Mechanisms Regulating Neurotensin Secretion and Function

Neurotensin (NT) is a tridecapeptide localized to specialized enteroendocrine cell (N-cells) predominantly in the small bowel. The most potent stimulus for NT release is the ingestion of dietary fats. NT facilitates fatty acid absorption, stimulates growth of colorectal, pancreatic and breast cancers that have the high affinity NT receptor (NTR1), and contributes to lipid metabolism and glucose control although its precise role in this process has not been delineated. Recently, a large population study identified a significant association of increased fasting pro-NT levels with the development of diabetes, increased risk of cardiovascular disease and mortality, and increased risk of breast cancer in women. Together, these findings identify an important role for NT in lipid metabolism and, moreover, links increased NT levels to various metabolic diseases and increased morbidity and mortality. Epidemiological evidence clearly shows direct linkage between overnutrition and obesity; however, the molecular mechanisms linking adiposity to overnutrition remain unknown. In exciting preliminary findings, we demonstrate that NT deficiency (using an NT knockout mouse model) protects against obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD) associated with high fat consumption. Conversely, the overexpression of NT in Drosophila midgut enteroendocrine cells increases lipid accumulation in the midgut, fat body and oenocytes (hepatocyte-like cells). Therefore, our findings show, for the first time, that NT promotes the storage of ingested fats and directly links overnutrition to obesity, suggesting that the inhibition of NT signaling may represent a novel therapeutic strategy for anti-obesity drug discovery. The central hypothesis for our proposal is that the predominant role of NT is to promote lipid storage by increasing intestinal absorption of lipids, increasing hepatic lipogenesis and/or fatty acid oxidation (FAO), and increasing fat lipolysis; furthermore, the overconsumption of fats leads to excess NT secretion which results in obesity (from continued fat storage) and metabolic disorders. To examine our hypothesis and achieve our long-term goals of better defining the effects of NT on lipid storage and metabolism, we have assembled a multidisciplinary and highly collaborative team with defined expertise in NT physiology and function; metabolism and systems biochemistry; Drosophila genetics; and, biostatistics/computational biology. Ultimately, our findings will: i) significantly advance the fields of GI physiology, endocrinology and metabolism; ii) change existing paradigms regarding the systemic effects of NT; and, iii) revolutionize our concept of gut hormones and their role in obesity and metabolic diseases.