Adcy3, short for adenylate cyclase 3, is a transmembrane enzyme and a ciliary adenylyl cyclase [1]. It localizes within primary cilia in the brain and is involved in multiple physiological processes. It has been linked to pathways related to body weight regulation, with its role in the hypothalamic leptin-melanocortin system being crucial for controlling the balance between appetite and energy expenditure [3]. Additionally, it may be involved in the cAMP-PKA signaling pathway, which is important for neuronal inhibition [2].

In rats, CRISPR-SpCas9-mediated mutation of the Adcy3 transmembrane domain led to increased adiposity, with key sex differences: males showed increased food intake, while females had decreased energy expenditure. Moreover, Adcy3mut/mut males had increased passive coping and decreased memory, and females displayed increased anxiety-like behavior, suggesting its role in the relationship between obesity and major depressive disorder (MDD) [5]. In mice, deletion of a cold-inducible truncated isoform of Adcy3 (Adcy3-at) increased energy expenditure and made them resistant to obesity and metabolic imbalances [6]. Also, loss of GPR75, a ciliary protein, failed to suppress obesity development in Adcy3-mutant mice on a chow diet, indicating an interaction in regulating food intake [4].

In conclusion, Adcy3 plays a significant role in body weight regulation, energy metabolism, and emotional behaviors. Mouse and rat models, especially those with gene mutations or knockouts, have revealed its importance in obesity-related phenotypes and potentially in MDD. These models contribute to understanding the underlying mechanisms and may provide insights for treating obesity and related disorders.