Fitzpatrick Mackenzie K, Dyson Christina, Beeson Angela, Adrian Leighelle, Marrs Glen, Grzybowski Michael, Klotz Jason, Geurts Aron M, Chen Rong, Weiner Jeffrey L, 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 Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Genes Brain Behav. 2025 Jun;24(3):e70028. doi: 10.1111/gbb.70028.
We have previously demonstrated that a transmembrane domain mutation in Adenylate cyclase 3 (Adcy3) causes increased adiposity and negative emotion-like behaviors in a rat model. We set out to replicate and expand upon our previous study by conducting comprehensive behavioral testing, and we also investigated the molecular changes that result from this mutation. Rats with a mutation in the second transmembrane helix of ADCY3 (Adcy3) and wild-type rats were fed a high-fat diet for 12 weeks. We measured body weight, body composition, and depression-like and anxiety-like behaviors using the following tests: sucrose splash test, sucrose preference test, forced swim test, open field test, elevated plus maze, successive alleys test, and novelty-suppressed feeding. We also measured serum leptin levels, hypothalamic cyclic AMP (cAMP) production, and membrane fraction ADCY3 content. Adcy3 male and female rats had increased adiposity. Adcy3 males showed increased despair- and anxiety-like behaviors, food seeking, and higher leptin levels relative to wild-type males. Adcy3 females showed only mildly increased anxiety-like behaviors relative to wild-type females. Adcy3 rats of both sexes had decreased cAMP production in the hypothalamus, with no changes in ADCY3 content in the membrane fraction. We conclude that the transmembrane domain of ADCY3 plays a critical role in regulating adiposity and behavior, as well as cAMP production. There were key differences between males and females for the observed phenotypes. This study supports the idea that Adcy3 contributes to emotion-like behaviors and potentially mental health disorders, and that the transmembrane domain of ADCY3 is important for protein function.
我们之前已经证明，腺苷酸环化酶3（Adcy3）中的跨膜结构域突变会在大鼠模型中导致肥胖增加和类似负面情绪的行为。我们着手通过进行全面的行为测试来重复并扩展我们之前的研究，并且我们还研究了这种突变所导致的分子变化。对ADCY3第二个跨膜螺旋发生突变的大鼠（Adcy3）和野生型大鼠喂食高脂饮食12周。我们使用以下测试来测量体重、身体成分以及类似抑郁和类似焦虑的行为：蔗糖甩溅试验、蔗糖偏好试验、强迫游泳试验、旷场试验、高架十字迷宫试验、连续小巷试验以及新奇抑制摄食试验。我们还测量了血清瘦素水平、下丘脑环磷酸腺苷（cAMP）生成量以及膜组分中ADCY3的含量。Adcy3雄性和雌性大鼠的肥胖程度均增加。相对于野生型雄性大鼠，Adcy3雄性大鼠表现出更多的绝望和类似焦虑的行为、觅食行为以及更高的瘦素水平。相对于野生型雌性大鼠，Adcy3雌性大鼠仅表现出轻度增加的类似焦虑的行为。两种性别的Adcy3大鼠下丘脑的cAMP生成量均减少，而膜组分中ADCY3的含量没有变化。我们得出结论，ADCY3的跨膜结构域在调节肥胖、行为以及cAMP生成方面起着关键作用。观察到的表型在雄性和雌性之间存在关键差异。这项研究支持了Adcy3促成类似情绪的行为以及潜在的精神健康障碍这一观点，并且ADCY3的跨膜结构域对蛋白质功能很重要。
