Loss of Nuclear and Membrane Estrogen Receptor-α Differentially Impairs Insulin Secretion and Action in Male and Female Mice

Camille Allard, Jamie J. Morford, Beibei Xu, Benjamin Salwen, Weiwei Xu, Lucie Desmoulins, Andrea Zsombok, Jason K. Kim, Ellis R. Levin, Franck Mauvais-Jarvis

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Estrogens favor glucose homeostasis primarily through the estrogen receptor-α (ERα), but the respective importance of nuclear ERα (NOER) and membrane ERα (MOER) pools to glucose homeostasis are unknown. We studied glucose homeostasis, insulin secretion, and insulin sensitivity in male and female mice expressing either the NOER or the MOER. Male and female MOER mice exhibited fasting and fed hyperglycemia and glucose intolerance. Female MOER mice displayed impaired central insulin signaling associated with hyperinsulinemia and insulin resistance due to unrestrained hepatic gluconeogenesis, without alterations in glucose-stimulated insulin secretion (GSIS). In contrast, male MOER mice did not exhibit detectable insulin resistance, but showed impaired GSIS associated with reduced brain glucose sensing. Female NOER mice exhibited milder hepatic insulin resistance and glucose intolerance. In conclusion, nuclear ERα signaling is predominant in maintaining glucose homeostasis in mice of both sexes. Lack of nuclear ERα alters the central control of insulin sensitivity in females and predominantly impairs the central regulation of insulin secretion in males.

Original languageEnglish (US)
Pages (from-to)490-501
Number of pages12
Issue number3
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (NIH) (R01-DK-074970 and DK-107444) and a U.S. Department of Veterans Affairs Merit Review Award (BX003725) to F.M.-J. C.A. was supported by American Diabetes Association Post-Doctoral Fellowship (1-16-PDF-004). A.Z. was supported by NIH R01-DK-099598.

Publisher Copyright:
© 2018 by the American Diabetes Association.


  • Animals
  • Blood Glucose/metabolism
  • Cell Membrane/metabolism
  • Cell Nucleus/metabolism
  • Estrogen Receptor alpha/metabolism
  • Female
  • Immunohistochemistry
  • Insulin/blood
  • Insulin Resistance/physiology
  • Insulin Secretion/physiology
  • Liver/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Estrogen/metabolism

PubMed: MeSH publication types

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


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