PROJECT SUMMARY/ABSTRACT
Obesity poses as a serious and worsening public health issue in the United States and is the second
most common cause of preventable death behind smoking. Obesity is associated with the risk of developing
additional comorbidities, such as hypertension, atherosclerosis, and diabetes.
Estrogens (primarily 17ß-estradiol, referred to as E2) can ameliorate weight gain and multiple aspects
of metabolic dysfunction. The effects of estrogens are mediated through multiple estrogen receptors (ERs),
including the classical nuclear ERs (ERa and ERß), which traditionally regulate gene expression, and the 7-
transmembrane G protein-coupled estrogen receptor (GPER), which predominantly mediates rapid “non-
genomic” signaling. Our preliminary results suggest a potential intervention employing a highly selective GPER
agonist, with promising outcomes against multiple negative effects of obesity. With the opportunity to employ
the GPER-selective agonist G-1 as a novel therapeutic for obesity, understanding the direct effects of GPER in
adipocytes is critical. The long-term goal is to determine whether selective activators of GPER, such as G-1,
can improve lipid homeostasis, oxidative stress, and inflammation in adipocytes. The overall objective of this
proposal is to understand the mechanisms of E2-mediated effects via GPER in metabolic regulation,
specifically in adipocytes. The central hypothesis to be tested is whether GPER signaling directly improves lipid
homeostasis, oxidative stress, inflammation, and mitochondrial function in adipocytes. These findings will
inform drug development by making significant advancements in our knowledge regarding the role of GPER in
obesity and lipid metabolism, ultimately advancing the current insufficient therapeutic treatment options
available for obesity. The specific aims of this proposal are: Aim 1: Evaluate the roles of GPER in lipid
metabolism of adipocytes. The working hypothesis for this aim is that GPER’s effects on obesity are in part
mediated by direct actions on lipid metabolism on adipocytes. Aim 2: Determine the role of GPER in
oxidative stress, inflammation, and mitochondrial function in adipocytes. The working hypothesis for this
aim is that GPER plays a direct protective role against oxidative stress, inflammation, and improves
mitochondrial function in adipocytes.
This proposal will investigate the direct effects of GPER in adipocytes pertaining to lipid homeostasis,
oxidative stress, inflammation, and mitochondrial function, with the potential to significantly advance the study
of novel therapeutics protecting against obesity.