Enhanced behavioral responses to ghrelin administration are unaffected by ghrelin deficiency in a DHT-induced PCOS mouse model.

Polycystic ovary syndrome [recently renamed to polyendocrine metabolic ovarian syndrome (PMOS)] is the most common endocrine disorder in women of reproductive age. Women with PMOS not only suffer from reproductive symptoms but are also more prone to develop metabolic dysfunction and aberrant eating behavior. The gut hormone ghrelin affects both metabolism and eating behavior in a sex-dependent fashion. Therefore, this study explored the effects of ghrelin deficiency on the phenotype of female mice with prepubertal, chronic dihydrotestosterone (DHT) exposure, a widely used mouse model of PMOS. DHT exposure markedly suppressed estrus cycling and corpora lutea number, increased lean mass (but not fat mass), and elevated inactive-phase food intake, but ghrelin deficiency had no marked effect on these outcomes. Interestingly, in wild-type mice, eating time and meal number of DHT-treated mice responded more strongly to acute ghrelin administration than those of controls. In ghrelin-deficient mice, responses to acute ghrelin administration were like DHT-treated wild-type mice, regardless of treatment. Besides effects on eating behavior, chronic DHT exposure also reduced locomotor activity in both wild-type and ghrelin-deficient mice, which is in line with reports on physical activity in women with PMOS. Locomotor activity was also decreased upon acute ghrelin administration, especially in ghrelin-deficient mice. Overall, chronic DHT exposure modified the behavioral responses to acute ghrelin administration in females, without evidence for additive effects of ghrelin deficiency, suggesting overlapping mechanisms of action. This work emphasizes the added value of detailed behavioral data in translational models of human disease to help elucidate potential mechanisms underlying aberrant eating behavior.NEW & NOTEWORTHY This study uniquely examined how ghrelin deficiency interacts with prepubertal chronic DHT exposure, a PMOS mouse model, shaping metabolism and eating behavior in female mice. Although ghrelin deficiency minimally altered DHT-induced reproductive or metabolic phenotypes, chronic DHT exposure affected behavioral responses to acute ghrelin, indicating interacting mechanisms between androgen and ghrelin signaling in PMOS. This work highlights the importance of detailed behavioral assessment of translational models of disease to explore mechanisms behind aberrant behavior.