A study led by UT Southwestern Medical Center researchers has shown that increasing glucose-dependent insulinotropic polypeptide receptor (GIPR) activity in fat cells leads to significant weight loss in obese mice. Published in Cell Metabolism, the research highlights GIPR’s potential as a therapeutic target for obesity and related metabolic diseases.
Christine M. Kusminski, Ph.D., Associate Professor of Internal Medicine (left), and Xinxin Yu, M.D., Research Scientist, are studying the effects of the glucose-dependent insulinotropic polypeptide receptor (GIPR) on fat cells as a possible therapy for 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 Dr. Christine M. Kusminski, Associate Professor of Internal Medicine at UT Southwestern.
Key findings
The researchers genetically engineered the fat cells of obese mice to overproduce GIPR, resulting in a 35% reduction in body weight within two weeks. In normal-weight mice, increased GIPR activity prevented obesity when fed a high-fat diet.
Further investigation revealed that GIPR in fat cells activated energy-intensive pathways involving sarco/endoplasmic reticulum calcium ATPase (SERCA). This process burned excess ATP, a molecule used for energy, without transporting calcium, creating a mechanism for increased energy expenditure and weight loss.
Notably, when GIPR overproduction was halted after several weeks, the mice did not regain their lost weight. This “metabolic memory” differs from the rapid weight regain often seen when humans discontinue existing weight-loss medications.
This immunofluorescence image shows the energy-wasting SERCA protein fat tissue overexpressing the GIP receptor. Credit: UT Southwestern
“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 noted.
Broader context and future directions
Lilly, which supported this research with grants along with the NIH, has developed tirzepatide (Mounjaro/Zepbound), a blockbuster dual GIP/GLP-1 receptor agonist generating over $4.3B in quarterly sales. One of the most successful pharma products in recent memory, along with semaglutide from Novo Nordisk, tirzepatide has fared well in a variety of clinical trials. In one, it supported an average weight reduction of up to 20.9% over 72 weeks and in another, it cut the risk of progressing from prediabetes to type 2 diabetes by 94% in individuals with obesity or overweight.
The study builds on previous research into drugs targeting incretin hormone receptors, such as GLP-1R and GIPR, which regulate appetite and metabolic processes. While GLP-1R-based therapies have been FDA-approved for obesity treatment, combining GLP-1R and GIPR has shown greater efficacy in clinical trials. The role of GIPR, however, remains under-explored.
Dr. Kusminski and her team aim to develop therapies that target GIPR as a standalone treatment or as part of multi-receptor agonist drugs. “Drugs that focus on the GIPR alone, or as a critical part of multi-agonist drugs, could represent a powerful approach to help people lose weight,” she said.
Contributors and funding
Other contributors to the study include Dr. Philipp Scherer, Director of the Touchstone Center for Diabetes Research, and several researchers from the Touchstone Center. The work was supported by grants from Eli Lilly and Co. and the National Institutes of Health.
These findings underscore the potential of GIPR-focused therapies to address obesity and metabolic disorders, providing a foundation for future clinical applications.
