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

Abstract

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. We mutated the TM domain of Adcy3 (Adcy3^mut/mut) and created a heterozygous knockout (Adcy3^+/-) in Wistar Kyoto (WKY) rats. Wild-type, Adcy3^+/-, and Adcy3^mut/mut 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. Adcy3^+/- and Adcy3^mut/mut 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^mut/mut males displayed increased passive coping and decreased memory, whereas Adcy3^mut/mut females displayed increased anxiety-like behavior. Adcy3^mut/mut males had decreased hypothalamic cAMP-response element binding protein (CREB) signaling, with decreased phospho-AMP-activated protein kinase (p-AMPK) signaling in both sexes. 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.