Editors' ChoiceMetabolism

Neurotensin makes us fat

Sci. Signal.  24 May 2016:
Vol. 9, Issue 429, pp. ec122
DOI: 10.1126/scisignal.aag1812

In response to ingesting fat, enteroendocrine cells of the small intestine release the 13–amino acid peptide neurotensin (NT). Increased abundance of the NT precursor pro-NT in the circulation is associated with increased risk for developing diabetes and cardiovascular disease. Li et al. found that mice lacking NT or treated with an NT receptor antagonist stored less fat and absorbed less dietary fatty acids than wild-type (WT) littermates, even when fed a high-fat diet (HFD). NT–/– mice did not expend more energy or consume less food than WT mice, but they were protected from obesity, obesity-associated insulin resistance, and hepatic steatosis when fed a HFD. In cultured rat intestinal epithelial cells, NT stimulated fatty acid uptake, whereas knocking down NT receptors reduced fatty acid uptake. Activation of the metabolic regulator AMPK (adenosine 5′-monophosphate–activated protein kinase), which stimulates lipolysis and inhibits fat storage, was increased in the intestines of NT–/– mice fed a standard diet. In cultured rat and human intestinal cells, NT reduced AMPK activation in response to oleate and prevented a pharmacological activator of AMPK from reducing fatty acid absorption. Expressing human NT in the enteroendocrine cells of fruit flies reduced the activation of AMPK in the gut and increased the accumulation of lipid droplets in cells and tissues involved in lipid processing and energy storage. Feeding these flies a HFD further increased fat accumulation. The authors also found that obese and insulin-resistant people had increased plasma pro-NT and that high plasma pro-NT in nonobese people correlated with increased risk for developing obesity later in life. Thus, NT has an evolutionarily conserved function in stimulating fat absorption and plays a role in HFD-induced obesity.

J. Li, J, Song, Y. Y. Zaytseva, Y. Liu, P. Rychahou, K. Jiang, M. E. Starr,
J. T. Kim, J. W. Harris, F. B. Yiannikouris, W. S. Katz, P. M. Nilsson,
M. Orho-Melander, J. Chen, H. Zhu, T. Fahrenholz, R. M. Higashi, T. Gao, A. J. Morris, L. A. Cassis, T. W.-M. Fan, H. L. Weiss, P. R. Dobner, O. Melander, J. Jia, B. M. Evers, An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 533, 411–415 (2016). [PubMed]