Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice.
In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null (Erα-/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in Erα-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women.
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Cheryl J
CJ
Park
Zhen
Z
Zhao
Christine
C
Glidewell-Kenney
Milos
M
Lazic
Pierre
P
Chambon
Andrée
A
Krust
Jeffrey
J
Weiss
Deborah J
DJ
Clegg
Andrea
A
Dunaif
J Larry
JL
Jameson
Jon E
JE
Levine
D000818:Animals; D001835:Body Weight / Q000235:genetics; D004435:Eating; D004734:Energy Metabolism / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D006801:Humans; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009043:Motor Activity; D009765:Obesity / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D047628:Estrogen Receptor alpha; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
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