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The ERα-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice

Liangru Zhu1, Pingwen Xu1, Xuehong Cao1

  • 1Children's Nutrition Research Center (L.Z., P.X., X.C., Y.Y., A.O.H., Y.Xi., K.S., X.Y., F.Z., H.D., C.W., C.Y., M.F., Y.Xu), Department of Pediatrics; Diabetes Research Center (P.S., L.C.), Department of Medicine; and Department of Molecular and Cellular Biology (L.C., Y.Xu), Baylor College of Medicine, and Brown Foundation Institute of Molecular Medicine (Q.T.), University of Texas Health Science Center at Houston, Houston, Texas 77030; Department of Gastroenterology (L.Z.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China; Medical College of Qingdao University (C.Y.), Qingdao 266020, People's Republic of China; Department of Cancer Biology (S.A.K.), Vontz Center for Molecular Studies, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267; Department of Pathology (J.Z.), Harvard Medical School, and Department of Cancer Biology Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and Department of Biomedical Research (D.J.C.), Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.

Endocrinology
|September 17, 2015
PubMed

Insights

Estrogen receptor alpha (ERα) in POMC neurons controls appetite and glucose. A newly discovered ERα-PI3K pathway in these neurons mediates estrogen

Area of Science:

  • Neuroendocrinology
  • Metabolic Regulation
  • Hormone Signaling

Background:

  • Estrogens regulate feeding and glucose homeostasis via estrogen receptor alpha (ERα).
  • The intracellular mechanisms mediating these ERα actions are not fully understood.
  • Proopiomelanocortin (POMC) neurons are key regulators of energy balance and glucose metabolism.

Purpose of the Study:

  • To elucidate the intracellular signaling pathways through which ERα in POMC neurons mediates the effects of estrogens on feeding and glucose homeostasis.
  • To investigate the role of the phosphatidylinositol 3-kinase (PI3K) pathway in ERα-mediated neuronal signaling.

Main Methods:

  • Generation of female mice lacking ERα specifically in POMC progenitor neurons.
  • Pharmacological activation of ERα using propyl pyrazole triol (PPT).
  • Genetic inhibition of the PI3K pathway in POMC neurons.
  • Assessment of feeding behavior, glucose tolerance, and insulin sensitivity.

Main Results:

  • Loss of ERα in POMC neurons blunted estrogen's anorexigenic effects and impaired glucose homeostasis.
  • ERα activation stimulated the PI3K pathway specifically in POMC neurons.
  • PI3K blockade attenuated ERα-induced POMC neuron activation.
  • Inhibition of PI3K in POMC neurons attenuated estrogen's effects on food intake and insulin sensitivity.

Conclusions:

  • Estrogenic actions on feeding and glucose metabolism are mediated by an ERα-PI3K signaling cascade within POMC progenitor neurons.
  • This pathway is critical for regulating appetite and improving insulin sensitivity.
  • Findings reveal a novel molecular mechanism linking estrogen signaling to metabolic control in the brain.

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