Follicle-stimulating hormone (FSH), a classical hormone derived from the pituitary, primarily affects the gonads and regulates the reproductive process.¹ FSH consists of an α and a β subunit, with the β subunit specifically binding to its G protein-coupled receptor (GPCR), FSHR.² The FSHR mediates the transduction of the FSH-induced signal. According to the recent work published in Nature Communications, FSH, through its receptor, regulates glucose-stimulated insulin secretion (GSIS) in pancreatic islets, and high levels of FSH play important roles in postmenopausal diabetes in females.³

An increasing body of evidence has demonstrated that FSH and its receptor FSHR also have extragonadal effects, including the regulation of fat accumulation, bone mass, and cognitive function.^4-7 However, limited research has been focused on the effect of FSH on metabolism. The pancreas is an important endocrine organ in regulating glucose metabolism. First, the authors explored whether FSHR was expressed in pancreas. They identified the expression of FSHR in human pancreas, mouse pancreatic islets, and the mouse insulinoma cell line MIN6. The expression of FSHR in pancreatic islets strongly suggests an association between FSHR and the endocrine function. In order to explore the function of FSH and FSHR on pancreatic islets, the authors established a conventional Fshr^−/−(knockout [KO]) mouse model. Blocking FSH signaling through Fshr KO resulted in impaired glucose tolerance. In this model, Fshr KO led to an increase in serum FSH levels as well as a decrease in serum estrogen levels. Females with Fshr KO administrated with estrogen also displayed impaired glucose tolerance. Furthermore, the authors generated a mouse model with specific deletion of Fshr in the pancreas (Fshr CKO), which showed no significant alterations in serum FSH and estrogen levels. Similarly, female Fshr CKO mice exhibited impaired glucose tolerance. The phenotype of glucose intolerance was also observed in male mice with Fshr KO and CKO male mice.

Glucose intolerance is primarily caused by impaired insulin secretion and action. The authors evaluated peripheral insulin action and found there was no significant insulin resistance in Fshr KO and CKO mice. However, decreased insulin secretion was observed in Fshr KO and CKO mice. In vitro, treatment of mouse pancreatic islets and MIN6 cells with FSH did not result in any significant changes in Ins1 and Ins2 mRNA levels or insulin content, suggesting that the effect of FSH on glucose tolerance was due to insulin secretion, not insulin synthesis. Interestingly, the authors discovered that FSH alone, in the absence of glucose, did not stimulate insulin secretion. FSH regulated GSIS in a bell curve manner. FSH promoted GSIS as FSH levels increased within the range of <10 IU/L. However, the promoting effect on GSIS was inhibited as FSH levels increased beyond 10 IU/L.

Typically, the FSHR has been shown to directly activate G proteins, thereby intensifying the FSH signal action.⁸ Previous studies have shown that G proteins mediate the activation of various signaling pathways, including Gαs/cyclic adenosine monophosphate (cAMP) and intracellular Ca²⁺-related signaling.⁹ Interestingly, cAMP and intracellular Ca²⁺ signals play a crucial role in the exocytosis of insulin granules.^{10, 11} In vitro, FSH at concentrations <10 IU/L significantly increased the intracellular cAMP levels, protein kinase A (PKA) activity, and intracellular Ca²⁺ level in a concentration-dependent manner. However, high concentrations of FSH (10–100 IU/L) decreased the intracellular cAMP levels, PKA activity, and intracellular Ca²⁺ levels in a dose-dependent way.

FSHR regulates intracellular cAMP levels by coupling with Gαs or Gαi protein in gonadal cells.^{8, 11} In the absence of FSH, Gαs and Gαi inhibitors did not affect insulin secretion and intracellular cAMP levels. At low FSH (10 IU/L) or high FSH (100 IU/L), the Gαs inhibitor led to a significant decrease in insulin secretion and intracellular cAMP content. However, Gαi inhibitor increases insulin secretion and intracellular cAMP levels only under 16.7 mM glucose with 100 IU/L FSH. Originally, it was thought that each GPCR signals through a single cognate G protein class to initiate the “canonical” signaling of the receptor. However, some studies have also shown that receptors can couple to more than one Gα protein to initiate noncanonical GPCR signaling.¹² The authors showed that FSHR might simultaneously couple with Gαs and Gαi proteins, depending on FSH levels.

This noncanonical FSHR signaling pattern may help explain the bell curve effect of FSH on GSIS. Previous studies have reported that high FSH levels in postmenopausal women are associated with bone loss, visceral adiposity, and cognitive impairment. In this study, the authors uncovered a critical extragonadal role of FSH in the regulation of GSIS in pancreatic islets. The bell curve effect suggests that FSH has dual effects. Before perimenopause, low levels of FSH promote an increase in GSIS. However, this promoting effect is inhibited during high FSH levels. Furthermore, the authors established an ovariectomized (OVX) mouse model to mimic the hormonal status of postmenopausal women. In OVX mice, both FSH and luteinizing hormone (LH) increased and estrogen decreased. The OVX mice were administered the gonadotropin-releasing hormone agonist (GnRHa) to reduce FSH and LH levels. Subsequently, OVX + GnRHa mice were injected with exogenous FSH to mimic postmenopausal high serum FSH levels and given estrogen to maintain relatively normal serum estrogen levels. In the OVX model, the authors demonstrated that high levels of FSH alone result in impaired glucose tolerance and insulin secretion.

In summary, this study not only reports the expression of FSHR on pancreatic islets but also characterizes the novel role of FSH as a dual regulator of GSIS. FSH regulates GSIS through the FSHR-Gαs/Gαi-intracellular cAMP and Ca²⁺ signaling pathway (Figure 1). Future research is necessary to identify the molecular targets that can block FSH signaling, which will provide new avenues for therapeutic strategies of postmenopausal diabetes.

卵泡刺激素（FSH）是一种源自垂体的经典激素，主要影响性腺并调节生殖过程。¹ FSH 由 α 和 β 亚基组成，其中 β 亚基与其 G 蛋白偶联受体 (GPCR) FSHR 特异性结合。² FSHR 介导 FSH 诱导信号的转导。根据最近发表在《Nature Communications》上的研究成果，FSH通过其受体调节胰岛中葡萄糖刺激的胰岛素分泌（GSIS），高水平的FSH在女性绝经后糖尿病中发挥着重要作用。³

越来越多的证据表明，FSH 及其受体 FSHR 还具有性腺外作用，包括调节脂肪积累、骨量和认知功能。^4-7然而，关于 FSH 对新陈代谢的影响的研究有限。胰腺是调节糖代谢的重要内分泌器官。首先，作者探讨了 FSHR 是否在胰腺中表达。他们鉴定了 FSHR 在人胰腺、小鼠胰岛和小鼠胰岛素瘤细胞系 MIN6 中的表达。胰岛中 FSHR 的表达强烈表明 FSHR 与内分泌功能之间存在关联。为了探索FSH和FSHR对胰岛的功能，作者建立了传统的Fshr ^−/−（基因敲除[KO]）小鼠模型。通过 Fshr KO 阻断 FSH 信号传导会导致葡萄糖耐量受损。在该模型中，Fshr KO 导致血清 FSH 水平升高以及血清雌激素水平降低。给予 Fshr KO 并给予雌激素的女性也表现出葡萄糖耐量受损。此外，作者还建立了一个胰腺中 Fshr 特异性缺失的小鼠模型（Fshr CKO），该模型显示血清 FSH 和雌激素水平没有显着变化。同样，雌性 Fshr CKO 小鼠表现出葡萄糖耐量受损。在 Fshr KO 和 CKO 雄性小鼠的雄性小鼠中也观察到了葡萄糖不耐症的表型。

葡萄糖不耐受主要是由胰岛素分泌和作用受损引起的。作者评估了外周胰岛素的作用，发现 Fshr KO 和 CKO 小鼠没有明显的胰岛素抵抗。然而，在 Fshr KO 和 CKO 小鼠中观察到胰岛素分泌减少。在体外，用 FSH 处理小鼠胰岛和 MIN6 细胞不会导致 Ins1 和 Ins2 mRNA 水平或胰岛素含量发生任何显着变化，这表明 FSH 对糖耐量的影响是由于胰岛素分泌，而不是胰岛素合成。有趣的是，作者发现，在没有葡萄糖的情况下，单独使用 FSH 并不能刺激胰岛素分泌。 FSH 以钟形曲线方式调节 GSIS。当 FSH 水平在 <10 IU/L 范围内增加时，FSH 会促进 GSIS。然而，当 FSH 水平超过 10 IU/L 时，对 GSIS 的促进作用受到抑制。

通常，FSHR 已被证明可以直接激活 G 蛋白，从而增强 FSH 信号作用。⁸先前的研究表明，G 蛋白介导多种信号传导途径的激活，包括 Gαs/环磷酸腺苷 (cAMP) 和细胞内 Ca ²⁺相关信号传导。⁹有趣的是，cAMP 和细胞内 Ca ²⁺信号在胰岛素颗粒的胞吐作用中发挥着至关重要的作用。^{10, 11}在体外，浓度<10 IU/L 的FSH以浓度依赖性方式显着增加细胞内cAMP 水平、蛋白激酶A (PKA) 活性和细胞内Ca ²⁺水平。然而，高浓度的 FSH (10–100 IU/L) 会以剂量依赖性方式降低细胞内 cAMP 水平、PKA 活性和细胞内 Ca ^2+水平。

FSHR 通过与性腺细胞中的 Gαs 或 Gαi 蛋白偶联来调节细胞内 cAMP 水平。^{8, 11}在没有 FSH 的情况下，Gαs 和 Gαi 抑制剂不会影响胰岛素分泌和细胞内 cAMP 水平。在低 FSH (10 IU/L) 或高 FSH (100 IU/L) 时，Gαs 抑制剂导致胰岛素分泌和细胞内 cAMP 含量显着降低。然而，Gαi 抑制剂仅在 16.7 mM 葡萄糖和 100 IU/L FSH 的情况下增加胰岛素分泌和细胞内 cAMP 水平。最初，人们认为每个 GPCR 通过单个同源 G 蛋白类别发出信号来启动受体的“规范”信号传导。然而，一些研究还表明受体可以与多个 Gα 蛋白偶联以启动非经典 GPCR 信号传导。¹²作者表明，FSHR 可能同时与 Gαs 和 Gαi 蛋白偶联，具体取决于 FSH 水平。

这种非典型的 FSHR 信号模式可能有助于解释 FSH 对 GSIS 的钟形曲线效应。先前的研究报告称，绝经后女性的高 FSH 水平与骨质流失、内脏肥胖和认知障碍有关。在这项研究中，作者发现了 FSH 在调节胰岛 GSIS 中的关键性腺外作用。钟形曲线效应表明 FSH 具有双重作用。围绝经期之前，低水平的 FSH 会促进 GSIS 的增加。然而，当 FSH 水平较高时，这种促进作用会受到抑制。此外，作者建立了卵巢切除（OVX）小鼠模型来模拟绝经后妇女的激素状态。在 OVX 小鼠中，FSH 和黄体生成素 (LH) 均增加，雌激素减少。给 OVX 小鼠注射促性腺激素释放激素激动剂 (GnRHa) 以降低 FSH 和 LH 水平。随后，OVX + GnRHa 小鼠被注射外源 FSH 以模拟绝经后高血清 FSH 水平，并给予雌激素以维持相对正常的血清雌激素水平。在 OVX 模型中，作者证明，单独高水平的 FSH 会导致糖耐量和胰岛素分泌受损。

总之，本研究不仅报告了胰岛上 FSHR 的表达，还表征了 FSH 作为 GSIS 双重调节因子的新作用。 FSH 通过 FSHR-Gαs/Gαi-细胞内 cAMP 和 Ca ²⁺信号通路调节 GSIS（图 1）。未来的研究有必要确定可以阻断 FSH 信号传导的分子靶点，这将为绝经后糖尿病的治疗策略提供新途径。