From an Empty Stomach to Anxiolysis: Molecular and Behavioral Assessment of Sex Differences in the Ghrelin Axis of Rats.
From an Empty Stomach to Anxiolysis: Molecular and Behavioral Assessment of Sex Differences in the Ghrelin Axis of Rats.
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DOI：
10.3389/fendo.2022.901669
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发表时间：
2022
影响因子：
5.2
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胃促生长素是一种胃内分泌的激素，在促进摄食、控制能量平衡和血糖调节方面的作用已被广泛认可。生长激素释放肽的功能，以确保生存延伸到：它的释放平行的皮质酮，和生长激素释放肽管理和禁食有抗焦虑和抗抑郁作用。这清楚地表明了压力和焦虑的作用。然而，大多数关于胃饥饿素对焦虑影响的研究都是专门针对雄性啮齿动物进行的。在这里，我们假设雌性大鼠与雄性大鼠相比具有更高的胃饥饿素敏感性。为了验证这一点，我们系统地比较了雄性和雌性Sprague道利大鼠之间的ghrelin轴的组成部分。接下来，我们评估了焦虑样行为和对内源性或外源性生长激素释放肽的摄食反应是否存在性别差异。在符合我们的假设，我们表明，雌性大鼠有较高的血清水平的生长激素释放肽和较低水平的内源性拮抗剂LEAP-2，与男性相比。此外，循环生长激素释放肽水平部分依赖于雌二醇;卵巢切除术大大降低循环生长激素释放肽水平，这部分恢复雌二醇替代。相反，睾丸切除术并不影响循环血浆ghrelin。此外，女性表达更高水平的内源性生长激素释放肽受体GHSR 1A在大脑区域参与喂养和焦虑：外侧下丘脑，海马和杏仁核。此外，整夜禁食增加女性杏仁核中GHSR 1A的表达，但不是男性。为了评估这些分子差异的行为后果，在高架十字迷宫（ESTA），开放领域（OF），和三个互补的生长激素释放肽操作后的声音惊吓反应（ASR）的雄性和雌性大鼠进行了测试：增加内源性生长激素释放肽水平通过过夜禁食，全身给药的生长激素释放肽，或封锁禁食诱导的生长激素释放肽信号与GHSR 1A拮抗剂。在这里，女性表现出更强的抗焦虑反应禁食和生长激素释放肽的ASR，符合我们的研究结果的性别差异生长激素释放肽轴。最重要的是，GHSR 1A拮抗剂治疗后，女性而非男性在ASR中显示出焦虑反应，并且与男性相比，在ESTA和OF中显示出更明显的焦虑反应。总的来说，雌性大鼠对禁食诱导的抗焦虑ghrelin信号更敏感。此外，生长激素释放肽轴的性别差异至少部分受到性腺类固醇（特别是雌二醇）的调节。总的来说，ghrelin在雌性大鼠焦虑样行为的调节中起着更突出的作用。
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 GHSR1A in brain areas involved in feeding and anxiety: the lateral hypothalamus, hippocampus, and amygdala. Moreover, overnight fasting increased GHSR1A 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 GHSR1A 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 GHSR1A 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.