Incretins modulate progesterone biosynthesis by regulating bone morphogenetic protein activity in rat granulosa cells

Yuki Nishiyama, Toru Hasegawa, Shiho Fujita, Nahoko Iwata, Satoko Nagao, Takeshi Hosoya, Kenichi Inagaki, Jun Wada, Fumio Otsuka

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of incretins on steroidogenesis, GIP and GLP-1 suppressed the expression of progesterogenic factors and enzymes, including StAR, P450scc, 3βHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. In addition, incretins moderately increased FSHR mRNA expression in granulosa cells. Of note, treatment with GIP, but not treatment with GLP-1, augmented Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1 induced by BMP-6 stimulation, suggesting that GIP upregulates BMP receptor signaling that can inhibit FSH-induced progesterone synthesis in rat granulosa cells. On the other hand, BMP-6 treatment suppressed the expression of GIP receptor but not that of GLP-1 receptor. Expression of the BMP type-I receptor ALK-3 was upregulated by treatment with GIP and GLP-1 and that of ALK-6 was also increased by GIP, while inhibitory Smad6 expression was impaired by GIP and GLP-1 in rat granulosa cells. Collectively, the results indicate that incretins, particularly GIP, impair FSH-induced progesterone production, at least in part, by upregulating BMP signaling in rat granulosa cells. The modulatory effects of incretins on endogenous BMP activity may be applicable to treatment of dysregulated steroidogenesis such as polycystic ovary syndrome.

Original languageEnglish
JournalJournal of Steroid Biochemistry and Molecular Biology
DOIs
Publication statusAccepted/In press - Jan 1 2017

Fingerprint

Incretins
Bone Morphogenetic Proteins
Granulosa Cells
Biosynthesis
Glucagon-Like Peptide 1
Progesterone
Rats
Bone Morphogenetic Protein 6
Type I Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein Receptors
Phosphorylation
Polycystic Ovary Syndrome
Transcription
Estrogens
Up-Regulation
Genes
Messenger RNA

Keywords

  • Bone morphogenetic protein (BMP)
  • Follicle-stimulating hormone (FSH)
  • Glucagon-like peptide (GLP)-1
  • Glucose-dependent insulinotropic polypeptide (GIP)
  • Granulosa cells
  • Incretins
  • Steroidogenesis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Incretins modulate progesterone biosynthesis by regulating bone morphogenetic protein activity in rat granulosa cells. / Nishiyama, Yuki; Hasegawa, Toru; Fujita, Shiho; Iwata, Nahoko; Nagao, Satoko; Hosoya, Takeshi; Inagaki, Kenichi; Wada, Jun; Otsuka, Fumio.

In: Journal of Steroid Biochemistry and Molecular Biology, 01.01.2017.

Research output: Contribution to journalArticle

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AU - Nagao, Satoko

AU - Hosoya, Takeshi

AU - Inagaki, Kenichi

AU - Wada, Jun

AU - Otsuka, Fumio

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