Journal
NATURE
Volume 566, Issue 7742, Pages 115-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0849-9
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Funding
- NIH [R35 HL135752, R01 HL128264, P01 HL131478, T32 AI118692]
- AHA EIA
- AHA Postdoctoral Award [16POST27250124]
- German Research Foundation (DFG)
- Swedish Research Council
- FWF Erwin Schroedinger Fellowship [J3486-B13]
- Boehringer Ingelheim Fonds MD Fellowship
- CIHR [154321]
- Canada Research Chairs program
- BBDC-Novo Nordisk Chair in Incretin biology
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The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways(1), how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin beta 7(+) natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin beta 7(-) mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-1(2), which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.
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