Editors' ChoiceMetabolic Syndrome

Estrogen and Energy Balance

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Science Translational Medicine  02 Feb 2011:
Vol. 3, Issue 68, pp. 68ec13
DOI: 10.1126/scitranslmed.3002176

Estrogen is well known as a reproductive hormone but also has critical roles in energy balance. For example, reduction of estrogen levels in animal models causes obesity. In its “classical” signaling pathway, estrogen invokes its biological responses through its interaction with an intracellular estrogen receptor (ER)—which exists in ERα and ERβ isoforms—that then binds to estrogen response elements in DNA to regulate the transcription of target genes. Nonclassical signaling pathways also exist, which do not involve ER binding to estrogen response elements. Experiments with knockout mice have shown that ERα mediates estrogen’s actions on energy balance and body weight: Erα-null (but not Erβ-null) mutant mice exhibit features of the metabolic syndrome, including obesity and altered glucose homeostasis. However, the mechanisms by which ERα signaling maintains normal energy balance have been uncertain. Well, until now.

In a series of elegant experiments using Erα-null mutant mice and knockin mice expressing a mutant form of ERα that can only signal through the nonclassical pathway, Park et al. found that nonclassical ERα signaling was sufficient to restore metabolic parameters—including body weight, adiposity, locomoter activity, energy expenditure, and blood glucose and leptin concentrations—that are dysregulated in Erα-null mice back to normal or near-normal values. In particular, the “rescue” of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity, which is typically decreased in ERα-deficient states. The investigators also found that restoring nonclassical ERα signaling in the mice was sufficient to prevent the development of insulin resistance.

Given the propensity of postmenopausal women to gain weight and develop type 2 diabetes, these studies in mice might be directly translatable to humans and suggest that nonclassical ERα signaling pathways may be important new drug targets for the treatment of metabolic disorders in estrogen-deficient states.

C. J. Park et al., Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. J. Clin. Invest. 18 January 2011 (10.1172/JCI41702). [Full Text]

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