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

• Published in: Nature (London) Vol. 533; no. 7603; pp. 411 - 415
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.05.2016; Nature Publishing Group
• Subjects: 14/1; 14/19; 14/34; 14/63; 38; 38/1; 38/109; 38/22; 38/77; 38/89; 38/90; 59; 59/57; 64; 64/24; 64/60; 692/163/2743/2037; 692/163/2743/393; 82; 82/29; 82/51; 82/80; 82/83; 96; Adaptor Proteins, Vesicular Transport - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Cell Line; Clinical Medicine; Diet, High-Fat - adverse effects; Disease Models, Animal; Drosophila melanogaster - cytology; Drosophila melanogaster - enzymology; Drosophila melanogaster - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Enteroendocrine Cells - metabolism; Enzyme Activation; Fat Body - metabolism; Fatty Acids - metabolism; Fatty Liver - metabolism; Fatty Liver - prevention & control; Female; Health aspects; Humanities and Social Sciences; Humans; Insulin Resistance - physiology; Intestinal Mucosa - metabolism; Intestines - cytology; Ketogenic diet; Klinisk medicin; letter; Lipid Metabolism; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Middle Aged; multidisciplinary; Neurotensin; Neurotensin - blood; Neurotensin - deficiency; Neurotensin - genetics; Neurotensin - metabolism; Obesity; Obesity - blood; Obesity - chemically induced; Obesity - metabolism; Obesity - prevention & control; Physiological aspects; Protein Precursors - blood; Protein Precursors - metabolism; Science
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature17662

Neurotensin, a peptide expressed in the enteroendocrine cells of the small intestine that is released upon fat ingestion, is shown to increase fatty acid absorption, with neurotensin-deficient mice being protected from obesity induced by a high-fat diet. Neurotensin is a factor in obesity Neurotensin (NT) is a 13-amino-acid peptide expressed in the enteroendocrine cells of the small bowel, and is released upon fat ingestion to facilitate fatty acid translocation. There are three known NT receptors, termed NTR1, NTR2 and NTR3. These authors show that NT increases fatty acid absorption and inhibition of downstream AMPK activity in intestinal cells via NTR1 and NTR3. Mice deficient in NT and on a high fat diet are protected from obesity, hepatic steatosis and insulin resistance, unlike their wild-type counterparts. Expression of NT in enteroendocrine cells of the fly increases lipid accumulation in the midgut, fat body and oenocytes, and also decreases AMPK activity, suggesting conservation of the pathway. Obese and insulin-resistant humans are shown to have elevated plasma levels of pro-NT, a precursor of NT, and high levels of pro-NT double the risk of obesity later in life. Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually 1 and are among the most prevalent and challenging conditions confronting the medical profession 2 , 3 . Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine 4 and released by fat ingestion 5 , facilitates fatty acid translocation in rat intestine 6 , and stimulates the growth of various cancers 7 . The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively) 8 . 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 9 ; 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.