Research ArticleMetabolic Disease

Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes

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Science Translational Medicine  29 Jan 2020:
Vol. 12, Issue 528, eaau5956
DOI: 10.1126/scitranslmed.aau5956

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Mimicking estrogen to target metabolism

Estrogen is known to have positive effects on obesity and metabolism. Here, Sharma et al. show that a small-molecule agonist of one of estrogen’s receptors, the G protein–coupled estrogen receptor (GPER), may have a similar, but more targeted potential as a therapeutic in metabolic disease. In ovariectomized mice, a model of postmenopausal obesity, G-1 agonist treatment increased energy expenditure and had beneficial effects on weight, adiposity, metabolism, and inflammation. However, unlike traditional estrogen replacement therapy, GPER agonism did not affect bone density or result in uterine feminizing effects. G-1 also elicited weight loss in ovariectomized mice on a high-fat diet and prevented weight gain in obese male mice.

Abstract

Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein–coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1–treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.

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