UT Southwestern researchers have identified a cellular mechanism that caused obese mice to lose more than a third of their body weight, pointing to a potential new direction for obesity treatment. The study, published in Cell Metabolism, focuses on a protein that has previously played a supporting role in current weight-loss medications.
The research centers on the glucose-dependent insulinotropic polypeptide receptor (GIPR), which appears in fat cells. When researchers increased the amount of this receptor in mouse fat cells, the animals lost approximately 35% of their body weight within two weeks.
“Our study brings GIPR in fat cells to light as a meaningful target for the development of future therapeutic interventions for the treatment of obesity and its associated metabolic diseases,” says study leader Christine M. Kusminski, Associate Professor of Internal Medicine in the Touchstone Center for Diabetes Research at UT Southwestern.
The findings gain significance against the backdrop of the global obesity crisis, which affects more than a billion people worldwide according to the World Health Organization. Obesity increases risk for numerous health problems, including cardiovascular diseases, Type 2 diabetes, sleep apnea, osteoarthritis, and certain cancers.
The research also reveals an intriguing phenomenon: when researchers stopped the extra GIPR production after several weeks, the mice maintained their lower weight. This “metabolic memory” continued to protect against obesity even without additional GIPR in fat cells. This finding contrasts with current weight-loss medications, where patients typically regain weight after stopping treatment.
The research team, including first author Xinxin Yu and Touchstone Center Director Philipp Scherer, discovered that the weight loss occurs through a process called futile calcium cycling. When fat cells produce extra GIPR, they increase activity in cellular pathways that transport calcium, burning extra energy even when the calcium isn’t being moved.
The study helps explain why newer weight-loss drugs that target both GIPR and another protein called GLP-1R show stronger results than medications targeting GLP-1R alone. While GLP-1R drugs work primarily by affecting appetite through brain signals, GIPR appears to work directly on fat cells to increase energy expenditure.
The findings also suggest potential for developing treatments that focus solely on GIPR. Even normal-weight mice with extra GIPR in their fat cells showed resistance to weight gain when fed a high-fat diet, indicating the protein’s protective effects against obesity.
The research, conducted at UT Southwestern’s Touchstone Center for Diabetes Research, received funding from Eli Lilly and Company and the National Institutes of Health. The work involved collaboration among multiple scientists, including researchers Shiuhwei Chen, Jan-Bernd Funcke, and graduate student Chanmin Joung.