Project Description Obesity and type 2 diabetes are increasing at an alarming rate in the United States and warrants novel drug targets to culminate these diseases. Gut derived hormone glucagon like peptide-1 (GLP-1) improves glucose homeostasis and offers great promises as therapeutic target for obesity and type 2 diabetes. The mechanisms that regulate intestinal GLP-1 secretion are not clear. The function of intestine is dynamically regulated by intestinal oxygenation. Low oxygen induces a hypoxic response mediated by the transcription factors namely hypoxia inducible factor (HIF). The critical role of HIF signaling in inflammation, iron homeostasis, and cancers has been well documented; however, its metabolic role is not well understood. Using genetic model, we reveal that constitutive activation of intestinal hypoxia signaling improves glucose tolerance due to augmented GLP-1 levels. The research focus of this application lies at the intersection between intestinal hypoxia signaling and GLP-1 in the regulation of glucose homeostasis. Our central hypothesis states that intestinal hypoxia signaling plays a key role in systemic glucose homeostasis by regulating GLP-1 secretion. We propose a combination of complimentary in vitro and in vivo mouse studies designed to test the following hypothesis: 1) intact intestinal hypoxia signaling is essential for systemic glucose homeostasis; 2) intestinal hypoxia signaling regulates glucose metabolism through GLP-1 dependent mechanism; and 3) targeting HIF signaling ameliorates glucose intolerance. During the K99 phase of this program, Drs. Shah and Seeley in the Department of Molecular and Integrative Physiology and Department of Surgery, respectively, will provide mentorship to the applicant. The career development activities will take advantage of the exceptional research environment and resources at the University of Michigan, and will be facilitated by the guidance of the highly motivated Advisory Committee of the applicant that includes Drs. Omary, Rui and Lee, in addition to the co-mentors. The applicants experience in several areas such as conceptual knowledge, research skills, leadership and lab management, effective communication, and mentoring young scientists will be strengthened through various training activities as detailed in applicants Career development activity.