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

Objective: has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2 transmembrane (TM) helix of 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.

Methods: We used CRISPR-SpCas9 to mutate the TM domain of in WKY rats (Adcy3). We also created a heterozygous knockout rat in the same strain (Adcy3). Wild-type (WT), 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, and memory.

Results: Adcy3 and Adcy3 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 males displayed increased passive coping and decreased memory while Adcy3 females displayed increased anxiety-like behavior.

Conclusions: These studies show that the ADCY3 TM domain plays a role in protein function, that may contribute to the relationship between obesity and MDD, and that sex influences the relationships between , metabolism, and behavior.