Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK

Pablo Blanco Martinez De Morentin, Ismael Gonzalez-Garcia, Luis Martins, Ricardo Lage, Diana Fernandez-Mallo, Noelia Martinez-Sanchez, Francisco Ruiz-Pino, Ji Liu, Donald A Morgan, Leonor Pinilla, Rosalia Gallego, Asish K Saha, Andries Kalsbeek, Eric Fliers, Peter H. Bisschop, Carlos Dieguez, Ruben Nogueiras, Kamal Rahmouni, Manuel Tena-Sempere, Miguel Lopez

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Abstract

Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis
Original languageEnglish
Pages (from-to)41-53
Number of pages13
JournalCell Metabolism
Volume20
Issue number1
Early online date22 May 2014
DOIs
Publication statusPublished - Jul 2014

Keywords

  • AMP-Activated Protein Kinases
  • Adipose Tissue, Brown
  • Animals
  • Energy Metabolism
  • Estradiol
  • Estrogen Receptor alpha
  • Female
  • Hypothalamus
  • Ovary
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Sympathetic Nervous System
  • Thermogenesis

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  • Cite this

    Martinez De Morentin, P. B., Gonzalez-Garcia, I., Martins, L., Lage, R., Fernandez-Mallo, D., Martinez-Sanchez, N., Ruiz-Pino, F., Liu, J., Morgan, D. A., Pinilla, L., Gallego, R., Saha, A. K., Kalsbeek, A., Fliers, E., Bisschop, P. H., Dieguez, C., Nogueiras, R., Rahmouni, K., Tena-Sempere, M., & Lopez, M. (2014). Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metabolism, 20(1), 41-53. https://doi.org/10.1016/j.cmet.2014.03.031