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Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.

TitleGroup 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.
Publication TypeJournal Article
Year of Publication2015
AuthorsBrestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D
JournalNature
Volume519
Issue7542
Pagination242-6
Date Published2015 Mar 12
ISSN1476-4687
KeywordsAdipocytes, Adipose Tissue, White, Animals, Energy Metabolism, Enkephalin, Methionine, Eosinophils, Female, Homeostasis, Humans, Immunity, Innate, Interleukins, Ion Channels, Lymphocytes, Male, Mice, Mitochondrial Proteins, Obesity, Receptors, Interleukin-4
Abstract

Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.

DOI10.1038/nature14115
Alternate JournalNature
PubMed ID25533952
Grant List2-P30 CA016520 / CA / NCI NIH HHS / United States
AI061570 / AI / NIAID NIH HHS / United States
AI074878 / AI / NIAID NIH HHS / United States
AI095466 / AI / NIAID NIH HHS / United States
AI095608 / AI / NIAID NIH HHS / United States
AI097333 / AI / NIAID NIH HHS / United States
AI102942 / AI / NIAID NIH HHS / United States
DP2 OD007288 / OD / NIH HHS / United States
DP2OD007288 / OD / NIH HHS / United States
DP5 OD012116 / OD / NIH HHS / United States
DP5OD012116 / OD / NIH HHS / United States
F30 AI112023 / AI / NIAID NIH HHS / United States
F30-AI112023 / AI / NIAID NIH HHS / United States
F31 AG047003 / AG / NIA NIH HHS / United States
F31AG047003 / AG / NIA NIH HHS / United States
K08 AR065577 / AR / NIAMS NIH HHS / United States
KL2-RR024132 / RR / NCRR NIH HHS / United States
P01 AI106697 / AI / NIAID NIH HHS / United States
P01AI06697 / AI / NIAID NIH HHS / United States
P30 AR057217 / AR / NIAMS NIH HHS / United States
P30-DK050306 / DK / NIDDK NIH HHS / United States
P30DK19525 / DK / NIDDK NIH HHS / United States
R01 AI061570 / AI / NIAID NIH HHS / United States
R01 AI074878 / AI / NIAID NIH HHS / United States
R01 AI095466 / AI / NIAID NIH HHS / United States
R01 AI097333 / AI / NIAID NIH HHS / United States
R01 AI102942 / AI / NIAID NIH HHS / United States
T32 AI060516 / AI / NIAID NIH HHS / United States
T32-AI007532 / AI / NIAID NIH HHS / United States
T32-AI060516 / AI / NIAID NIH HHS / United States
U01 AI095608 / AI / NIAID NIH HHS / United States