Adult stem cells play a vital role in tissue homeostasis and damage repair, and changes in diet, stress level and age affect many tissues through hormonal changes. Research on intrinsic and local niche factors have shed light on how stem cells are regulated, yet much less is known about how an organism's physiological state influences the function of stem cells and their progeny. Pioneering studies from our lab demonstrated that Drosophila ovarian stem cells and their progeny respond to diet via multiple nutrient sensing pathways. For example, our early studies revealed that insulin-like peptides (ILPs) directly regulate germline stem cell proliferation (GSC), cyst growth and vitellogenesis, and indirectly control GSC maintenance via the niche. More recently, our lab showed that ecdysone and Target of rapamycin (TOR) are required for GSC maintenance and proliferation while TOR also regulates follicle stem cell proliferation but not maintenance. Nevertheless, it is likely that nutrient sensing pathways act on multiple tissues in addition to the ovary, and that other tissues communicate their nutritional status to the ovary to further tailor the response of ovarian stem cells to changes in whole body physiology. The role of multi-organ communication in the dietary response of stem cells, however, remains a largely understudied question. The overarching goal of this proposal is to address how nutrient sensing by the adipose tissue modulates ovarian stem cell lineages. The mammalian adipose tissue and Drosophila fat body (composed of adipocytes and hepatocyte-like oenocytes) are sensitive to nutrients, and have energy storage and endocrine roles. For example, amino acid sensing via the TOR pathway in the Drosophila larval fat body controls organismal growth in part through the production of a factor that induces secretion of ILPs from the brain. Fat body-conditioned media support imaginal disc growth and the larval fat body induces neuroblast proliferation in vitro and in vivo. Little is known, however, regarding the function of adult adipocytes in ovarian stem cell regulation. We hypothesize that nutrient sensing by Drosophila fat body adipocytes results in changes in circulating factors produced by fat cells, which in turn regulate the response of ovarian stem cells and their descendants to diet. We will test this hypothesis by determining if insulin, TOR or ecdysone signaling act within adipocytes to remotely modulate ovarian stem cells (Aim 1) and by identifying diet-dependent fat body factors that transmits dietary information to the ovary (Aim 2).
Our focus on the role of adipocytes in adult stem cell regulation is highly relevant to the current obesity epidemic and to the poorly understood link between obesity and cancers, which share self-renewal properties and key signaling pathways with stem cells. Given that normal stem cells and cancer cells are diet-responsive and have a large proliferative potential, information about this under-explored dimension of stem cell regulation can potentially inspire novel stem cell-based therapies or treatments targeting cancerous cells.