# Mechanisms Regulating Neurotensin Secretion and Function

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2022 · $669,684

## Abstract

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:...

## Key facts

- **NIH application ID:** 10536470
- **Project number:** 2R01DK112034-06A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Bernard Mark Evers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $669,684
- **Award type:** 2
- **Project period:** 2017-02-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536470

## Citation

> US National Institutes of Health, RePORTER application 10536470, Mechanisms Regulating Neurotensin Secretion and Function (2R01DK112034-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10536470. Licensed CC0.

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