Health Canada (Commonwealth Union) – For the first time, the research reveals the existence of a GLP-1-brain-immune axis that governs inflammation, extending its influence even to peripheral organs devoid of GLP-1 receptors.
Daniel Drucker, a senior investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute and University Professor in the department of medicine in the University of Toronto’s Temerty Faculty of Medicine, spearheaded a research team that unveiled a gut-brain-immune network regulating inflammation throughout the body, impacting organ health significantly.
Published in Cell Metabolism, the study focuses on the impact of glucagon-like peptide-1 (GLP-1) receptor agonists, commonly employed by clinicians to address Type 2 diabetes and recently acknowledged for their efficacy in weight loss.
Drucker, who holds the BBDC-Novo Nordisk Chair in Incretin Biology, indicated that beyond the control of blood sugar and body weight, GLP-1 drugs also appear to mitigate the complications of chronic metabolic disease. Drucker further pointed out that while clinical studies demonstrate these remarkable effects in individuals, the exact mechanisms underlying these outcomes remain incompletely understood.
Seeking answers to this question, Drucker’s team delved into the anti-inflammatory properties of GLP-1 drugs, particularly relevant in chronic metabolic diseases characterized by persistent inflammation, often leading to organ damage. While the prevailing assumption implicated GLP-1 receptors on immune cells in mediating this effect, primarily evident in the gut, where GLP-1 activates a substantial number of immune cells, the negligible presence of GLP-1 receptors on immune cells in other organs suggested an alternative mechanism at play.
“The strange thing is that you can’t find many GLP-1 receptors in all these other organs where GLP-1 seems to work,” added Drucker, whose prior research demonstrated the that GLP-1 gut hormone functions at the molecular level as well as making the way for several diabetes and weight-loss drugs, that consist of Ozempic and Wegovy.
Drucker and his team suspected the involvement of the brain in controlling inflammation for two key reasons: the abundance of GLP-1 receptors in the brain and the established communication between the brain and the immune system affecting all organs in the body.
In a study led by Chi Kin Wong, a postdoctoral scientist in the Drucker lab, systemic inflammation was induced in mice through injection of a bacterial cell wall component or a bacterial slur, causing sepsis and widespread inflammation leading to organ damage.
Notably, GLP-1 agonists demonstrated the ability to reduce inflammation, but this effect was observed only when the receptors in the brain were unblocked. When these brain receptors were either pharmacologically inhibited or genetically removed in mice, the anti-inflammatory properties of the drugs were compromised.
These findings unveiled a novel GLP-1-brain-immune axis, indicating that it regulates inflammation throughout the body independently of weight loss, even in organs lacking GLP-1 receptors, as highlighted by Drucker.
Drucker’s groundbreaking work on GLP-1 has earned him prestigious awards in the life sciences, such as the 2023 VinFuture Emerging Innovation Prize and the 2023 Wolf Prize in Medicine. Additionally, the GLP-1-based diabetes drugs that originated from Drucker’s early research were recognized as the 2023 Breakthrough of the Year by the journal Science.
“As the scientific community deservingly celebrates GLP-1 agonists and their impact, there are many unknowns left,” added Anne-Claude Gingras, who is director of the Lunenfeld-Tanenbaum Research Institute, vice-president of research at Sinai Health and professor in the department of molecular genetics at Temerty. “Dr. Drucker and his team have remained tenacious in their efforts to unpack how these drugs work, and this study deepens our understanding of metabolism and the complex brain-immune network that regulates it.”
Currently, Drucker’s team is engaged in the task of identifying the specific brain cells that engage with GLP-1. Simultaneously, they are exploring diverse mouse models associated with inflammation, such as heart disease, atherosclerosis, and inflammation in the liver and kidneys. Their aim is to determine conclusively whether the positive impacts of GLP-1 are, indeed, orchestrated through interactions within the brain.
