IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity.
IL-15Rα is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15Rα take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15Rα promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15Rα on metabolism and obesity are currently unknown. We report that mice lacking IL-15Rα (IL-15Rα(-/-)) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15Rα(-/-) mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15Rα(-/-) are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15Rα in metabolism and obesity.
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania;
Emanuele
http://orcid.org/0000-0002-0822-4514
E
Loro
Department of Pathology, Anatomy, and Cell Biology and MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania;
Erin L
EL
Seifert
Department of Pathology, Anatomy, and Cell Biology and MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania;
Cynthia
C
Moffat
Department of Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Freddy
F
Romero
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania;
Manoj K
MK
Mishra
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, Pennsylvania;
Zheng
Z
Sun
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia; and.
Predrag
P
Krajacic
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, Pennsylvania.
Frederick
F
Anokye-Danso
Department of Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Ross S
RS
Summer
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, Pennsylvania.
Rexford S
RS
Ahima
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; tsk@mail.med.upenn.edu.
Tejvir S
TS
Khurana
D000818:Animals; D001786:Blood Glucose; D001823:Body Composition; D001831:Body Temperature; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D013817:Thermography
D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit
diet-induced obesity; fatigue recovery; fatty acid oxidation; glucose homeostasis; interleukin-15 receptor alpha; muscle