GPER-selective agonist G-1 reduced body weight and improved glucose homeostasis in female mouse models of obesity and diabetes

Human obesity has reached epidemic levels, yet safe and effective pharmacological treatments are scarce. Postmenopausal women experience a significant drop in ovarian estradiol (E2), which dramatically increases their risk of obesity and metabolic dysfunction, highlighting the hormone's critical metabolic role. Traditionally, E2's benefits are thought to be mediated by the classical estrogen receptors ERα and ERβ. However, the specific contribution of the G protein-coupled estrogen receptor (GPER) has remained largely unexplored. This study investigates whether selectively activating GPER could provide the metabolic benefits of estrogen without the unwanted feminizing side effects, offering a novel therapeutic avenue for metabolic syndrome.

The study evaluated the preclinical efficacy of the GPER-selective small-molecule agonist G-1 (also called Tespria). Researchers used multiple mouse models: ovariectomized female mice to simulate postmenopausal obesity, and diet-induced obesity (DIO) models in both male and female mice. The primary endpoints were changes in body weight, glucose homeostasis, energy expenditure, and body composition. Key biomarkers like fasting cholesterol, glucose, insulin, and inflammatory markers were also measured. The study assessed potential side effects by examining uterine imbibition (a measure of feminizing effects) and bone health.

In ovariectomized female mice, G-1 treatment reduced body weight and improved glucose homeostasis. This occurred without any changes in food intake, fuel source usage, or locomotor activity. Instead, the weight loss was driven by increased energy expenditure. These mice also showed lower body fat content and reduced fasting cholesterol, glucose, insulin, and inflammatory markers. Critically, G-1 did not cause uterine imbibition, indicating a lack of unwanted feminizing effects, though it also did not benefit bone health. In DIO male mice, G-1 did not cause weight loss but did prevent further weight gain and improved glucose tolerance, suggesting its glucose-regulating effects are independent of weight loss.

However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, highlighting potential sex-specific differences in its mechanism of action. The results demonstrate that GPER agonism effectively counters obesity and metabolic dysfunction across multiple preclinical models.