ReviewSexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis
Introduction
The role of sex hormones in regulating metabolic function has become a topic of interest and is of great importance, largely due to the function of sex hormones in regulating the sexual dimorphisms seen in body weight, food intake, obesity, reproduction, and eating disorders. Estrogens (17β-estradiol) have been demonstrated to play a role in regulating adiposity, reproduction (Bellefontaine and Elias, 2014) and insulin sensitivity (Brown and Clegg, 2010, Ropero et al., 2008). Additionally, recent papers have demonstrated a critical role for three putative estrogen receptors in modulating adiposity, insulin sensitivity, and energy homeostasis. Specifically, estrogen receptor alpha (ERα/ERS1), estrogen receptor beta (ERβ/ERS2), as well as G protein-coupled estrogen receptor (GPER) have been demonstrated to regulate energy homeostasis (Brown and Clegg, 2010, Mauvais-Jarvis et al., 2013, Sharma et al., 2013, Shi et al., 2009). Importantly, the findings with respect to GPER and its effects on metabolic homeostasis differ between publications. In the late 1990s, four independent laboratories cloned a putative G protein-coupled receptor (GPCR) using different approaches (Carmeci et al., 1997, O'Dowd et al., 1998, Owman et al., 1996, Takada et al., 1997). Expression studies indicate that GPER mRNA is expressed in numerous tissues throughout the body (e.g. placenta, lung, liver, prostate, ovary, and brain), although there are contradictions in patterns of tissue expression (Carmeci et al., 1997, Owman et al., 1996, Takada et al., 1997).
Estrogens bind to GPER and the selective estrogen antagonists, ICI 182,780 and tamoxifen, block GPER's estrogenic effects (Thomas et al., 2005). Despite demonstrations of the estrogenic activity of GPER, controversy about the cellular and organismal function of GPER remains. GPER knockout (GPER KO) mice have been used to explore the in vivo estrogenic activation of GPER to mediate thymus size (mice were 8–10 weeks old; Wang et al., 2008), vascular disease (mice were 10–11 months old; Haas et al., 2009), glucose tolerance (mice were 6 months of age; Martensson et al., 2009), pancreatic islet survival (mice were 8 weeks old; Liu et al., 2009), and reproductive function (mice were 8–10 weeks old; Otto et al., 2009). Importantly, the role for GPER in regulating energy homeostasis remains controversial. Haas et al. (2009) reported increased body weight and visceral adiposity in male and female GPER KO mice using the Wang et al. mouse model (mice were 10–11 months of age; Wang et al., 2008); however, these findings contrasted those of Liu et al. using the same mutant mouse model from a different laboratory (mice were 7–9 weeks in the Liu et al. experiments; Liu et al., 2009). Other laboratories have reported that neither male nor female mice show significant differences in body weight or visceral adiposity when compared to their WT littermates (mice were 3–4 months of age; Otto et al., 2009, Windahl et al., 2009). Martensson et al. (2009) reported female, but not male mutant mice present with reduced body weight and skeletal growth (mice were 3–4 months of age). In contrast, Isensee et al. reported no significant differences in body weight or fat mass between WT and GPER KO animals when exposed to either a normal or high fat diet (mice were 6 months old; Isensee et al., 2009). And lastly, Sharma et al. (2013) recently demonstrated that male GPER mice have increased body adiposity (mice were 12 months old), insulin resistance (mice were 12–18 months old), increased proinflammatory cytokines (mice were 12–24 months old), and reductions in circulating adiponectin levels (mice were 12–24 months old). These disparate findings with respect to the role of GPER in modulating energy homeostasis suggest that environmental factors, method of gene deletion, age of mice, and the genetic background of GPER KO mouse models may contribute to controversies associated with the role of GPER in body weight homeostasis.
Recently, Sharma et al. demonstrated that male GPER KO mice have increased body weight, adiposity, inflammation, and energy expenditure (Sharma et al., 2013). Importantly, the temporal development of body weight gain and sexual dimorphisms in the onset of weight gain have not been determined. Here we present data demonstrating a metabolic phenotype of GPER KO mice developed by Wang et al. (2008). Our mouse model was generated using a heterozygous breeding strategy. We compared the phenotype of GPER KO mice directly to WT littermates obtained from these heterozygous intercrosses. Additionally, our GPER KO mice have been backcrossed for more than 10 generations onto the C57BL6 background indicating a 99% inbred background strain. We determined that GPER KO males and females differ from WT males and females with respect to circulating concentrations of leptin, insulin, adiponectin, and thermogenic brown adipose tissue proteins and sensitivity to leptin, CCK and estradiol. Lastly, we demonstrate the intracellular location of GPER within adipose tissue.
Section snippets
Animals
All work was conducted in accordance with the animal care committee at UT Southwestern Medical Center. The GPER KO mice and wild-type (WT) littermates were a generous gift of Dr. Janice S. Rosenbaum (Proctor & Gamble, Cincinnati, OH) (Haas et al., 2009, Sharma et al., 2013, Wang et al., 2008). GPER KO mice were generated by transfecting embryonic stem cells with a targeting construct containing the GPER (gene encoding GPER) locus followed by verification of successful gene targeting (Wang et
Food intake and body weight
There were no differences between the GPER KO and WT mice with respect to breeding capabilities, litter size, or pup weights at time of birth. Male and female GPER KO mice were weaned at 3–4 weeks of age and their food intake and body weights were determined weekly. Data presented are from a minimum of 20 different litters of mice, and there were no differences between mice within a litter or from different litters. Body weights of GPER KO mice are indistinguishable at weaning; however, as the
Discussion
The main findings of this study are that there is a strong sexual dimorphism in the temporal onset of body weight gain in GPER KO mice. We also found that: 1) male GPER KO mice develop moderate obesity as they age and this is associated with reductions in energy expenditure, increased fat cell size, and increased lipid in brown adipose tissue; 2) female GPER KO mice do not differ with respect to adiposity when compared to WT mice initially; however, as the mice age there is a divergence in body
Acknowledgments
We thank Dr. Roger Unger for providing us the human leptin. We also thank Dr. Nedungadi for performing the leptin and insulin assays. This work was supported by the National Institute of Health grant numbers DK073689 and DK088761.
References (51)
- et al.
Minireview: metabolic control of the reproductive physiology: insights from genetic mouse models
Horm. Behav.
(2014) - et al.
Central effects of estradiol in the regulation of food intake, body weight, and adiposity
J. Steroid Biochem. Mol. Biol.
(2010) - et al.
Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice
Physiol. Behav.
(2006) - et al.
Modulation of the satiety effect of cholecystokinin by estradiol
Physiol. Behav.
(1993) - et al.
Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer
Genomics
(1997) - et al.
The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis
Mol. Metab.
(2013) - et al.
GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release
Trends Endocrinol. Metab.
(2005) Endocrine controls of eating: CCK, leptin, and ghrelin
Physiol. Behav.
(2004)- et al.
Discovery of three novel G-protein-coupled receptor genes
Genomics
(1998) - et al.
Cloning of cDNA encoding a putative chemoattractant receptor
Genomics
(1996)
Proximal events in signaling by plasma membrane estrogen receptors
J. Biol. Chem.
The role of estrogen receptors in the control of energy and glucose homeostasis
Steroids
Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators
Front. Neuroendocrinol.
Sexual differences in the control of energy homeostasis
Front. Neuroendocrinol.
Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress
Biochem. Biophys. Res. Commun.
Attenuation of fasting-induced phosphorylation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus in response to refeeding
Neurosci. Lett.
Gonadal effects on food intake and adiposity: a metabolic hypothesis
Physiol. Behav.
PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis
Cell Metab.
Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Changes in proopiomelanocortin messenger ribonucleic acid levels in the rostral periarcuate region of the female rat during the estrous cycle
Endocrinology
Effects of leptin administration on long-term selected fat mice
Genet. Res.
A sexually dimorphic distribution pattern of the novel estrogen receptor G-protein-coupled receptor 30 in some brain areas of the hamster
J. Endocrinol.
Gonadal hormones determine sensitivity to central leptin and insulin
Diabetes
Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats
Diabetes
Estradiol treatment increases feeding-induced c-Fos expression in the brains of ovariectomized rats
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Cited by (82)
Aromatase enzyme: Paving the way for exploring aromatization for cardio-renal protection
2023, Biomedicine and PharmacotherapyGPER involvement in inflammatory pain
2023, SteroidsEstrogen as a key regulator of energy homeostasis and metabolic health
2022, Biomedicine and Pharmacotherapy