MKK6 controls T3-mediated browning of white adipose tissue

Nat Commun. 2017 Oct 11;8(1):856. doi: 10.1038/s41467-017-00948-z.

Abstract

Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.Brown and beige adipose tissues dissipate heat via uncoupling protein 1 (UCP1). Here the authors show that the stress activated kinase MKK6 acts as a repressor of UCP1 expression, suggesting that its inhibition promotes adipose tissue browning and increases organismal energy expenditure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, White / metabolism
  • Adipose Tissue, White / enzymology*
  • Adult
  • Aged
  • Animals
  • Case-Control Studies
  • Diabetes Mellitus / etiology
  • Diet, High-Fat
  • Energy Metabolism
  • Female
  • Humans
  • MAP Kinase Kinase 6 / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Metabolic Syndrome / etiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Obesity / enzymology*
  • Obesity / etiology
  • Triiodothyronine / physiology
  • Uncoupling Protein 1 / metabolism*
  • Ventromedial Hypothalamic Nucleus / metabolism

Substances

  • Uncoupling Protein 1
  • Triiodothyronine
  • MAP Kinase Kinase 6
  • MAP2K6 protein, human
  • Map2k6 protein, mouse