NYMC Researchers Partners with Regeneron to Discover GPR75 Gene Mutations that Protect Against Obesity
Publication in Science Reports That People With These Protective Mutations Have 54% Reduced Risk of Obesity
Researchers from New York Medical College (NYMC) and Regeneron Genetics Center (RGC) have discovered rare genetic mutations in the GPR75 gene associated with protection against obesity. As reported in Science, almost 650,000 people were sequenced to find rare individuals with this genetic 'superpower,' providing new insights into the genetic basis of obesity. It is estimated that more than one billion people could be suffering from obesity (body mass index [BMI] of 30 or higher) by 2030.
NYMC researchers in the labs of Michal L. Schwartzman, Ph.D., professor and chair of the Department of Pharmacology, and Victor Garcia, Ph.D., assistant professor of pharmacology, in collaboration with RGC scientists found that individuals who have at least one inactive copy of the GPR75 gene have lower BMI and, on average, tend to weigh about 12 pounds less and face a 54 percent lower risk of obesity than those without the mutation. Protective 'loss of function' mutations were found in about one of every 3,000 people sequenced.
Previous to this latest study, Dr. Garcia, while still an NYMC graduate student under Dr. Schwartzman’s mentorship, found the orphaned G-protein coupled receptor, GPR75, to be the cellular target for the vasoactive and pro-inflammatory lipid 20-HETE (Circulation Research 2017). In a subsequent 2021 study published in the British Journal of Pharmacology, the molecular underpinnings of GPR75, were further characterized by Dr. Garcia’s lab, with relatively low levels of 20-HETE found to trigger a physiological response in GPR75. Jonathan Pascale, a graduate student in the NYMC Graduate School of Basic Medical Sciences (GSBMS) Integrated Ph.D. Program, served as the lead author on the publication.
That initial discovery led to the beginning of a steadfast collaborative effort between Dr. Schwartzman’s lab and Regeneron to develop and characterize mice deficient in GPR75 using Regeneron’s VelociMouse® technology. Such mice gained 44 percent less weight than mice without the mutation when both groups were fed a high-fat diet.
“In our preliminary studies, we identified protection from diet-driven obesity and associated metabolic and cardiovascular complications in GPR75 knockout mice,” said Dr. Schwartzman. “This remarkable observation mirrored previous findings that identified an association between high-fat, diet-induced obesity in animal models and BMI in humans and 20-HETE levels, implicating 20-HETE as a key mediator driving weight gain and a diabetic phenotype (hyperglycemia and insulin resistance) in mice.” These studies were conducted by Ankit Gilani, GSBS’18 and Sakib Hossain, GSBS Class of 2022.
During the height of the COVID-19 pandemic, Dr. Schwartzman was approached by Regeneron with some interesting new findings generated by the RGC in which they analyzed de-identified genetic and associated health data from over 640,000 patients and identified several key GPR75 variants associated with protection from obesity.
“This collaboration between NYMC and Regeneron highlights the clinical significance behind understanding the biology of 20-HETE and its receptor, GPR75,” said Dr. Schwartzman.
While the discovery of GPR75 helps to better understand the influence of genetics on obesity, further studies and evaluation are needed to determine if reducing weight in this manner can also lower the risk of conditions commonly associated with high BMI, such as heart disease, diabetes, high blood pressure and fatty liver disease. Dr. Schwartzman and Dr. Garcia continue their research into 20-HETE receptor (GPR75) blockers as novel therapeutics for the treatment of obesity. In addition, Sachin Gupte, M.D., Ph.D., professor of pharmacology, is exploring the role of GPR75 in pulmonary hypertension, while Ercument Dirice, Ph.D., assistant professor of pharmacology is studying GPR75’s role in diabetes.
"The discovery of GPR75 is already enabling Regeneron and our collaborators to identify potential ways to safely replicate the effect of this mutation through novel therapeutic approaches," said Aris Baras, M.D., senior vice president at Regeneron and head of the RGC. "This is the latest in a long line of protective human genetics discoveries that have fueled new therapeutics programs at Regeneron. The pace is only quickening, as we uncover more and more about the human genome and work to rapidly translate those discoveries to the development of new medicines."
