An Inhibitor of the Protein Kinases TBK1 and IKK-ɛ Improves Obesity-Related Metabolic Dysfunctions in Mice

Nat Med. 2013 Mar;19(3):313-21. doi: 10.1038/nm.3082. Epub 2013 Feb 10.

Abstract

Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) are induced in liver and fat by NF-κB activation upon high-fat diet feeding and in turn initiate a program of counterinflammation that preserves energy storage. Here we report that amlexanox, an approved small-molecule therapeutic presently used in the clinic to treat aphthous ulcers and asthma, is an inhibitor of these kinases. Treatment of obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders.

Publication types

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

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Anti-Allergic Agents / pharmacology
  • Anti-Obesity Agents / pharmacology*
  • Cell Line
  • Diet, High-Fat
  • Energy Metabolism / drug effects*
  • Enzyme Activation
  • Fatty Liver / drug therapy
  • Glucose Metabolism Disorders / drug therapy
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Insulin Resistance* / immunology
  • Intra-Abdominal Fat / drug effects
  • Intra-Abdominal Fat / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • NF-kappa B / metabolism
  • Obesity / drug therapy
  • Obesity / immunology
  • Obesity / metabolism*
  • Oxygen Consumption / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Weight Loss / drug effects

Substances

  • Aminopyridines
  • Anti-Allergic Agents
  • Anti-Obesity Agents
  • NF-kappa B
  • amlexanox
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase