ABSTRACT Our multidisciplinary research team has been studying the function and effects of neurotensin (NT), a tridecapeptide localized to specialized enteroendocrine cells predominantly in the small bowel, for almost three decades. The most potent stimulus for NT release is ingestion of dietary fats. NT facilitates fatty acid (FA) absorption in the intestine, stimulates growth of cancers that have the high affinity NT receptor 1 (NTR1), and contributes to overall metabolism although its precise role in these processes has not been clearly delineated. Recent studies have identified a significant association of increased fasting pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) levels with the development of diabetes, increased risk of cardiovascular disease and mortality, non-alcoholic fatty liver disease (NAFLD), and increased risk of breast cancer in women. These findings identify a possible role for NT in lipid metabolism and link increased NT levels to various metabolic diseases, certain cancers and increased morbidity and mortality. The signaling pathways and role for NT in the absorption and storage of ingested fats represents a major gap in our current knowledge. Epidemiological evidence clearly shows a direct linkage between overnutrition and obesity; however, the molecular mechanisms linking adiposity to overnutrition remain unknown. We have shown that NT deficiency (using an NT knockout mouse model) decreases body weight gain, insulin resistance and NAFLD associated with high fat consumption; we further demonstrated that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption through a mechanism involving NTR1 and NTR3/sortilin. Importantly, in humans, we show that increased levels of pro-NT strongly predict new onset obesity in a graded manner, which is independent of body mass index and insulin resistance, suggesting that NT may provide a prognostic marker of future obesity and a potential target for obesity prevention and treatment. Therefore, to extend the findings made during this grant period, the central hypothesis for this renewal application is that NT promotes triglyceride synthesis and suppresses FA oxidation in the intestine and liver likely through a mechanism involving AMPK inhibition; moreover, NT contributes to high-fat diet-disrupted adipocyte lipolysis via inhibiting activity of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). We speculate that overconsumption of dietary fats, which leads to excess NT secretion, results in obesity (from continued fat storage) and metabolic disorders (e.g., NAFLD and insulin resistance). To examine our long-term goal of better defining intestinal NT function, we have assembled a highly collaborative team with defined expertise in NT physiology and function; signal transduction, metabolism and systems biochemistry; and biostatistics and computational biology. Ultimately, our findings will: i) significantly advance the fields of gastrointestinal 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 metabolic diseases.

Project Narrative We have shown that neurotensin (NT), a hormone localized predominantly to the small bowel, acts as a “thrifty” gene to efficiently absorb ingested fats; NT deficiency in mice protects against obesity, insulin resistance and hepatic steatosis associated with high fat diet consumption. Moreover, we found that elevated NT levels in humans is strongly predictive of future obesity. Our current studies, which will define the mechanisms regulating NT-mediated intestinal lipid absorption and fat metabolism in liver and adipose tissues, will significantly impact the fields of GI physiology and metabolism and may eventually lead to innovative therapies for diet-induced obesity and resultant metabolic disorders based on inhibition of NT signaling.