Adult stem cells are required for tissue homeostasis and repair in response to damage. Nutrient availability, stress, age, infection, and other physiological changes affect the number and function of stem cells. For example, nutrient-dependent pathways act within the Drosophila ovary to regulate germline stem cells (GSCs), such that their numbers and proliferation are higher on yeast-rich versus -poor diets. Further, multiple endocrine organs likely communicate their nutritional status to other organs (such as the ovary) to influence the behavior and function of adult stem cell lineages. For example, our laboratory showed that reduced amino acid sensing within adipocytes (which co-exist with hepatocyte-like oenocytes in a nutrient-sensitive, endocrine organ termed fat body) contributes to the decrease in GSC number on a poor diet. The rise of obesity and associated diseases including cancers underscores the need for understanding how adipocytes regulate the function of other tissues within the body; however, the mechanisms whereby adipocytes influence adult stem cells in other organs remain underexplored. Nuclear receptors (NRs) are transcription factors that can act in diet dependent pathways to control stem cell lineages and metabolism. Obesity is a risk factor for cancer and obesity-related changes in adipose tissue and NR signaling are linked to this risk. NRs are commonly mutated in cancers, making these proteins potential targets for drug discovery. NRs also function within the ovarian stem cell lineages to regulate many processes. For example, the heterodimeric receptor composed of the Ecdysone Receptor (EcR) and Ultraspiracle (Usp) controls GSC maintenance and division, and differentiation of their GSC daughters. Ecdysone-induced protein 78C (E78) is required for establishment of proper GSC number and follicle viability, whereas Ecdysone-induced protein 75B (E75) is required for vitellogenesis. NR signaling within the larval fat body also controls developmental and metabolic processes. The mechanisms whereby NR signaling in adult adipocytes influences the GSC lineage, however, remain largely underexplored. We have evidence to suggest that NR signaling within adult adipocytes may relay nutritional information to the ovary. A previous proteomic analysis in our lab revealed that the levels of three nuclear receptors (Svp, HNF4, and HR4) are altered in adipocytes within 12 hours of dietary changes. Further, my preliminary results show that inhibition of Svp activity or ecdysone signaling in adult adipocytes reduces GSC numbers. Based on these data, I hypothesize that NR signaling within adult adipocytes leads to changes in key downstream factors to modulate the GSC lineage. I will test this hypothesis by determining how ecdysone signaling in adult adipocytes regulates GSCs and their progeny (Aim 1) and by identifying additional NRs that regulate GSCs in response to diet (Aim 2).
The rise of obesity and associated chronic diseases underscores the need for understanding how adipose tissue regulates the function of other tissues within the body; however, the mechanisms whereby adipocytes influence adult stem cells in other organs in response to diet remain underexplored. Normal and cancer cells are diet-responsive, have a large proliferative potential, and share similar signaling pathways. Therefore, understanding how stem cell function is controlled by physiological factors from adipocytes could provide insight to how adipocyte-stem cell regulation may be disrupted in cancers and suggest potential therapeutic targets.
| Weaver, Lesley N; Drummond-Barbosa, Daniela (2018) Maintenance of Proper Germline Stem Cell Number Requires Adipocyte Collagen in Adult Drosophila Females. Genetics 209:1155-1166 |
