In this Mentored Career Development Award (K23) proposal, this candidate proposes to solidify a basic science foundation and clinical research acquired during his PhD and post-doctoral work with a long-term goal of becoming an academic authority in enteroendocrine L-cell regulation of satiety in obesity. The candidate aims to acquire a strong foundation in clinical translation science and to acquire a set of novel complementary skills necessary for an independent research career in gastrointestinal regulation of food intake. Understanding pathophysiology of human obesity is limited by the heterogeneity of patients' phenotype and multiple etiological mechanisms. These factors contribute to the highly variable inter-individual weight loss response to all interventions. Recently, we identified a sub-population of obesity with significantly decreased satiety (defined as lack of sensation of feeling full or rapid return of hunger). Our preliminary data shows that, in addition to decreased perception of fullness after a meal, these individuals, compared to other obesity phenotypes, have very low postprandial levels of the GI satiety hormones GLP-1 and PYY which are secreted by enteroendocrine (EE) L-cells. The low levels of the satiety hormone PYY and possibly other EE cell products suggests that the increased calorie intake originates from a deficit in the gut hormones, and this phenotype is summarized as a ?hungry gut?. The suboptimal EE cell function, which could be mediated by altered synthesis or secretion by the EE cells themselves, or a decrease in luminal concentrations of molecules that normally stimulate EE cells, such as amino acids, bile acids, or short-chain fatty acids. Our preliminary results also suggest that these individuals have lower levels of FGF-19, a surrogate of the luminal bile acid concentration. Based on these preliminary studies, it is essential to understand the mechanisms that are responsible for the deficient EE signals that lead to the ?hungry gut? phenotype of obesity. To test this concept, we propose the following two aims: 1) to study the mechanism of the hungry gut phenotype down to the level of the EE cells, and compare these findings to other obesity phenotypes and normal weight, healthy controls. 2) To restore normal satiety by increasing enteroendocrine cell function and secretion in patients after Roux-in-y gastric bypass surgery or in response to treatment with luminal bile acids. These findings will provide the foundation for further studies of the ?hungry gut? phenotype in a future R01 application. This work will be performed in an academically nurturing environment within Mayo Clinic and with full support of the Division of Gastroenterology. The candidate will be guided by a strong mentorship committee (Drs. Michael Camilleri, Nicholas LaRusso and Adrian Vella). As a result of this work, the candidate will significantly advance our understanding of EE cell function in human obesity and develop his career into an independent physician scientist.
The prevalence of obesity continues to increase worldwide and, in the United States, 69% of adults are overweight or obese, and patients with obesity feel less full than normal weight people. The goal of this proposal is to understand why the sensation of fullness (satiety) is abnormal in obesity and whether this abnormality can be corrected to treat obesity; therefore, we propose to answer this question by studying obese patients with normal satiety and abnormal satiety and then study a key cell in our intestinal mucosa that regulate satiety, assuming that function of these cells, known as L-cells, is reduced in obesity. This work will attempt to understand the mechanisms behind the reduced L-cells function by using novel techniques to study them independently from other cells in the intestinal mucosa as well as use novel agents to restore their function.
