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

被引：141

作者：

Lynch, Lydia ^{[1
,2
]}

Hogan, Andrew E. ^{[3
,4
]}

Duquette, Danielle ^{[1
]}

Lester, Chantel ^{[1
]}

Banks, Alexander ^{[2
]}

LeClair, Katherine ^{[5
]}

Cohen, David E. ^{[5
]}

Ghosh, Abhisek ^{[1
]}

Lu, Bing ^{[1
]}

Corrigan, Michelle ^{[3
,4
]}

Stevanovic, Darko ^{[6
]}

Maratos-Flier, Eleftheria ^{[6
]}

Drucker, Daniel J. ^{[7
]}

O'Shea, Donal ^{[3
,4
,8
]}

Brenner, Michael ^{[1
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA

[3] Univ Coll Dublin, Educ & Res Ctr, Dublin 4, Ireland

[4] Univ Coll Dublin, St Vincents Univ Hosp, Conway Inst, Dublin 4, Ireland

[5] Harvard Med Sch, Brigham & Womens Hosital, Dept Med, Div Gastroenterol, Boston, MA 02115 USA

[6] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA

[7] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[8] Univ Coll Dublin, St Vincents Univ Hosp, Dept Endocrinol, Dublin 4, Ireland

来源：

CELL METABOLISM | 2016年 / 24卷 / 03期

基金：

欧洲研究理事会;

关键词：

GLUCAGON-LIKE PEPTIDE-1; KILLER T-CELLS; INNATE LYMPHOID TYPE-2; INVARIANT NKT CELLS; ADIPOSE-TISSUE; ANTIGEN PRESENTATION; ENERGY-EXPENDITURE; OBESITY; EOSINOPHILS; ADIPOCYTES;

D O I：

10.1016/j.cmet.2016.08.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 alpha-galactosylceramide (alpha GalCer), 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 aGalCer 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.

引用

页码：510 / 519

页数：10

共 36 条

[1] Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis
Badman, Michael K.
Koester, Anja
Flier, Jeffrey S.
Kharitonenkov, Alexei
Maratos-Flier, Eleftheria
[J]. ENDOCRINOLOGY, 2009, 150 (11) : 4931 - 4940
[2] Biology of incretins: GLP-1 and GIP
Baggio, Laurie L.
Drucker, Daniel J.
[J]. GASTROENTEROLOGY, 2007, 132 (06) : 2131 - 2157
[3] Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity
Brestoff, Jonathan R.
Kim, Brian S.
Saenz, Steven A.
Stine, Rachel R.
Monticelli, Laurel A.
Sonnenberg, Gregory F.
Thome, Joseph J.
Farber, Donna L.
Lutfy, Kabirullah
Seale, Patrick
Artis, David
[J]. NATURE, 2015, 519 (7542) : 242 - +
[4] CD1: Antigen presentation and T cell function
Brigl, M
Brenner, MB
[J]. ANNUAL REVIEW OF IMMUNOLOGY, 2004, 22 : 817 - 890
[5] COUSIN B, 1992, J CELL SCI, V103, P931
[6] Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese
Enerback, S
Jacobsson, A
Simpson, EM
Guerra, C
Yamashita, H
Harper, ME
Kozak, LP
[J]. NATURE, 1997, 387 (6628) : 90 - 94
[7] FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, Ffolliott M.
Kleiner, Sandra
Douris, Nicholas
Fox, Elliott C.
Mepani, Rina J.
Verdeguer, Francisco
Wu, Jun
Kharitonenkov, Alexei
Flier, Jeffrey S.
Maratos-Flier, Eleftheria
Spiegelman, Bruce M.
[J]. GENES & DEVELOPMENT, 2012, 26 (03) : 271 - 281
[8] The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes
Gaich, Gregory
Chien, Jenny Y.
Fu, Haoda
Glass, Leonard C.
Deeg, Mark A.
Holland, William L.
Kharitonenkov, Alexei
Bumol, Thomas
Schilske, Holger K.
Moller, David E.
[J]. CELL METABOLISM, 2013, 18 (03) : 333 - 340
[9] Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells
Hadjiyanni, I.
Siminovitch, K. A.
Danska, J. S.
Drucker, D. J.
[J]. DIABETOLOGIA, 2010, 53 (04) : 730 - 740
[10] Cutting Edge: IL-25 Elicits Innate Lymphoid Type 2 and Type II NKT Cells That Regulate Obesity in Mice
Hams, Emily
Locksley, Richard M.
McKenzie, Andrew N. J.
Fallon, Padraic G.
[J]. JOURNAL OF IMMUNOLOGY, 2013, 191 (11) : 5349 - 5353

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