title: Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Gerriets
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Danzaki
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Rigel J
authors.initials: RJ
authors.lastname: Kishton
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC, USA.
authors.forename: William
authors.initials: W
authors.lastname: Eisner
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Nichols
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Donte C
authors.initials: DC
authors.lastname: Saucillo
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC, USA.|Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Mari L
authors.initials: ML
authors.lastname: Shinohara
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC, USA.|Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Nancie J
authors.initials: NJ
authors.lastname: MacIver
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage*; D044342:Malnutrition; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020738:Leptin
keywords: EAE; Glucose metabolism; HIF-1α; Leptin; Malnutrition; Th17; Treg cells