iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy.
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.
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.
Lydia
L
Lynch
Education and Research Center and Conway Institute, St. Vincent's University Hospital, University College Dublin, Dublin 4, Ireland.
Andrew E
AE
Hogan
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Danielle
D
Duquette
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chantel
C
Lester
Division of Endocrinology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Alexander
A
Banks
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hosital, Harvard Medical School, Boston, MA 02115, USA.
Katherine
K
LeClair
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hosital, Harvard Medical School, Boston, MA 02115, USA.
David E
DE
Cohen
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abhisek
A
Ghosh
Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bing
B
Lu
Education and Research Center and Conway Institute, St. Vincent's University Hospital, University College Dublin, Dublin 4, Ireland.
Michelle
M
Corrigan
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Darko
D
Stevanovic
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Eleftheria
E
Maratos-Flier
The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
Daniel J
DJ
Drucker
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.
Donal
D
O'Shea
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.
Michael
M
Brenner
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000378:metabolism*; D022722:Thermogenesis / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1