by UT Southwestern Medical Center

Credit: Cell Metabolism (2024). DOI: 10.1016/j.cmet.2024.11.003

Obese mice whose fat cells were genetically altered to produce an increased amount of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lost more than a third of their body weight through a mechanism that burns energy, UT Southwestern Medical Center researchers report in a new study.

Published in Cell Metabolism, the findings highlight the potential of GIPR—a protein thought of as a minor player in a class of popular weight-loss drugs—to have its own starring role in therapies to fight obesity.

“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,” said study leader and corresponding author Christine M. Kusminski, Ph.D., Associate Professor of Internal Medicine in the Touchstone Center for Diabetes Research at UT Southwestern.

According to the World Health Organization, more than a billion people have obesity. This condition has been linked to a vast number of health problems, including cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, osteoarthritis, and some types of cancer.

Within the past several years, multiple drugs that take aim at the glucagon-like peptide-1 receptor (GLP-1R) have been approved by the Food and Drug Administration (FDA) to treat obesity. The mechanism by which these drugs exert their beneficial effects has been well-established, with studies showing that they act on central areas of the brain that regulate appetite.

More recently, the FDA approved a new generation of weight-loss drugs that focus on both the GLP-1R and the GIPR. Clinical trials have shown that these drugs are even more impressive for weight loss in individuals with Type 2 diabetes and obesity. However, the role of GIPR in enhancing GLP-1R agonists has not been fully defined.

GIP is a gut-derived incretin hormone. To better understand how it affects body weight, Dr. Kusminski and colleagues, including first author Xinxin Yu, M.D., Research Scientist, and Philipp Scherer, Ph.D., Professor of Internal Medicine and Cell Biology and Director of the Touchstone Center, worked with mice that had fat cells genetically engineered to overproduce the GIPR.

Dr. Kusminski said that after she and her team genetically switched on the extra GIPR in fat cells, obese mice lost massive amounts of weight—approximately 35% within two weeks. Furthermore, when the extra receptors were switched on in mice of normal weight, they were resistant to developing obesity when fed a high-fat diet.

To find a mechanism by which the GIPR in fat cells triggers this profound weight loss, the researchers looked for clues as to how gene pathways and metabolic pathways are altered in fat. They found that when the animals’ fat cells began overproducing GIPR, they had increased activity in sarco/endoplasmic reticulum calcium ATPase (SERCA) pathways, processes that use energy to transport calcium within cells.

A closer look revealed that the extra GIPR caused the cells to burn extra ATP—a molecule used for energy—without transporting the calcium. This process of futile calcium cycling burned significantly more energy in mice that overproduced GIPR in fat cells, thus prompting more weight loss.

When the researchers shut off extra GIPR production after several weeks, the mice surprisingly did not regain their body weight—they appeared to have a “metabolic memory,” which offered protection against obesity, even without additional GIPR being present in fat cells, Dr. Kusminski said. These findings are different from those in human patients taking existing weight-loss drugs—once they stop these medications, rapid weight regain typically ensues.

“Having a better understanding of how GIPR operates in fat cells helps to explain why targeting GIPR, in addition to GLP-1R, causes individuals with obesity to lose more weight than those who take GLP-1R drugs,” Dr. Kusminski said. “Furthermore, drugs that focus on the GIPR alone, or as a critical part of multi-agonist drugs, could represent a powerful approach to helping people lose weight.”

More information: Xinxin Yu et al, The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice, Cell Metabolism (2024). DOI: 10.1016/j.cmet.2024.11.003

Journal information:Cell Metabolism

Provided by UT Southwestern Medical Center

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