reduced both α- and β-diversity and decreased the abundance of beneficial butyrate-producing genera Roseburia, Oscillospira, and Ruminococcus and plasma level of butyric acid. This shift in microbiota composition was accompanied by decreased expression of G-protein coupled receptor 43 (GPR43), fasting-induced adipocyte factor (FIAF), and increased expression of lipoprotein lipase (LPL). In accordance with the altered GPR43/FIAF/LPL pathway, increased expression of lipogenic transcription factors was observed in SL-DHT animals, but this did not result in hepatic lipid deposition.

Conclusions: Early postnatal overfeeding is important factor in the development of PCOS-related metabolic features, and it is associated with reduced α- and β-diversity and decreased abundance of beneficial butyrate-producing genera in the PCOS animal model. These changes impaired hepatic lipid metabolism via the GPR43/FIAF/LPL pathway. Although these changes are not associated with hepatic steatosis, they may pave the way for fatty liver disease in the long term.