Insulin-Like Growth Factor (IGF) 2 Stimulates Steroidogenesis and Mitosis of Bovine Granulosa Cells Through the IGF1 Receptor: Role of Follicle-Stimulating Hormone and IGF2 Receptor1

Abstract

Little is known regarding the role of insulin-like growth factor 2 (IGF2) and the regulation of the IGF2 receptor (IGF2R) during follicular development. Granulosa cells were collected from small (1-5 mm) and large (8-22 mm) bovine follicles and were treated with IGF2 for 1-2 days in serum-free medium, and steroid production, cell proliferation, specific 125 I-IGF2 binding, and gene expression were quantified. IGF2 increased both estradiol and progesterone production by granulosa cells, and cells from large follicles were more responsive to the effects of IGF2 than those from small follicles. Abundance of aromatase (CYP19A1) mRNA was stimulated by IGF2 and IGF1. The effective dose (ED 50 ) of IGF2 stimulating 50% of the maximal estradiol production was 63 ng/ml for small follicles and 12 ng/ ml for large follicles, and these values were not affected by FSH. The ED 50 of IGF2 for progesterone production was 20 ng/ml for both small and large follicles. IGF2 also increased proliferation of granulosa cells by 2-to 3-fold, as determined by increased cell numbers and 3 H-thymidine incorporation into DNA. Treatment with IGF1R antibodies reduced the stimulatory effect of IGF2 and IGF1 on estradiol production and cell proliferation. Specific receptors for 125 I-IGF2 existed in granulosa cells, and 2-day treatment with estradiol, FSH, or cortisol had no significant effect on specific 125 I-IGF2 binding. Also, FSH treatment of small-and large-follicle granulosa cells had no effect on IGF2R mRNA levels, whereas IGF1 decreased IGF2R mRNA and specific 125

Nutritional sensitivity of fifth instar prothoracic glands in the tobacco hornworm, Manduca sexta

“…More recently, IGF2 has also been shown to stimulate estradiol and progesterone secretion by granulosa cells (Spicer and Aad, 2007). There is also evidence of insulin/IGFs influencing steroidogenesis in other mammalian glands such as the adrenals.…”

Seasonal effects on the response of ovarian follicles to IGF1 in mares

“…Considering the role of IGF2R in regulating IGF2 bioavailability in the follicle, the present results suggest that the ability of IGF2 to activate IGF1R may be impaired in transitional follicles relative to ovulatory follicles. Although the effects of IGF1 injection on IGF2R were not determined in this study, IGF2R expression in bovine granulosa cells has been shown to decrease in response to IGF1 (Spicer & Aad 2007).…”

“…The expression levels of IGF2R, FSHR and LHCGR in granulosa cells were determined because the responses of follicular cells to IGF1 may depend, at least in part, on their concurrent responsiveness to IGF2 (Spicer & Aad 2007) and gonadotrophins (Glister et al 2001). IGF2 is naturally produced in equine follicular cells , Watson et al 2004a) and IGF2 expression is lower during the transitional period than during the ovulatory season (Watson et al 2004a).…”

“…IGF2 is naturally produced in equine follicular cells , Watson et al 2004a) and IGF2 expression is lower during the transitional period than during the ovulatory season (Watson et al 2004a). IGF2 has been shown to promote bovine granulosa cell proliferation and steroidogenesis by binding to IGF1R (Spicer & Aad 2007). In contrast, IGF2 binding to IGF2R results in the inactivation of IGF2 (Delaine et al 2007).…”

“…Expression of IGF1R has been reported to change during antral follicle growth in sheep (Perks et al 1995) whereas changes in IGF1R have been reported in theca cells but not granulosa cells during growth of bovine follicles (Stewart et al 1996, Armstrong et al 2000, Llewellyn et al 2007). In addition to IGF1, IGF2 is found in equine follicular fluid and can bind and activate IGF1R (Spicer & Aad 2007). IGF2 activity is negatively regulated by IGF2 binding to a second receptor, IGF2R (Delaine et al 2007).…”