Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets

Abstract

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet β-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Atlas of Fshr Expression from Novel Reporter Mice

“…In addition, our finding of Fshr expression in adipose tissues is consistent with the observations from previous works 12 , 72 . Recently, Fshr expression was reported to be present in -cells of the pancreas to regulate glucosestimulated insulin secretion, further supporting our findings of the Fshr expression pattern 73 .…”

Metabolic hormones are integral regulators of female reproductive health and function

“…For instance: While this review highlights effects of metabolic hormones on reproductive function, lines of communication between metabolic tissues and the reproductive system are bidirectional, and merit further study. For example, FSH was recently shown to regulate insulin secretion via FSH receptors expressed in pancreatic islets [ 605 ], and gonadal steroid hormones contribute towards sexual dimorphism in energy partitioning and metabolic homeostasis [ 8–10 , 606 ]. Exogenous hormonal contraceptives cause metabolic changes [ 607–609 ], and conversely, the presence of diabetes, obesity, and/or other metabolic disorders has implications for the systemic impacts of hormonal contraceptives [ 610 , 611 ].…”

“…While this review highlights effects of metabolic hormones on reproductive function, lines of communication between metabolic tissues and the reproductive system are bidirectional, and merit further study. For example, FSH was recently shown to regulate insulin secretion via FSH receptors expressed in pancreatic islets [ 605 ], and gonadal steroid hormones contribute towards sexual dimorphism in energy partitioning and metabolic homeostasis [ 8–10 , 606 ].…”

FSH regulates glucose‐stimulated insulin secretion: A bell‐shaped curve effect

“…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][5][6][7] However, limited research has been focused on the effect of FSH on metabolism.…”

“…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 …”