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Updated: Jun 5, 2025

Fat Preference: A Novel Model of Eating Behavior in Rats
Published on: June 27, 2014
Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats
Mackenzie K Fitzpatrick1, Alexandria Szalanczy1, Angela Beeson1
1Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
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 (Adcy3mut/mut) and created a heterozygous knockout (Adcy3+/-) in Wistar Kyoto (WKY) rats. Wild-type, Adcy3+/-, and Adcy3mut/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.
Results:
Adcy3+/- and Adcy3mut/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. Adcy3mut/mut males displayed increased passive coping and decreased memory, whereas Adcy3mut/mut females displayed increased anxiety-like behavior. Adcy3mut/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.
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.
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