Fitzpatrick Mackenzie K, Szalanczy Alexandria, Beeson Angela, Vora Anusha, Scott Christina, Grzybowski Michael, Klotz Jason, Der Nataley, Chen Rong, Geurts Aron M, Solberg Woods Leah C
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Obesity (Silver Spring). 2025 Jan;33(1):91-103. doi: 10.1002/oby.24178. Epub 2024 Dec 4.
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) and created a heterozygous knockout (Adcy3) in Wistar Kyoto (WKY) rats. Wild-type, 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, memory, and downstream proteins.
Adcy3 and Adcy3 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 males displayed increased passive coping and decreased memory, whereas Adcy3 females displayed increased anxiety-like behavior. Adcy3 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.
腺苷酸环化酶3（Adcy3）与肥胖症和重度抑郁症均有关联。我们在大鼠的Adcy3跨膜（TM）螺旋中鉴定出一种蛋白质编码变体；在人类中也鉴定出了类似的肥胖相关变体。本研究调查了一种TM变体在肥胖和行为中的作用。
我们对Adcy3的TM结构域进行了突变，并在Wistar Kyoto（WKY）大鼠中创建了杂合敲除（Adcy3）模型。将野生型、Adcy3和Adcy3大鼠喂食高脂饮食12周。我们测量了体重、脂肪量、葡萄糖耐量、食物摄入量、新陈代谢、情绪样行为、记忆力以及下游蛋白质。
由于脂肪量增加，Adcy3和Adcy3大鼠的体重比野生型大鼠更重。存在关键的性别差异：肥胖在雄性中是由食物摄入量增加驱动的，而在雌性中是由能量消耗减少驱动的。Adcy3雄性表现出被动应对增加和记忆力下降，而Adcy3雌性表现出焦虑样行为增加。Adcy3雄性下丘脑环磷酸腺苷反应元件结合蛋白（CREB）信号传导减少，两性中磷酸化腺苷酸活化蛋白激酶（p-AMPK）信号传导均减少。
ADCY3 TM结构域通过p-AMPK和CREB信号传导在蛋白质功能中发挥作用。Adcy3可能促成了肥胖症与重度抑郁症之间的关系，并且性别影响了Adcy3、新陈代谢和行为之间的关系。
