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Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice
N Geary1, L Asarian, K S Korach
1Bourne Behavioral Research Laboratory, Department of Psychiatry, New York-Presbyterian Hospital-Weill Medical College of Cornell University, White Plains, New York 10605, USA. ndgeary@med.cornell.edu
Abstract:
To test the role of gene expression of the classical ER (ER alpha) in the inhibitory effects of E on food intake and body weight, we ovariectomized and administered E2 benzoate (75 pg/d) or vehicle to wild-type (WT) mice and mice with a null mutation of ER alpha (alpha ERKO). Mice were ovariectomized at age 9 wk, at which time there was no significant effect of genotype on food intake or body weight. During an 18-d test after recovery from ovariectomy, vehicle-treated WT mice increased daily food intake and gained more body weight than E2-treated WT mice, whereas food intake and body weight gain were not different in E2- and vehicle-treated alpha ERKO mice. Carcass analysis revealed parallel changes in body lipid content, but not water or protein content. Because an increase in the potency of the peripheral cholecystokinin (CCK) satiation-signaling system mediates part of E2's influence on feeding in rats, the influence of ip injections of 250 microg of the selective CCK(A) receptor antagonist devazepide was then tested. Devazepide increased 3-h food intake in E2-treated WT mice, but was ineffective in both groups of alpha ERKO mice. Furthermore, ip injections of 4 microg/kg CCK-8 increased the number of cells expressing c-Fos immunoreactivity in the nuclei of the solitary tract of E2-treated WT mice more than it did in vehicle-treated WT mice, whereas E2 had no such effect in alpha ERKO mice. Thus, ER alpha is necessary for normal responsivity of food intake, body weight, adiposity, and the peripheral CCK satiation-signaling system to E2 in mice, and ER beta is not sufficient for any of these effects. This is the first demonstration that ER alpha gene expression is involved in the estrogenic control of feeding behavior and weight regulation of female mice.
Insights
Estrogen receptor alpha (ER alpha) gene expression is essential for estrogen
Area of Science:
- Endocrinology
- Neuroscience
- Molecular Biology
Background:
- Estrogen plays a role in regulating food intake and body weight.
- The specific role of estrogen receptor alpha (ER alpha) in these effects is not fully understood.
Purpose of the Study:
- To investigate the necessity of ER alpha gene expression for estrogen's inhibitory effects on food intake and body weight.
- To determine if ER beta can compensate for the absence of ER alpha.
Main Methods:
- Ovariectomized wild-type (WT) and ER alpha knockout (alpha ERKO) mice were administered estrogen (E2) or vehicle.
- Food intake, body weight, and body composition were measured.
- The effects of cholecystokinin (CCK) signaling and CCK receptor antagonist devazepide were assessed.
- Central nervous system responses to CCK were evaluated using c-Fos immunoreactivity.
Main Results:
- E2 reduced food intake and body weight gain in WT mice, but not in alpha ERKO mice.
- E2 treatment increased sensitivity to CCK in WT mice, evidenced by reduced food intake and increased c-Fos expression in the solitary tract, an effect absent in alpha ERKO mice.
- ER alpha was necessary for E2's effects on adiposity and CCK signaling.
Conclusions:
- ER alpha gene expression is critical for estrogen's regulation of food intake, body weight, and adiposity in female mice.
- ER alpha mediates estrogen's influence on the peripheral CCK satiation system.
- ER beta is insufficient to mediate these estrogenic effects.