Neurotensin inhibits AMPK activity and concurrently enhances FABP1 expression in small intestinal epithelial cells associated with obesity and aging

TL;DR

Neurotensin reduces AMPK activity and increases fat absorption in intestinal cells, worsening obesity and aging effects, but its absence improves health and lifespan.

Contribution

The study reveals a novel mechanism linking neurotensin to AMPK inhibition and FABP1 upregulation in intestinal cells during obesity and aging.

Findings

Neurotensin deficiency preserves AMPK activity and reduces fat absorption in mice on high-fat diets.

AICAR and metformin fail to activate AMPK in aged intestinal cells but suppress FABP1 expression.

Reducing neurotensin levels extends lifespan in both Drosophila and mice.

Abstract

We previously demonstrated that neurotensin, a 13-amino-acid gut hormone peptide, enhances small intestinal epithelial cell fatty acid uptake through inhibition of AMPK. Here, utilizing Drosophila and mouse models in vivo, as well as mouse and human small intestinal epithelial organoids or monolayers ex vivo, we determine the targets of neurotensin and AMPK associated with obesity and aging. High-fat diet and aging decreased AMPK and insulin signaling, which was prevented by neurotensin deficiency. High-fat diet feeding increased FABP1 protein expression in wild-type mice; this effect was attenuated in neurotensin-deficient mice. AICAR and metformin increased AMPK phosphorylation in young but not in aged small intestinal epithelial cells. By contrast, AICAR and metformin inhibited FABP1 mRNA and protein expression. Moreover, cytosolic colocalization of AMPKα1 and FABP1 was noted in IEC-6 cells. AMPK phosphorylation and FABP1 expression was decreased in aged wild-type small intestinal epithelial cells; however, this effect was reversed in neurotensin-deficient cells. Results from human duodenal organoids confirm the effects of neurotensin, palmitic acid and metformin on AMPK phosphorylation and FABP1. Finally, overexpressing neurotensin in enteroendocrine cells reduced the lifespan of Drosophila; neurotensin deficiency extended the lifespan of mice fed a high-fat diet. Our findings indicate that neurotensin inhibits AMPK and increases FABP1 in small intestinal epithelial cells under conditions of obesity. Neurotensin deficiency preserves AMPK and FABP1 levels, thus attenuating some of the negative effects of obesity and aging.

Neurotensin (NTS) is a hormone primarily localized to the gut and brain that affects various bodily functions. Researchers have found that high levels of a form of NTS, called pro-NTS, are linked to diabetes and heart problems. Researchers used mice and fruit flies to study NTS’s role in fat absorption during obesity and aging. They found that NTS can reduce the activity of a protein called AMPK, which helps to control energy use in cells. In mice lacking NTS, AMPK activity was higher, leading to less fat absorption and better insulin function. This suggests that NTS might contribute to obesity by lowering AMPK activity. The study also showed that reducing NTS levels could improve health and extend lifespan in mice. These findings suggest that targeting NTS could help to manage obesity and related health issues.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

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