An obligatory role for neurotensin in high-fat-diet-induced obesity

Jing Li, Jun Song, Yekaterina Y. Zaytseva, Yajuan Liu, Piotr Rychahou, Kai Jiang, Marlene E. Starr, Ji Tae Kim, Jennifer W. Harris, Frederique B. Yiannikouris, Wendy S. Katz, Peter M. Nilsson, Marju Orho-Melander, Jing Chen, Haining Zhu, Timothy Fahrenholz, Richard M. Higashi, Tianyan Gao, Andrew J. Morris, Lisa A. CassisTeresa W.M. Fan, Heidi L. Weiss, Paul R. Dobner, Olle Melander, Jianhang Jia, B. Mark Evers

Research output: Contribution to journalArticlepeer-review

165 Scopus citations


Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

Original languageEnglish
Pages (from-to)411-415
Number of pages5
StatePublished - May 11 2016

Bibliographical note

Funding Information:
We thank D. A. Gilbreath, C. E. Anthony, H. N. Russell-Simmons and J. F. Rogers for manuscript preparation; D. Napier for tissue sectioning and staining; G. Epperly for intestinal crypt measurements and the use of the Aperio ScanScope; E. Y. Lee for consultation and assessment of histological sections and immunohistochemistry; R. Carraway and P. Forgez for their suggestions and helpful advice; J. Ambati and K. Grzech for their review of the manuscript; J. Young Kwon for the Gr36C-Gal4 line, M. Vidal for the voila-Gal4 line, N. Perrimon and T. Ip for the TKg-Gal4 line, and S. Hou for MyoIAGal4 and Esg-Gal4 lines; the Bloomington Stock Center, Vienna Drosophila RNAi Center (VDRC) and TRiP at Harvard Medical School for fly stocks; the Developmental Studies Hybridoma Bank (DSHB) for antibodies; B. Gebelein for the anti-HNF4 antibody; the Biospecimen and Tissue Procurement, Redox Metabolism, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (supported by National Cancer Institute grant P30 CA177558). This study was further supported by National Institutes of Health (NIH) grants R37 AG10885 and R01 DK048498 to B.M.E.; R01 GM079684 to J.J.; U24 DK097215, R01 ES022191, P01 CA163223 and P20 GM103527 to T.W.-M.F. and R.M.H.; R01 HL120507 to A.J.M.; RO1 NS077284 to H.Z.; R01 HL073085 and P20 GM103527 to L.A.C. O.M., P.M.N. and M.O.-M. are funded by the Swedish National Research Council; the Swedish Heart-Lung Foundation; Novo Nordisk Foundation; Swedish Diabetes Association; Region Skåne, ALF; and European Research Council grant StG-2011-282255. B.M.E. is also supported by the Markey Cancer Foundation. Y.Y.Z. and J.W.H. are supported by NIH postdoctoral training grants T32 CA165990 and T32 CA160003, respectively. The LC-MS/MS equipment was acquired using a National Center for Research Resources High-End Instrumentation grant (S10 RR029127 to H.Z.).

Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.

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