Publication Date:
2016-05-20
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Jing -- Song, Jun -- Zaytseva, Yekaterina Y -- Liu, Yajuan -- Rychahou, Piotr -- Jiang, Kai -- Starr, Marlene E -- Kim, Ji Tae -- Harris, Jennifer W -- Yiannikouris, Frederique B -- Katz, Wendy S -- Nilsson, Peter M -- Orho-Melander, Marju -- Chen, Jing -- Zhu, Haining -- Fahrenholz, Timothy -- Higashi, Richard M -- Gao, Tianyan -- Morris, Andrew J -- Cassis, Lisa A -- Fan, Teresa W-M -- Weiss, Heidi L -- Dobner, Paul R -- Melander, Olle -- Jia, Jianhang -- Evers, B Mark -- P01 CA163223/CA/NCI NIH HHS/ -- P20 GM103527/GM/NIGMS NIH HHS/ -- R01 DK048498/DK/NIDDK NIH HHS/ -- R01 ES022191/ES/NIEHS NIH HHS/ -- R01 GM079684/GM/NIGMS NIH HHS/ -- R01 HL073085/HL/NHLBI NIH HHS/ -- R01 HL12050/HL/NHLBI NIH HHS/ -- R01 NS077284/NS/NINDS NIH HHS/ -- R37 AG10885/AG/NIA NIH HHS/ -- T32 CA160003/CA/NCI NIH HHS/ -- T32 CA165990/CA/NCI NIH HHS/ -- U24 DK097215/DK/NIDDK NIH HHS/ -- England -- Nature. 2016 May 11;533(7603):411-5. doi: 10.1038/nature17662.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA. ; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Clinical Sciences, Lund University, Malmo, 221 00 Lund, Sweden. ; Department of Internal Medicine, Skane University Hospital, Malmo, 205 02 Malmo, Sweden. ; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA. ; Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA. ; Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA. ; Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky and Lexington Veterans Affairs Medical Center, Lexington, Kentucky 40536, USA. ; Department of Biostatistics, University of Kentucky, Lexington, Kentucky 40536, USA. ; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27193687" target="_blank"〉PubMed〈/a〉
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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