Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice

Abstract

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. IntroductionIn addition to its critical functions as a reproductive hormone, estradiol-17β (E 2 ) plays a vital role in the regulation of energy balance and body weight (1). Estrogen deficiency at menopause is associated with an increased probability of obesity as well as increased risk for the development of type 2 diabetes (2). In experimental animals, reduction of circulating estrogen levels by ovariectomy leads to the development of obesity, which can be reversed or prevented by E 2 treatment (1). The effects of E 2 on energy balance bear many similarities to the actions of leptin and insulin, key molecules involved in energy homeostasis (3, 4). Genetic and pharmacological studies have demonstrated that leptin and insulin act directly on neural networks to modulate energy homeostasis, where the net effect is to decrease food intake and increase energy expenditure (5-9). Both can activate STAT3 in various tissues, and hypothalamic leptin and insulin signaling are known to converge on the PI3K pathway (10-13). Similarly, E 2 is now also known to activate STAT3 as well as PI3K signaling cascades, suggestive of possible cross-talk among these molecules and possibly representing a common neuronal signaling mechanism that may help explain the similarities in their central effects on energy homeostasis (14-17).That these metabolic actions of E 2 are mediated by estrogen receptor α (ERα) has been demonstrated in Erα-null (Erα -/-) mutant mice, in which the ablation of ERα signaling results in a metabolic syndrome characterized by increased body weight, adiposity, altered glucose homeostasis, decreased energy expenditure, hyperinsulinemia, and hyperleptinemia (18)(19)(20). However, these metabolic character-

Estrogen receptor–α in medial amygdala neurons regulates body weight

“…Thus, PPT effects are likely mediated directly via ERα expressed by MeA SIM1 neurons. These findings are consistent with earlier observations that estrogens directly activate other neural populations (12,35,36). Furthermore, we tested the physiological functions of MeA SIM1 neural activation via the DRE-ADD approach.…”

The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol

“…Besides its critical role in reproduction, it has long been recognized that E 2 is an anorexigenic hormone, based on the findings that E 2 replacement attenuates post-ovariectomy weight gain in rodents through decreasing food intake and increasing energy expenditure (4,10,12,29,35,54). These actions of E 2 are thought to be mediated in large part by the transcriptional activity of ER␣, since a loss-of-function mutation in the receptor is associated with hyperinsulinemia and obesity in humans (42), and globally deleting it causes obesity in mice (14,16).…”

Shp2 Controls Female Body Weight and Energy Balance by Integrating Leptin and Estrogen Signals

“…Consistently, ovariectomized rats deficient for estrogen develop obesity and leptin resistance, which can be reversed by E2 replacement therapy (9). A recent report indicates that a mutant ER␣ retaining the activity for noncanonical signaling (lacking the DNA-binding ability to the estrogen response element [ERE]) is sufficient to mediate the antiobese effect of ER␣ in energy homeostasis (28). However, it remains to be elucidated how the estrogen and leptin signals are coupled in regulation of energy metabolism.…”