Metabolic Events Controlling Ovarian Steroidogenesis

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The secretion of progesterone is a primary function of the corpus luteum (CL) and a prerequisite for normal maintenance of pregnancy in all mammals. The coordinated differentiation of granulosa cells (GC) and theca cells (TC) into a functional CL is required for fertility. The single most important factor involved in regulating the secretion of progesterone in the CL, irrespective of species, is luteinizing hormone (LH). This pituitary gonadotropin induces luteinization of GC and TC, formation of the CL, and is capable of extending the functional life span of the CL. Secretion of progesterone is absolutely required for establishment and maintenance of pregnancy and inadequate progesterone secretion contributes to early pregnancy loss in women and cattle, the two model systems employed in this project. Despite substantial scientific progress achieved in understanding the initial events leading to the differentiation of granulosa cells, little is known about the differentiation of theca cells into functional luteal cells. This incomplete knowledge interferes with the development of novel therapeutic interventions to enhance CL function (steroidogenesis), provide contraception, and ultimately to control fertility. Recent developments in other fields of research have shed light on the composition and role of intracellular lipid droplets as dynamic contributors to metabolic events and disease states. These understudied organelles are prominent components of steroidogenic cells but almost nothing is known about their role in the ovary. Despite their differences, both GC and TC accumulate lipid droplets (LD) during CL formation, presumptively for storage of the steroid precursor, cholesterol, and cellular energy in the form of fatty acids. The composition and precise function of LDs likely differs between these two cells because of their unique origins and functions. There is a gap in our knowledge of the formation, composition, and function of LDs in ovarian steroidogenic cells. This proposal will test the hypothesis that LDs provide a metabolic or hormone-sensitive organelle which can provide cellular energy and/or store and mobilize substrate for progesterone synthesis. We will employ state-of-the-art lipidomic, metabolomics and proteomic analysis to examine LDs and metabolic events driven by LH in differentiating bovine granulosa cells and theca cells and human granulosa-luteal cells. Experiments will determine the role of protein kinase A (PKA) and adenosine monophosphate activated protein kinase (AMPK) in controlling cellular metabolic activities that either enhance or inhibit progesterone synthesis. Our long-term objectives are to fully understand the cellular mechanisms of action of gonadotropins and the regulation of steroidogenesis. The short-term goals of this research are to discover new signaling events initiated by LH and to determine how these novel mechanisms contribute to innovative strategies for enhancing progesterone synthesis, fertility, and contraception.