Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis

EMBO Rep. 2017 Jul;18(7):1123-1138. doi: 10.15252/embr.201643827. Epub 2017 May 24.


BAT-controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet-induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold-stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1-cre (BAT-Mfn2-KO) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet (HFD) results in improved insulin sensitivity and resistance to obesity, while impaired cold-stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender-specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP-synthesizing fat oxidation, whereas in BAT from males, complex I-driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT-Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole-body cold-stimulated thermogenesis.

Keywords: Mitofusin 2; brown adipose tissue; insulin resistance; obesity; thermogenesis.

Publication types

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

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Diet, High-Fat
  • Energy Metabolism
  • Female
  • GTP Phosphohydrolases / deficiency*
  • GTP Phosphohydrolases / genetics*
  • Glycolysis
  • Insulin Resistance*
  • Male
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Obesity
  • Thermogenesis / genetics*


  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse