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GPER-selective agonist

Cancer-fighting compound combats obesity and diabetes in mice

When the researchers treated these obese female mice with G-1, the mice lost weight and their diabetes went into remmission

G-1, a cancer-fighting compound currently in phase 1 clinical trials for cancer, reduces fat in obese mice, according to researchers led by a team from the University of New Mexico Health Science Center. In the paper, ‘Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes’, published in the journal Science Translational Medicine, they reported that a small-molecule agonist of one of oestrogen’s receptors, the G protein coupled estrogenic receptor (GPER), may have a similar, but more targeted potential as a therapeutic in metabolic disease.

Obesity affects 40% of adults in the US, resulting in health conditions that include heart disease, high blood pressure, type 2 diabetes and some cancers. According to the US Centers for Disease Control and Prevention, obesity and its related conditions far outweigh other causes of death. Current drugs for obesity do not effectively reduce it or have undesirable side effects.

Dr Eric Prossnitz and his team from the University of New Mexico Health Science Center have been studying GPER, the G protein-coupled estrogenic receptor that G-1 (also called Tespria) activates, because GPER affects certain breast cancer cells. When breast cancer drugs like tamoxifen and fulvestrant block estrogenic receptors in a cell's nucleus, they also activate GPER, which is found in cell membranes.

Prossnitz's previous studies showed that GPER may play a role in resistance to tamoxifen and similar drugs, and that led him to wonder how G-1 affects non-cancerous cells when oestrogen is lacking.

Oestrogen is considered a female hormone, although men produce it at low levels. Low oestrogen in women is a hallmark of menopause, and postmenopausal women also have higher rates of heart disease, high blood pressure, obesity and diabetes. To understand whether G-1 might affect metabolism in postmenopausal women, Prossnitz and his team studied mice with low oestrogen levels.

In ovariectomised 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 oestrogen replacement therapy, GPER agonism did not affect bone density or result in uterine feminising effects. G-1 also elicited weight loss in ovariectomised mice on a high-fat diet and prevented weight gain in obese male mice.

In addition, the low-oestrogen female mice gained weight rapidly, even on a normal diet, and quickly became obese and diabetic. When the researchers treated these obese female mice with G-1, the mice lost weight and their diabetes went into remmission.

The researchers determined that the weight loss wasn't due to the mice eating less or moving around more; it resulted from what their bodies did with the calories they ate. Instead of storing calories as fat, the mice used them as fuel.

"Their metabolism changed," explained Prossnitz. "The mice showed an increased energy expenditure. This result suggests that G-1 has separate effects on obesity and diabetes. The G-1-treated male mice were metabolically healthier, even though they were still obese."

These results could point to a sex difference in the effects of the drug or in the way GPER signals in the cells of males and females, he added.

To learn about how G-1 increases energy expenditure, the team studied brown fat cells, which generate heat instead of storing excess calories as fat. What they found surprised them: when treated with G-1, the cells expended more energy.

"This fits nicely with what we saw in mice and suggests that G-1 may reduce obesity by targeting brown fat cells that burn extra calories."

The researchers concluded that “G-1 is a bona fide first-in-class candidate prototype drug for potential translation into clinical applications. Future translational studies in men and women will ultimately establish the value of G-1 in obese and diabetic patients.”

In a future series of experiments, Prossnitz plans to study how signals from GPER induce the cellular changes that cause more energy to be used. He hopes that one day soon G-1 could revolutionise the treatment of metabolic disorders.

In the meantime, he and his team are starting the long path toward clinical trials that will test the ability G-1 to fight obesity and diabetes in people.

To access this paper, please click here

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