3 minute lightning oral presentation (and poster) ESA-SRB-APEG-NZSE 2022

Chemogenetic Inhibition of AgRP neurons Improves Metabolic PCOS traits in a Hyperandrogenic PCOS Mouse Model (#101)

Irene E Sucquart 1 , Caitlin Mitchell 2 , Valentina Rodriguez Paris 1 , Caitlin Tedesco 2 , Max Katz-Barber 2 , Robert B Gilchrist 1 , Kirsty A Walters 1 , Denovan P Begg 2
  1. School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
  2. School of Psychology, University of New South Wales, Sydney, NSW, Australia

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductively aged women, and associated with a wide range of reproductive, metabolic, and endocrine traits. Hyperandrogenism is a PCOS key trait, and many women with PCOS also exhibit luteinizing hormone hypersecretion due to disruptions in the hypothalamic-pituitary-ovarian (HPO) axis. Hypothalamic agouti-related protein (AgRP)-expressing neurons are key mediators of energy homeostasis and HPO axis regulators, and studies have shown an increased AgRP population in a PCOS sheep model. Therefore, we aimed to investigate if chemogenetic inhibition of AgRP neurons can ameliorate PCOS-like traits in a PCOS mouse model. PCOS was induced in peripubertal AgRP-Cre mice using dihydrotestosterone (DHT) implants. AgRP neurons were chemogenetically inhibited using designer receptor exclusively activated by designer drugs (DREADDs). The development of PCOS traits was then assessed in mice treated ± DHT and ± AgRP inhibition. As expected, DHT exposure induced reproductive and metabolic PCOS-like features. AgRP inhibition had no effect on acyclicity in PCOS mice. A main effect of DHT exposure caused an increase in total body weight, inguinal, parametrial and retroperitoneal fat pads (all P<0.05). Parametrial (P<0.05) and inguinal (P<0.05) fat pad weights were significantly decreased in PCOS mice following AgRP neuron inhibition. A DHT main effect led to an increase in food intake in PCOS mice (P<0.05). A trend towards decreased food intake was observed in PCOS mice after AgRP neuron inhibition. Basal glucose levels and insulin tolerance were not significantly different between any treatment group. In summary, chemogenetic inhibition of AgRP neurons ameliorated the development of some adverse metabolic PCOS features in a PCOS mouse model. These results suggests that AgRP neurons are likely implicated in androgen driven neuroendocrine disruption of PCOS associated metabolic features, and thus are a potential target for the future development of therapeutics for PCOS associated weight gain.