A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis
Carmen Hurtado del Pozo,
Henry H. Ruiz,
Lakshmi Arivazhagan,
Juan Francisco Aranda,
Cynthia Shim,
Peter Daya,
Julia Derk,
Michael MacLean,
Meilun He,
Laura Frye,
Randall H. Friedline,
Hye Lim Noh,
Jason K. Kim,
Richard A. Friedman,
Ravichandran Ramasamy,
Ann Marie Schmidt
Affiliations
Carmen Hurtado del Pozo
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Henry H. Ruiz
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Lakshmi Arivazhagan
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Juan Francisco Aranda
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Cynthia Shim
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Peter Daya
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Julia Derk
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Michael MacLean
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Meilun He
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Laura Frye
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Randall H. Friedline
Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, Worcester, MA 01605, USA
Hye Lim Noh
Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, Worcester, MA 01605, USA
Jason K. Kim
Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, Worcester, MA 01605, USA; Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, Worcester, MA 01605, USA
Richard A. Friedman
Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, and Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA
Ravichandran Ramasamy
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA
Ann Marie Schmidt
Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30th Street, New York, NY 10016, USA; Corresponding author
Summary: Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation—processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress. : Hurtado del Pozo et al. show that the deletion of adipocyte RAGE, whose ligands accumulate in metabolic stress, protects from obesity and cold challenges through the modulation of protein kinase A activities. This work adds RAGE to the immunometabolic networks that regulate energy expenditure in environmental and metabolic stress. Keywords: adaptive thermogenesis, adipocyte, adipose tissue, cold tolerance, obesity, protein kinase A, receptor for advanced glycation end products, RAGE, signal transduction, advanced glycation end products
