Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.

Gerriets, Valerie A

Danzaki, Keiko

Kishton, Rigel J

Eisner, William

Nichols, Amanda G

Saucillo, Donte C

Shinohara, Mari L

MacIver, Nancie J

Germany

2016-07-16T14:24:29Z

2016-08

Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg-cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff-cell number, function, and glucose metabolism, but did not alter Treg-cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff-cell, but not Treg-cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of Th17 differentiation and Teff-cell glucose metabolism, and found HIF-1α expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells.

http://www.ncbi.nlm.nih.gov/pubmed/27222115

1521-4141

https://hdl.handle.net/10161/12472

eng

Wiley

Eur J Immunol

10.1002/eji.201545861

EAE

Glucose metabolism

HIF-1α

Leptin

Malnutrition

Th17

Treg cells

Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.

Journal article

Shinohara, Mari L|0000-0002-6808-9844

MacIver, Nancie J|0000-0003-3676-9391

http://www.ncbi.nlm.nih.gov/pubmed/27222115

1970

1983

8

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Immunology

Institutes and Centers

Molecular Genetics and Microbiology

Pediatrics

Pediatrics, Endocrinology

Pharmacology & Cancer Biology

School of Medicine

Published

46