Obesity affects 40% of adults in the United States, resulting in health conditions that include heart disease, high blood pressure, type 2 diabetes and some cancers. According to the U.S. Centers for Disease Control and Prevention, obesity and its related conditions far outweigh other causes of death. Current drugs for obesity don’t effectively reduce it or have undesirable side effects. PhD Eric Prossnitz and his team hope to help 93 million obese Americans fight their fat. In a paper published in Science Translational Medicine, they reported that G-1, an anticancer compound they discovered some years ago, reduces fat in obese mice. Although G-1 is currently in phase 1 clinical trials for cancer, Prossnitz and his team are planning preclinical studies to use G-1 to fight obesity. Prossnitz and his team have been studying GPER, the G protein-coupled estrogen receptor discovered 20 years ago. Classically, estrogens have been associated with intracellular receptors of the steroid superfamily, called nuclear receptors. These are transcription factors, whose activity is regulated upon binding with hormones. This interaction allows the expression of a battery of genes responsible for the bioactivity of each hormone.
GPER, instead of being inside cells, is located on their surface, as a membrane receptor. G-1 activates this receptor, because GPER affects certain breast cancer cells. When breast cancer drugs like tamoxifen and fulvestrant block nuclear estrogen receptors, they also activate GPER. 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 estrogen is lacking. Estrogen is considered a female hormone, although men produce it at low levels. Low estrogen in women is a hallmark of menopause, and postmenopausal women also have higher rates of heart disease, high blood pressure, obesity and diabetes. So to understand whether G-1 might affect metabolism in postmenopausal women, the team studied mice with low estrogen levels. In their studies, low-estrogen 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, they lost weight and their diabetes went away.
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. In other words, their metabolism changed and the mice showed an increased energy expenditure. Prossnitz’s team also studied male mice, which have naturally low levels of estrogen. The male mice were fed a high-fat diet, which made them obese and diabetic, and then some were treated with G-1. Although the treated mice did not lose weight, they did not gain additional weight either, like the untreated mice. More importantly, their diabetes improved; this 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. Finally, the team also fed a high-fat diet to low-estrogen female mice. These mice became obese very quickly, but just like their sisters on a normal mouse diet, they lost weight and their diabetes improved when they were treated with G-1.
These results, says Prossnitz, 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. 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 suggesting that G-1 may reduce obesity by targeting brown fat cells that burn extra calories. 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 revolutionize the treatment of metabolic disorders. In the meantime, researchers are starting the long path toward clinical trials that will test the properties of G-1.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in CLinical Biochemistry