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. 2025 Jan;33(1):91-103.
doi: 10.1002/oby.24178. Epub 2024 Dec 4.

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

Mackenzie K Fitzpatrick  1 , Alexandria Szalanczy  1 , Angela Beeson  1 , Anusha Vora  1 , Christina Scott  1 , Michael Grzybowski  2 , Jason Klotz  2 , Nataley Der  1 , Rong Chen  3 , Aron M Geurts  2 , Leah C Solberg Woods  1
Affiliations

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

Mackenzie K Fitzpatrick et al. Obesity (Silver Spring). 2025 Jan.

Abstract

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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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors declared no conflicts of interest.

Update of

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