The effects of G protein-coupled receptor 30 (GPR30) on cardiac glucose metabolism in diabetic ovariectomized female rats

Abstract

Background Diabetic cardiometabolic disorders are characterized by significant changes in cardiac metabolism and are increased in postmenopausal women, which emphasize the role of 17β-estradiol (E2). Despite this, there are few safe and effective pharmacological treatments for these disorders. The role of G protein-coupled estrogen receptor (GPR30), which mediates the non-genomic effects of E2, is mostly unexplored. Methods In this study, we used ovariectomy (menopausal model) and type 2 diabetic (T2D) rats’ models to evaluate the preclinical action of G-1 (GPR30 agonist) against cardiometabolic disorders. T2D was induced by a high-fat diet and a low dose of streptozotocin. G-1 was administrated for six weeks after the establishment of T2D. Results We found that G-1 counteracts the effects of T2D and ovariectomy by increasing the body weight, reducing fasting blood sugar, heart weight, and heart weight to body weight ratio. Also, both ovariectomy and T2D led to decreases in the cardiac protein levels of hexokinase 2 (HK2) and GLUT4, while G-1–treated female rats reversed these changes and only increased HK2 protein level. In addition, T2D and ovariectomy increased glucose and glycogen content in the heart, but G-1 treatment significantly reduced them. Conclusions In conclusion, our work demonstrates that G-1 as a selective GPR30 agonist is a viable therapeutic approach against T2D and cardiometabolic diseases in multiple preclinical female models.

The G-Protein-Coupled Estrogen Receptor Agonist Prevents Cardiac Lipid Accumulation by Stimulating Cardiac Peroxisome Proliferator-Activated Receptor α: A Preclinical Study in Ovariectomized-Diabetic Rat Model

“…The protective cardio-metabolic effects of GPER in diabetic patients ( 17 ) and menopausal-diabetic rats ( 15 ) have recently been reported, but the mechanisms involved are not yet well understood. Since both diabetes and menopause are associated with changes in cardiac metabolism, which lead to functional changes in the heart and reduced cardiac function ( 16 , 20 ), in this study, we used a model of postmenopausal diabetes to determine the impact of selective GPER agonist on cardiac lipid metabolism as a possible protective mediator. The most important findings of this study are as follows: First, T2DM increased the accumulation of lipids within cardiomyocytes by increasing the cardiac level of FFAs and the expression of CD36, as well as decreasing the expression of PPARα.…”

“…After 72 hours, blood samples were collected from their tails, and rats with a fasting blood sugar (FBS) of ≥ 300 mg/dL were considered diabetic and included in the study. After confirmation of T2DM, a vehicle (0.1% dimethyl sulfoxide [DMSO]; Sigma USA) and G1 (200 μg/Kg; Tocris Bioscience, USA) were administered intraperitoneally 3 days per week for 6 weeks ( 16 ). Body weight was recorded at the end of the experiment.…”

“…ERα and ERβ act through the genomic pathway, while GPER acts through the non-genomic pathway and is responsible for the rapid effects of E2 ( 15 ). Studies have shown that GPER has cardiovascular protective ( 16 ) and anti-diabetic effects ( 17 ) in a postmenopausal diabetic condition, but its mechanism of action is not well understood. Based on genetic and pharmacological approaches, a growing body of experimental evidence highlights the role of GPER in E2 function and, in particular, the adjustment of metabolism and cardiovascular function ( 17 ).…”

Tamoxifen Like Estradiol Attenuates Systemic Inflammation in Young and Aged Female Mice Fed with High-Fat Diet

“…It has been found that there is a direct link between the consumption of HFD and aging (12), which is associated with tissue and systemic inflammation and general dysfunction of the body (13). On the other hand, the prevalence of inflammatory diseases in women is lower than in men, which is probably due to the effects of ovarian hormones, especially E2 (14,15). However, this protection decreases with age, menopause, and ovariectomy (16).…”

Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate

“…Es are undeniably protective in women, and their decline during and after menopause coincides with increased CV risk and HF development [ 11 ]. Es are known to positively impact cardiac function, remodeling, and metabolism among their functions [ 8 , 12 , 13 , 14 ]. For these reasons, E replacement therapy (ERT) has been proposed as a therapeutic strategy to treat post-menopausal women [ 14 , 15 , 16 , 17 , 18 , 19 ].…”