A Hypothalamic Phosphatase Switch Coordinates Energy Expenditure with Feeding

Cell Metab. 2017 Aug 1;26(2):375-393.e7. doi: 10.1016/j.cmet.2017.07.013.


Beige adipocytes can interconvert between white and brown-like states and switch between energy storage versus expenditure. Here we report that beige adipocyte plasticity is important for feeding-associated changes in energy expenditure and is coordinated by the hypothalamus and the phosphatase TCPTP. A fasting-induced and glucocorticoid-mediated induction of TCPTP, inhibited insulin signaling in AgRP/NPY neurons, repressed the browning of white fat and decreased energy expenditure. Conversely feeding reduced hypothalamic TCPTP, to increase AgRP/NPY neuronal insulin signaling, white adipose tissue browning and energy expenditure. The feeding-induced repression of hypothalamic TCPTP was defective in obesity. Mice lacking TCPTP in AgRP/NPY neurons were resistant to diet-induced obesity and had increased beige fat activity and energy expenditure. The deletion of hypothalamic TCPTP in obesity restored feeding-induced browning and increased energy expenditure to promote weight loss. Our studies define a hypothalamic switch that coordinates energy expenditure with feeding for the maintenance of energy balance.

Keywords: AgRP; Beige adipocyte; Diet-induced thermogenesis; Energy expenditure; Hypothalamus; Insulin; Obesity; Protein tyrosine phosphatase; TCPTP; White adipose tissue browning.

MeSH terms

  • Agouti-Related Protein / genetics
  • Agouti-Related Protein / metabolism
  • Animals
  • Eating / psychology*
  • Energy Metabolism / physiology*
  • Hypothalamus / metabolism*
  • Mice
  • Mice, Transgenic
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Obesity / genetics
  • Obesity / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / biosynthesis*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics


  • Agouti-Related Protein
  • Agrp protein, mouse
  • Neuropeptide Y
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2