Loss of ciliary adenylyl cyclase 3 in the ventromedial hypothalamus resulted in a sex-dependent obese phenotype.

Obesity, a metabolic disorder characterized by an excessive accumulation of body fat, continues to be a major economic and health burden to the global populace, as it is the most significant risk factor for heart disease, diabetes, and hypertension. Genome-wide association studies have identified several genes involved in obesity development, including ADCY3, a gene encoding for the enzyme adenylyl cyclase 3 (AC3). AC3 is a critical mediator of the cyclic adenosine monophosphate (cAMP) signaling pathway and is enriched in the primary cilium, a solitary immotile organelle protruding from most mammalian cells, including neurons. The primary cilia act as the cellular antenna to sense and relay changes in the extracellular microenvironment and mounting evidence support a role for the primary cilia as a critical regulator of the energy homeostasis. Patients carrying loss-of-function ADCY3variants are obese and are at increased risk of developing type II diabetes mellitus (T2DM). Consistently, whole-body Adcy3knockout mice also develop obesity; however, the underlying mechanisms by which AC3 affects metabolic homeostasis remain unclear. Here, we examined the impact of AC3 loss within the ventromedial nucleus of hypothalamus (VMH), a brain region critical for coordinated control of energy and glucose homeostasis, on energy metabolism. We generated mice with VMH-specific Adcy3loss (Adcy3SF-1KO mice) by crossing SF-1 Cre+ mice with Adcy3F/F mice and subjected them to metabolic phenotyping to assess energy balance and glucose homeostasis. We observed a sexually dimorphic effect on body weight under standard chow diet; male Adcy3SF-1KO mice displayed normal body weight gain comparable to control littermates, whereas female Adcy3SF-1KO mice gained a significant more weight compared to control littermates (Con 24.34g v KO 30.61g, p < 0.0001). Strikingly, however, both sexes of Adcy3SF-1KOmice exhibited improved glucose tolerance (AUC: M Con 17,826 v KO 15,165, p = 0.02; F Con 15,263 v KO 13,238, p = 0.03) without affecting fed and overnight fasting blood glucose levels. Taken together, these results underscore the importance of AC3-mediated ciliary cAMP signaling in VMH neurons for the regulation of energy balance and glucose homeostasis in a sex-dependent manner.