Blockbuster anti-obesity drugs like Ozempic and Wegovy have become household names in the past few years. They work by activating the glucagon-like peptide 1 receptor (GLP-1R) to stimulate insulin secretion, which makes one feel fuller for longer.1
A few years ago, researchers found that combining GLP-1R agonists with molecules that activate the glucose-dependent insulinotropic polypeptide receptor (GIPR) offers greater benefits, such as lower body fat and improved blood sugar.2 “A lot of studies have been done on the Ozempic form—the GLP-1R agonist—and the mechanism of how they work has been very well established,” said Christine Kusminski, a diabetes researcher at The University of Texas Southwestern Medical Center (UTSW). In contrast, the role of GIPRs in weight loss remains relatively undefined, she added.
Now, Kusminski and her team have found that GIPR activation in the fat tissue of mice enhances energy expenditure and triggers weight loss.3 Their findings, published in Cell Metabolism, highlight the potential benefits of targeting GIPRs in fat cells as a therapy for obesity and metabolic disorders.
“[The study] just really goes to show that the adipose tissue is an important player in this whole pathway [of GIPR agonism],” said Jacqueline Beaudry, an adipocyte biologist at the University of Toronto who was not involved in the study. She noted that researchers have largely focused on studying GIPRs in the brain and pancreas.
Kusminski and her team started their investigations by analyzing the distribution of GIPR in humans and found that many tissues express the receptors. They focused subsequent analyses on GIPR-expressing cells in the white adipose tissue due to the tissue’s role in metabolic health. To get a closer look at the receptor’s role in adipocytes, the researchers genetically engineered a tetracycline-inducible system where drug treatment triggered GIPR overexpression. Stopping the treatment reversed the expression to baseline levels.
Compared to wild type mice, those with GIPR overexpression gained less weight when fed a high-fat diet. Further, when the researchers induced GIPR overexpression in obese mice, the animals lost nearly a third of their body weight. “That was rather surprising to us,” said Kusminski.
RNA sequencing of the GIPR-expressing cells provided insight into a molecular mechanism by which GIPR regulates weight loss. GIPR overexpression in the animals’ adipocytes resulted in increased expression of genes associated with the sarco/endoplasmic reticulum calcium-ATPase (SERCA) pathways, which burn energy to transport calcium ions.
Sarco/endoplasmic reticulum calcium-ATPase (red) mediated futile calcium cycling in adipocytes overexpressing GIP receptors to drive energy burning and weight loss. Nuclei are depicted in blue
Christine Kusminski
One of these pathways burns energy without transporting calcium, resulting in a futile cycle that wastes energy.4 Kusminski and her team observed that GIPR overexpression in adipocytes activated this pathway and increased energy expenditure, as indicated by increased temperature of the tissue. Knocking out one of the genes in this SERCA pathway reduced tissue temperature, establishing that GIPR stimulation activates futile calcium cycling in fat cells, which helps mice burn energy and maintain their weight.
A major challenge faced by people taking GLP-1R agonists is rapid weight gain soon after discontinuing the treatment.5 Kusminski and team investigated this phenomenon in mice. They treated wild type and GIPR-overexpressing mice with GLP-1R agonists, resulting in weight loss in both the groups but a more pronounced effect in the GIPR-overexpressing mice. While wild type mice rapidly regained weight after the researchers stopped treatment, GIPR overexpressing mice maintained their weight loss. Further, shutting off GIPR overexpression after 12 weeks did not result in weight gain, suggesting a GIPR-dependent metabolic memory.
“[The results provide] a better understanding of what happens clinically when a patient takes a dual agonist…and which of these tissues may contribute in a significant way to the weight loss and to the metabolic improvements,” said coauthor Philipp Scherer, a diabetes researcher and physiologist at UTSW. This opens doors to targeting pathways in adipose tissues for therapy in the future, he added.
“The study suggests potential targets outside the brain and pancreas that may regulate weight loss,” agreed Beaudry. However, she cautioned that how well the results translate from mice to humans remains to be seen.
“Future studies will have to determine whether this happens in humans,” agreed Kusminski.
- Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756.
- Finan B, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151.
- Yu X, et al. The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice. Cell Metab. 2025;37(1):187-204.e7.
- Sharma AK, et al. Futile cycles: Emerging utility from apparent futility. Cell Metab. 2024;36(6):1184-1203.
- Kelly AS, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl J Med. 2020;382(22):2117-2128.
