GLP-1R/NPY2R regulate gene expression, ovarian and adrenal morphology in HFD mice.

Glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y receptors (NPYRs) are expressed in reproductive tissues contributing to the regulation of gonadal function. This exploratory study examines the potential impact of their modulation by assessing effects of exendin-4 (Ex-4) and peptide YY (PYY) (3-36) on endocrine ovaries and adrenals, in high-fat diet (HFD) mice. Ex-4 and PYY(3-36) reduced blood glucose and energy intake, with no effects on body weight. While HFD did not impact estrous cycle, Ex-4 increased metestrus frequency and decreased diestrus frequency resulting in 0% mice experiencing repeated diestrus or becoming acyclic. LH levels were significantly higher in the Ex-4 and PYY(3-36) groups compared to ND and HFD controls. In the adrenals, reduced capsule and zona glomerulosa thickness cause by HFD was reversed after peptide treatments. Within the ovaries, HFD increased the number of atretic follicles, an effect that disappeared after Ex-4 and PYY(3-36) treatments. Ex-4 also increased the number of corpora lutea owing to the prolonged metestrus phase. Gene expression analysis within the adrenals revealed upregulation of Insr and downregulation of Prgtr in HFD mice, while Ex-4 downregulated the expression of Gipr. Ovarian gene expression of Gipr, Npy1r and Prgtr were downregulated by Ex-4 treatment, while PYY(3-36) significantly downregulated Prgtr expression compared to HFD mice. These data indicate that manipulating GLP-1R and NPY2R lead to changes in the reproductive physiology of mice. Additionally, the observed alterations in the morphology and gene expression in the adrenals and ovaries imply a direct impact of these peptides on female reproductive function.