Activation of estrogen response element-independent ERα signaling protects female mice from diet-induced obesity

Ali Yasrebi, Janelle A. Rivera, Elizabeth A. Krumm, Jennifer A. Yang, Troy A. Roepke

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


17β-estradiol (E2) regulates central and peripheral mechanisms that control energy and glucose homeostasis predominantly through estrogen receptor a (ERa) acting via receptor binding to estrogen response elements (EREs). ERa signaling is also involved in mediating the effects of E2 on diet-induced obesity (DIO), although the roles of ERE-dependent and-independent ERa signaling in reducing the effects of DIO remain largely unknown. We hypothesize that ERE-dependent ERa signaling is necessary to ameliorate the effects of DIO. We addressed this question using ERa knockout (KO) and ERa knockin/knockout (KIKO) female mice, the latter expressing an ERa that lacks a functional ERE binding domain. Female mice were ovariectomized, fed a low-fat diet (LFD) or a high-fat diet (HFD), and orally dosed with vehicle or estradiol benzoate (EB) (300 μg/kg). After 9 weeks, body composition, glucose and insulin tolerance, peptide hormone and inflammatory cytokine levels, and hypothalamic arcuate nucleus and liver gene expression were assessed. EB reduced body weight and body fat in wild-type (WT) female mice, regardless of diet, and in HFD-fed KIKO female mice, in part by reducing energy intake and feeding efficiency. EB reduced fasting glucose levels in KIKO mice fed both diets but augmented glucose tolerance only in HFD-fed KIKO female mice. Plasma insulin and interleukin 6 were elevated in KIKO and KO female mice compared with LFD-fed WT female mice. Expression of arcuate neuropeptide and receptor genes and liver fatty acid biosynthesis genes was altered by HFD and by EB through ERE-dependent and-independent mechanisms. Therefore, ERE-independent signaling mechanisms in both the brain and peripheral organs mediate, in part, the effects of E2 during DIO.

Original languageEnglish (US)
Pages (from-to)319-334
Number of pages16
Issue number2
StatePublished - Feb 1 2017

All Science Journal Classification (ASJC) codes

  • Endocrinology


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