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Cell Metab. 2016 Sep 13;24(3):510-519. doi: 10.1016/j.cmet.2016.08.003. Epub 2016 Sep 1.

iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy.

Author information

1
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Endocrinology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: llynch@bwh.harvard.edu.
2
Education and Research Center and Conway Institute, St. Vincent's University Hospital, University College Dublin, Dublin 4, Ireland.
3
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Division of Endocrinology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
5
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hosital, Harvard Medical School, Boston, MA 02115, USA.
6
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
7
The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
8
Education and Research Center and Conway Institute, St. Vincent's University Hospital, University College Dublin, Dublin 4, Ireland; Department of Endocrinology, St. Vincent's University Hospital, University College Dublin, Dublin 4, Ireland. Electronic address: info@dosheaendo.ie.
9
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: mbrenner@research.bwh.harvard.edu.

Abstract

Adipose-resident invariant natural killer T (iNKT) cells are key players in metabolic regulation. iNKT cells are innate lipid sensors, and their activation, using their prototypic ligand α-galactosylceramide (αGalCer), induces weight loss and restores glycemic control in obesity. Here, iNKT activation induced fibroblast growth factor 21 (FGF21) production and thermogenic browning of white fat. Complete metabolic analysis revealed that iNKT cell activation induced increased body temperature, V02, VC02, and fatty acid oxidation, without affecting food intake or activity. FGF21 induction played a major role in iNKT cell-induced weight loss, as FGF21 null mice lost significantly less weight after αGalCer treatment. The glucagon-like peptide 1 (GLP-1) receptor agonist, liraglutide, also activated iNKT cells in humans and mice. In iNKT-deficient mice, liraglutide promoted satiety but failed to induce FGF21, resulting in less weight loss. These findings reveal an iNKT cell-FGF21 axis that defines a new immune-mediated pathway that could be targeted for glycemic control and weight regulation.

PMID:
27593966
PMCID:
PMC5061124
DOI:
10.1016/j.cmet.2016.08.003
[Indexed for MEDLINE]
Free PMC Article

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