Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2 nd transmembrane (TM) helix of Adcy3 in rats, and similar obesity variants have been identified in humans. The current study investigates the role of a TM variant in adiposity and behavior.
We used CRISPR-SpCas9 to mutate the TM domain of Adcy3 in WKY rats (Adcy3 mut/mut). We also created a heterozygous knockout rat in the same strain (Adcy3 +/−). Wild-type (WT), 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, and memory.
Adcy3 +/− and Adcy3 mut/mut rats weighed more than WT 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 while Adcy3 mut/mut females displayed increased anxiety-like behavior.