Elucidating extragonadal functions of follicle stimulating hormone using genetic approaches in mice

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According to the U.S. Census Bureau, the number of Americans aged 65 or older will rise to over 71 million by the year 2030. Among the major health challenges faced by individuals as they age are osteoporosis, obesity, and metabolic diseases. Although considerable progress has been made in developing interventions, including drugs, to prevent or treat these conditions, the development of new therapeutic strategies to mitigate bone loss and metabolic dysfunction could have a major impact on the overall health of our elderly population. One signaling molecule that has an important role in regulating both bone density and metabolic function is follicle stimulating hormone (FSH), which is a key component of the ovarian-pituitary reproductive axis. FSH, which is a hormone that signals through a G protein-coupled receptor, is made by gonadotrophs in the anterior pituitary gland and acts on support cells in the ovary to regulate folliculogenesis. FSH has effects on other tissues as well, and understanding the precise physiological mechanisms underlying the extragonadal functions of this hormone will be critical for developing the most effective strategies to target this signaling pathway for clinical applications. Among the extragonadal tissues affected by FSH are bone and adipose tissue. Seminal studies from the laboratories of Mone Zaidi and Clifford Rosen showed that systemic inhibition of FSH signaling in mice can cause increases in bone mass, reduced adiposity, increased beiging of white adipocytes, and increased energy expenditure. Based on the findings that the FSH receptor (FSHR) is expressed by osteoclasts and by adipocytes and that both of these cell types are responsive to FSH in vitro, these extragonadal effects of blocking FSH have been proposed to result from loss of FSH signaling directly to these tissues. Although these findings are consistent with a direct role for FSH signaling in these tissues, definitive studies demonstrating that FSH directly regulates these cell types in vivo have not yet been reported. Here, we will take a genetic approach to elucidate the physiological mechanisms underlying the extragonadal functions of FSH, specifically on bone and adipose tissue. The overall question that we will be addressing is whether effects of FSH on these tissues are mediated by direct signaling to those tissues or whether these are secondary effects of signaling to other tissues. Our general approach will be to use a knock-in mouse line that we have generated carrying a conditional Fshr flox allele in order to target FSH signaling in specific cell types. The Specific Aims of this project are to determine the effects of targeting Fshr (1) in adipocytes, (2) in osteoclasts, and (3) in a regionally-restricted manner in the body. Taken together, we believe that these studies will provide key insights into the physiological mechanisms underlying the regulation of extragonadal tissues by FSH. We believe that these studies are significant in that the findings will potentially have implications for the development of strategies to modulate signaling by FSH for a wide range of clinical applications characterized by metabolic dysfunction and bone loss, especially in the elderly.