Trends in Endocrinology & Metabolism
ReviewEmerging roles of GPER in diabetes and atherosclerosis
Section snippets
Estrogen: modulator of metabolic function
The clinical consequences of obesity, insulin resistance, and diabetes account for most of the morbidity and mortality in industrialized countries, largely caused by atherosclerosis leading to coronary artery disease and myocardial infarction, stroke, and peripheral vascular disease [1]. Both atherosclerotic vascular disease and obesity-associated metabolic dysfunction such as in insulin resistance and diabetes share a strong inflammatory component, contributing to disease propagation and
An intracellular transmembrane estrogen receptor
GPER was originally identified through cloning approaches and homology analysis as a 7-transmembrane-spanning GPCR in the mid-1990s 9, 11. As no ligand could be identified in early studies, it was termed GPR30, an orphan receptor designation. Only in 2007, after several laboratories had independently demonstrated estrogen binding to and function through GPR30 12, 13, 14, did the International Union of Basic and Clinical Pharmacology (IUPHAR) officially designate GPR30 as GPER [9].
Models and phenotypes of GPER deficiency
Given the expansive functions of E2 in both sexes discussed above, ascertaining the distinct contributions of individual ERs requires their specific genetic or pharmacological manipulation. The use of transgenic mice has been highly informative in the dissection of the roles of ERα and ERβ [55]. As GPER expression has been detected in most organs and tissues throughout the body 52, 56, yet with cell-type specificity [26], GPER is likely to play important roles in mediating many
GPER and obesity
Both male and female GPER0 mice are obese, with substantial increases in visceral, subcutaneous, and perivascular fat 47, 58, 59, 60, 61. Following ovariectomy, GPER0 mice also exhibit a reduced response to E2 in terms of effects on body weight and adipocyte size and show no improvement in glucose tolerance with E2 supplementation [58]. While GPER0 mice show a decrease in energy expenditure, suggesting alterations in energy metabolism 58, 60, recent data also indicate that hypothalamic
GPER and glucose homeostasis
Estrogen and its receptors play critical roles in glucose homeostasis, the result of glucose-induced insulin production by the pancreas and peripheral insulin responsiveness, including metabolism and storage in multiple peripheral tissues (particularly skeletal muscle, adipose, and liver) 73, 74, 75. In the pancreas, E2 exhibits several important effects, including promoting insulin secretion 76, 77 and synthesis 74, 78, enhancing β cell survival 5, 6, increasing islet oxygenation during
GPER in lipid metabolism, atherosclerosis, and inflammation
Inflammation has been identified as a unifying theme of obesity, diabetes, dyslipidemia, and atherosclerosis and inhibition of inflammation is currently pursued as a means to induce plaque stabilization 1, 2. Dyslipidemia [i.e., high levels of low-density lipoprotein (LDL) cholesterol and triglycerides] is a major risk factor for the development of coronary atherosclerosis and is typically found in patients with obesity, insulin resistance, or diabetes, translating into an increased
Concluding remarks and future perspectives
Since the discovery of GPER, research has helped to identify multiple physiological functions and roles in many organs and we are now beginning to understand its role in disease. There is now good evidence that GPER plays an essential role in metabolic regulation (including lipid and glucose homeostasis as well as insulin production and action), arterial tone, blood pressure, and immune functions (Figure 2), factors that are all linked to the risk of developing coronary artery disease [1].
Disclaimer statement
E.R.P. is an inventor on patents for GPER-targeted ligands and imaging agents owned by the University of New Mexico.
Acknowledgements
Original work by the authors was supported by Swiss National Science Foundation (SNSF) grants 108 258 and 122 504 (M.B.) and National Institutes of Health (NIH) R01 grants CA116662, CA118743, CA127731, and CA163890 (E.R.P.). The authors apologize to those investigators whose work could not be cited due to space limitations.
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