Department of Physiology, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
Front Endocrinol (Lausanne). 2022 Jun 16;13:901669. doi: 10.3389/fendo.2022.901669. eCollection 2022.
Ghrelin, a stomach-produced hormone, is well-recognized for its role in promoting feeding, controlling energy homeostasis, and glucoregulation. Ghrelin's function to ensure survival extends beyond that: its release parallels that of corticosterone, and ghrelin administration and fasting have an anxiolytic and antidepressant effect. This clearly suggests a role in stress and anxiety. However, most studies of ghrelin's effects on anxiety have been conducted exclusively on male rodents. Here, we hypothesize that female rats are wired for higher ghrelin sensitivity compared to males. To test this, we systematically compared components of the ghrelin axis between male and female Sprague Dawley rats. Next, we evaluated whether anxiety-like behavior and feeding response to endogenous or exogenous ghrelin are sex divergent. In line with our hypothesis, we show that female rats have higher serum levels of ghrelin and lower levels of the endogenous antagonist LEAP-2, compared to males. Furthermore, circulating ghrelin levels were partly dependent on estradiol; ovariectomy drastically reduced circulating ghrelin levels, which were partly restored by estradiol replacement. In contrast, orchiectomy did not affect circulating plasma ghrelin. Additionally, females expressed higher levels of the endogenous ghrelin receptor GHSR in brain areas involved in feeding and anxiety: the lateral hypothalamus, hippocampus, and amygdala. Moreover, overnight fasting increased GHSR expression in the amygdala of females, but not males. To evaluate the behavioral consequences of these molecular differences, male and female rats were tested in the elevated plus maze (EPM), open field (OF), and acoustic startle response (ASR) after three complementary ghrelin manipulations: increased endogenous ghrelin levels through overnight fasting, systemic administration of ghrelin, or blockade of fasting-induced ghrelin signaling with a GHSR antagonist. Here, females exhibited a stronger anxiolytic response to fasting and ghrelin in the ASR, in line with our findings of sex differences in the ghrelin axis. Most importantly, after GHSR antagonist treatment, females but not males displayed an anxiogenic response in the ASR, and a more pronounced anxiogenesis in the EPM and OF compared to males. Collectively, female rats are wired for higher sensitivity to fasting-induced anxiolytic ghrelin signaling. Further, the sex differences in the ghrelin axis are modulated, at least partly, by gonadal steroids, specifically estradiol. Overall, ghrelin plays a more prominent role in the regulation of anxiety-like behavior of female rats.
胃饥饿素是一种由胃产生的激素，其作用是促进进食、控制能量平衡和糖调节，这一点已得到广泛认可。胃饥饿素的作用不仅限于此：它的释放与皮质酮的释放平行，给予胃饥饿素和禁食会产生抗焦虑和抗抑郁作用。这清楚地表明它在应激和焦虑中发挥作用。然而，大多数关于胃饥饿素对焦虑影响的研究仅在雄性啮齿动物中进行。在这里，我们假设雌性大鼠对胃饥饿素的敏感性高于雄性大鼠。为了验证这一点，我们系统地比较了雄性和雌性 Sprague Dawley 大鼠之间的胃饥饿素轴的各个组成部分。接下来，我们评估了内源性或外源性胃饥饿素引起的焦虑样行为和进食反应是否存在性别差异。与我们的假设一致，我们发现与雄性大鼠相比，雌性大鼠的血清胃饥饿素水平更高，内源性拮抗剂 LEAP-2 水平更低。此外，循环胃饥饿素水平部分依赖于雌二醇；卵巢切除术大大降低了循环胃饥饿素水平，而雌二醇替代部分恢复了循环胃饥饿素水平。相比之下，睾丸切除术并不影响循环血浆胃饥饿素。此外，雌性大鼠在参与进食和焦虑的脑区中表达更高水平的内源性胃饥饿素受体 GHSR：外侧下丘脑、海马体和杏仁核。此外，夜间禁食会增加雌性大鼠杏仁核中的 GHSR 表达，但不会增加雄性大鼠的表达。为了评估这些分子差异的行为后果，雄性和雌性大鼠在经过三种互补的胃饥饿素处理后进行了高架十字迷宫（EPM）、旷场（OF）和听觉惊跳反应（ASR）测试：通过夜间禁食增加内源性胃饥饿素水平，全身给予胃饥饿素，或用 GHSR 拮抗剂阻断禁食诱导的胃饥饿素信号。在这里，雌性大鼠在 ASR 中对禁食和胃饥饿素表现出更强的抗焦虑反应，这与我们在胃饥饿素轴中发现的性别差异一致。最重要的是，在给予 GHSR 拮抗剂后，只有雌性大鼠而不是雄性大鼠在 ASR 中表现出焦虑反应，并且在 EPM 和 OF 中比雄性大鼠表现出更明显的焦虑发作。总的来说，雌性大鼠对禁食诱导的抗焦虑胃饥饿素信号更敏感。此外，胃饥饿素轴的性别差异至少部分受到性腺类固醇的调节，特别是雌二醇。总之，胃饥饿素在调节雌性大鼠的焦虑样行为方面发挥着更重要的作用。
