title: An obligatory role for neurotensin in high-fat-diet-induced obesity.
abstract: 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.
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.|Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.|Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Song
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yekaterina Y
authors.initials: YY
authors.lastname: Zaytseva
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.|Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rychahou
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Marlene E
authors.initials: ME
authors.lastname: Starr
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.|Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Ji Tae
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.|Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Harris
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Frederique B
authors.initials: FB
authors.lastname: Yiannikouris
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Katz
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, 221 00 Lund, Sweden.|Department of Internal Medicine, Skåne University Hospital, Malmö, 205 02 Malmö, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, 221 00 Lund, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.|Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.|Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA.|Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fahrenholz
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA.|Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Higashi
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Gao
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky and Lexington Veterans Affairs Medical Center, Lexington, Kentucky 40536, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA.|Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Teresa W-M
authors.initials: TW
authors.lastname: Fan
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Biostatistics, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Dobner
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, 221 00 Lund, Sweden.|Department of Internal Medicine, Skåne University Hospital, Malmö, 205 02 Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jianhang
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA.|Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism; D004789:Enzyme Activation; D005216:Fat Body / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009496:Neurotensin / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism; D000099183:Sortilin
chemical_list: D055372:AMP-Activated Protein Kinases; D033942:Adaptor Proteins, Vesicular Transport; D005227:Fatty Acids; D009496:Neurotensin; D011498:Protein Precursors; D000099183:Sortilin; C411471:proneurotensin