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.
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. “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. 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.
By Sneha Khedkar
Article can be accessed on: The Scientist