A Functional Link Between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

Cell Rep. 2016 Aug 23;16(8):2231-2242. doi: 10.1016/j.celrep.2016.07.045. Epub 2016 Aug 11.


AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Body Weight
  • Bone Morphogenetic Proteins / genetics*
  • Bone Morphogenetic Proteins / metabolism
  • Bone Morphogenetic Proteins / pharmacology
  • Energy Metabolism / genetics
  • Female
  • Gene Expression Regulation
  • Glutamic Acid / metabolism
  • Hypothalamic Area, Lateral / metabolism*
  • Male
  • Mice, Knockout
  • Orexin Receptors / genetics
  • Orexin Receptors / metabolism
  • Orexins / genetics*
  • Orexins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sex Factors
  • Signal Transduction
  • Thermogenesis / genetics*
  • Ventromedial Hypothalamic Nucleus / metabolism*
  • Vesicular Glutamate Transport Protein 2 / antagonists & inhibitors
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism


  • Bone Morphogenetic Proteins
  • Hcrtr1 protein, rat
  • Orexin Receptors
  • Orexins
  • Slc17a6 protein, rat
  • Vesicular Glutamate Transport Protein 2
  • Glutamic Acid
  • AMP-Activated Protein Kinases