Gut microbiota and its derived SCFAs regulate the HPGA to reverse obesity-induced precocious puberty in female rats

Abstract

The intestinal microbiota and its derived short-chain fatty acids (SCFAs) can reverse obesity and obesity-related metabolic diseases, but whether it has an effect on obesity complicated by precocious puberty and its potential mechanism need to be further understood. The purpose of this study was to investigate the effect of the gut microbiota and its derived short-chain fatty acids (SCFAs) on obesity-induced precocious puberty rats and their regulatory mechanisms. We constructed obesity-induced precocious puberty rats using a high-fat diet (HFD) had notable similarity to precocious puberty caused by obesity due to overeating in children. We then added acetate, propionate, butyrate or their mixture to the HFD, and investigated the effect of intestinal microbiota and its derived SCFAs on the hypothalamic-pituitary-gonadal axis (HPGA) in rats with obesity-induced precocious puberty. We found that obesity-induced precocious puberty rats had an early first estrous cycle, increased hypothalamic mRNA expression of Kiss1, GPR54 and GnRH, and early gonadal maturation. Meanwhile, the intestinal microbiota imbalance and the main SCFAs production decreased in the colon. The addition of acetate, propionate, butyrate or their mixture to the HFD could significantly reverse the precocious puberty of rats, reduce GnRH release from the hypothalamus and delay the development of the gonadal axis through the Kiss1–GPR54–PKC–ERK1/2 pathway. Our findings suggest that gut microbiota-derived SCFAs are promising therapeutic means for the prevention of obesity-induced precocious puberty and provide new therapeutic strategies with clinical value.

Commentary: Gut microbiota and its derived SCFAs regulate the HPGA to reverse obesity-induced precocious puberty in female rats

“…In this study, Wang et al found that microbiota-derived SCFAs reversed the high-fat-induced obesity-mediated precocious puberty, with mechanisms of impact on the HPGA (14). Hence, a novel remote brake (gut microbiota-SCFA) of precocious puberty was characterized.…”

“…The authors ( 14 ) firstly confirmed that treatment of HFD after weaning induced obesity and precocious puberty in female rats and upregulated HPGA gene expressions, including Kiss1 (kisspeptin-1), GPR54 (G protein-coupled receptor 54, Kiss1R), GnRH (gonadotropin-releasing hormone), Erα (estrogen receptor α) in the hypothalamus, GnRHR (gonadotropin-releasing hormone receptor) in the pituitary, and LHR (luteinizing receptor), FSHR (follicle-stimulating hormone receptor), and Erα in the ovary. In view of flora, the authors found that HFD significantly changed the composition of intestinal microbiota, with increased levels of Bacteroidota, Proteobacteria, and Verrucomicrobiota but decreased levels of Firmicutes.…”

“…Although intestinal microbiota, as a remote regulator, was involved in the onset of precocious puberty in high-fat diet (HFD) conditions (9)(10)(11)(12), and microbiota-derived SCFAs (short-chain fatty acids) have been characterized as multifunctional molecules impacting human physiology (13), detailed mechanisms remain unclear. Here, Wang et al found that the reduced microbiotaderived SCFA was accounting for the HFD-induced precocious puberty in female rats (14).…”

“…Here, Wang et al. found that the reduced microbiota- derived SCFA was accounting for the HFD-induced precocious puberty in female rats ( 14 ).…”

“…One of the most important innovations of this study is that the authors identified SCFAs as key mediators of HFD-induced precocious puberty in female rats ( 14 ). In addition to providing energy, intestinal SCFAs have been previously recognized to regulate metabolism ( 13 , 15 , 16 ), mucosal function ( 17 ), immunity ( 18 ), and behaviors ( 19 ), while the potential regulation of precocious puberty is underappreciated.…”