Abstract
ObjectiveStudies using the estrogen receptor alpha (ERα) knock-out (αERKO) mice have demonstrated that ERα plays a crucial role in various estrogen-mediated metabolic regulations. ERα is a ligand dependent transcription regulator and its activity is regulated by estrogenic compounds. ERα consists of two transcriptional activation domains, AF-1 and AF-2. The activities of these domains are regulated through different mechanisms; however, the specific physiological role in metabolic regulation by these domains is still unclear. MethodsWe utilized an ERα AF-2 mutant knock-in mouse (AF2ERKI) to evaluate the physiological functionality of ERα transactivation domains. Due to the estrogen insensitive AF-2 mutation, the phenotypes of AF2ERKI mice are seemingly identical to the global αERKO including obesity in the females. Distinct from the αERKO, the AF-1 function of AF2ERKI mice can be activated by tamoxifen (Tam). Ovariectomized (OVX) AF2ERKI and WT females were treated with Tam and fed a high-fat diet (HFD) for 10 weeks. Additionally, indirect calorimetric analysis was performed using metabolic chambers with food intake and locomotor activity recorded for Tam-treated AF2ERKI and αERKO females. ResultsObesity in HFD-fed AF2ERKI females was prevented by Tam treatment; particularly, inguinal fat accumulation was strongly blocked by Tam treatment. Alterations in fat metabolism genes, however, were not found in either inguinal fat nor visceral fat to be Tam-regulated, even though fat accumulation was strongly reduced by Tam treatment. Indirect calorimetric analysis revealed that without alteration of food intake and locomotor activity Tam treatment increased energy expenditure in AF2ERKI but not αERKO females. ConclusionsThese results suggest that the activation of ERα AF-1 prevents fat accumulation. The prevention of obesity through AF-1 is mediated by induction of energy expenditure rather than ERα AF-1 functionality of lipid metabolism gene regulation in fat tissues.
Highlights
Menopausal women develop various symptoms, including weight gain and reduction in metabolism, due to the natural reduction of ovarian estrogen production
Obesity in high fat diet (HFD)-fed AF2ERKI females was prevented by Tam treatment; inguinal fat accumulation was strongly blocked by Tam treatment
Indirect calorimetric analysis revealed that without alteration of food intake and locomotor activity Tam treatment increased energy expenditure in AF2ERKI but not alpha (ERa) knock-out (aERKO) females. These results suggest that the activation of estrogen receptor alpha (ERa) AF-1 prevents fat accumulation
Summary
Menopausal women develop various symptoms, including weight gain and reduction in metabolism, due to the natural reduction of ovarian estrogen production. Animal studies using the estrogen receptor (ER) a knock-out (aERKO) mice have demonstrated that the effects and phenotypes of aERKO females are similar to those experienced by post-menopausal women [1]. ERa is a ligand dependent transcription regulator, and its activity is modulated by estrogenic compounds. Estrogenic compounds bind to the ligand binding domain and control the functionality of the transcriptional activation domains of ERa, named AF-1 and AF-2. The aERKO mouse model, which does not express ERa protein, cannot define such precise domain functionality in vivo. For this purpose, AF-1 or AF-2 deleted mutant mice (ERaAF-1/ ERaAF-1À/À or ERaAF-2, respectively) have been reported [3]. Genetic modification in the ERaAF-1 mouse forces translation of a N-
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