Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats.

OBJECTIVE

Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of Adcy3 in rats; similar obesity variants have been identified in humans. This study investigates the role of a TM variant in adiposity and behavior.

METHODS

We mutated the TM domain of Adcy3 (Adcy3) and created a heterozygous knockout (Adcy3) in Wistar Kyoto (WKY) rats. Wild-type, Adcy3, and Adcy3 rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, memory, and downstream proteins.

RESULTS

Adcy3 and Adcy3 rats weighed more than wild-type rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3 males displayed increased passive coping and decreased memory, whereas Adcy3 females displayed increased anxiety-like behavior. Adcy3 males had decreased hypothalamic cAMP-response element binding protein (CREB) signaling, with decreased phospho-AMP-activated protein kinase (p-AMPK) signaling in both sexes.

CONCLUSIONS

The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. Adcy3 may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between Adcy3, metabolism, and behavior.