Beyond Weight Loss: Disentangling the Direct Effects of Semaglutide vs Equivalent Calorie Restriction on Reproductive...

Semaglutide (SEMA), a glucagon-like peptide-1 (GLP-1) analogue approved for treatment of obesity, is now one of the most used anti-obesity pharmacotherapeutic agents worldwide. The effects of SEMA on body weight, appetite, and adiposity are well established. Moreover, sex differences in these effects are clearly emerging. Metabolism and reproduction are intimately intertwined; yet, whether and how these blockbuster drugs affect the reproductive system of males and females is poorly understood. To address this gap, we investigated the impact of chronic SEMA treatment on gonads and circulating reproductive hormones in diet-induced obese male and female rats. GLP-1 receptor is expressed in ovaries and testes, potentially allowing a direct effect of SEMA. Testicular expression of this receptor was 4-fold higher than in ovaries, supporting a potential male bias for potency of the drug effect. To disambiguate the direct effect of the drug from potential downstream effects of weight loss, and ensuing improvements in metabolism produced by the drug, we also evaluated pair-fed (PF) controls. After 4 weeks of treatment, PF and SEMA males displayed improvements in reproductive measures like sperm motility and mucus penetration parameters. Morphological analysis of male and female gonads largely suggested increased fertility. In males, changes in germinal epithelium and seminiferous tubules were detected. In females, increased folliculogenesis was identified in both SEMA and PF rats. Structural changes in the gonads were accompanied by changes in circulating gonadal hormones in a sex-specific manner. In males, SEMA attenuated the weight-loss-induced reduction in all androgens measured. In females, levels of progesterone, pregnenolone, and estradiol were reduced in a treatment specific manner. Pituitary hormones were also affected in both sexes. Altogether, this study highlights broad SEMA-specific, as well as weight loss induced but rescued by SEMA, effects at transcriptional, functional, and systemic levels on the reproductive systems of males and females.