Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development.

Abstract

ERα is expressed in macrophages and other immune cells known to exert dramatic effects on glucose homeostasis. We investigated the impact of ERα expression on macrophage function to determine whether hematopoietic or myeloid-specific ERα deletion manifests obesity-induced insulin resistance in mice. Indeed, altered plasma adipokine and cytokine levels, glucose intolerance, insulin resistance, and increased adipose tissue mass were observed in animals harboring a hematopoietic or myeloid-specific deletion of ERα. A similar obese phenotype and increased atherosclerotic lesion area was displayed in LDL receptor-KO mice transplanted with ERα(-/-) bone marrow. In isolated macrophages, ERα was necessary for repression of inflammation, maintenance of oxidative metabolism, IL-4-mediated induction of alternative activation, full phagocytic capacity in response to LPS, and oxidized LDL-induced expression of ApoE and Abca1. Furthermore, we identified ERα as a direct regulator of macrophage transglutaminase 2 expression, a multifunctional atheroprotective enzyme. Our findings suggest that diminished ERα expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice.

• Authors: Vicent Ribas, Brian G Drew, Jamie A Le, Teo Soleymani, Pedram Daraei, Daniel Sitz, Laila Mohammad, Darren C Henstridge, Mark A Febbraio, Sylvia C Hewitt, Kenneth S Korach, Steven J Bensinger, Andrea L Hevener
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 39 Pg. 16457-62 (Sep 27 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21900603 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Interleukin-4
• Glucose

Topics

• Adiposity
• Animals
• Atherosclerosis (pathology)
• Bone Marrow (metabolism)
• Estrogen Receptor alpha (genetics, metabolism, physiology)
• Female
• Glucose (metabolism)
• Homeostasis
• Insulin Resistance
• Interleukin-4 (physiology)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout