Investigating the role of PRDM16 in enteroendocrine cell differentiation and response to nutritional change in the small intestinal epithelium

The intestinal epithelium consists of specialized cell populations essential for the uptake of vital nutrients from food and the secretion of mucous, hormones, and antimicrobial factors. A small population of hormone-producing enteroendocrine cells (EECs), which comprise only ~1% of the intestinal epithelium, are crucial for maintaining endocrine homeostasis. There are different types of EECs: serotonin-producing enterochromaffin cells that regulate gastrointestinal motility, insulin release, and inflammation, and non-enterochromaffin cells, which produce various other hormones that regulate glucose metabolism, appetite, and satiety. Dysregulated EEC function contributes to several metabolic and gastrointestinal diseases, including obesity, type 2 diabetes, and inflammatory bowel disease. Moreover, while EECs are present throughout the stomach and small and large intestines, the types and functions of EECs differ depending on their location along the digestive tract. However, there is still a limited understanding of how the differentiation, regional distribution, and function of these cells are controlled. A recent study focusing on EEC differentiation identified selective expression of the transcription factor PRDM16 along the enteroendocrine cell differentiation trajectory. PRDM16 is a zinc finger-containing transcription factor highly expressed in the proximal small intestine. Preliminary data from our lab show that Prdm16 deletion, specifically within the EEC lineage, strongly decreased the expression of many enterochromaffin cell marker genes. PRDM16 is a known regulator of fatty acid oxidation and mitochondrial biogenesis in several cell types, including the intestinal epithelium. EECs are essential for sensing changes in nutrients and respond by secreting hormones that allow for adaptation to different dietary changes. For example, EEC composition and function can change in response to increased fat absorption during a high-fat diet. Given PRDM16’s regional expression in the small intestine and its known role regulator as a of fatty acid oxidation, this gene could mediate the pathways involved in fat metabolism in the EEC lineage and regulate the differentiation trajectory of EECs in a region-specific manor. Therefore, I will investigate the role of PRDM16 during the development of the EEC lineage and determine how PRDM16 mediates the response of mature EECs to changes in dietary nutrients. A T32 HD083185 Award to NW, a K01 from NIDDK to RS, a Pilot and Feasibility Grant to RS from the CMSDLD, and a Pilot and Feasibility Award to RS from the PennCHOP Microbiome Center. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.