A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis

Cell Rep. 2019 Jul 16;28(3):773-791.e7. doi: 10.1016/j.celrep.2019.06.061.

Abstract

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.

Keywords: RAGE; adaptive thermogenesis; adipocyte; adipose tissue; advanced glycation end products; cold tolerance; obesity; protein kinase A; receptor for advanced glycation end products; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / enzymology
  • Adipocytes / metabolism*
  • Adipose Tissue / enzymology
  • Adipose Tissue / metabolism*
  • Animals
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Energy Metabolism
  • Fasting / metabolism
  • Fasting / physiology
  • Humans
  • Lipolysis / genetics
  • Lipolysis / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / metabolism
  • Phosphorylation
  • Receptor for Advanced Glycation End Products / antagonists & inhibitors
  • Receptor for Advanced Glycation End Products / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Thermogenesis* / genetics
  • Transplantation, Homologous
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Receptor for Advanced Glycation End Products
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Cyclic AMP-Dependent Protein Kinases
  • p38 Mitogen-Activated Protein Kinases