Researchers at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health, have discovered a gut-brain-immune network and posit a new gut-brain glucagon-like peptide 1 (GLP-1R) that controls inflammation across the body, a discovery which holds promise for understanding and treating metabolic diseases. GLP-1 agonists are known to have a fortuitous side effect of improving metabolic health, but how this is regulated in the body remains unclear. Now, research led by Dr Daniel Drucker, has begun to unravel the mystery with a novel finding, it all starts in the brain.
"One of the really interesting things about the GLP-1 drugs is that beyond the control of blood sugar and body weight, they also seem to reduce the complications of chronic metabolic disease," explained Drucker, who holds the BBDC-Novo Nordisk Chair in Incretin Biology and is Professor of Medicine at the Temerty Faculty of Medicine, University of Toronto, Canada.
Drucker's previous work on the GLP-1 hormone provided an understanding of how it works at the molecular level and paved the way for multiple diabetes drugs, Ozempic among them. In his latest study, Ducker and colleagues focused on how GLP-1 drugs reduce inflammation, which is a common factor in chronic metabolic diseases. Inflammation is the process by which the immune system recognizes and removes foreign agents such as viruses and bacteria and promotes healing. In chronic form, however, it can persist without an external cause and lead to organ damage.
Given that immune cells are embedded within most organs, an obvious assumption was that the drugs dampen inflammation by interacting with GLP-1 receptors on the immune cells. This is the case in the gut, where large numbers of immune cells are activated by GLP-1. However, in other organs the number of immune cells containing GLP-1 receptors is negligible, indicating another mechanism to be 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," he added. The research team hypothesised that the brain might be involved for two reasons: the GLP-1 receptors are abundant in the brain, and the brain and the immune system communicate with all organs in the body.
For the study, postdoctoral scientist Chi Kin Wong, induced systemic inflammation in mice by either injecting them with a bacterial cell wall component or a bacterial slur to induce sepsis, an extensive inflammation throughout the body that leads to organ damage. Remarkably, GLP-1 agonists reduced inflammation, but only when its receptors in the brain were left unblocked. When these brain receptors were pharmacologically inhibited or genetically removed in mice, the drugs' ability to reduce inflammation was lost.
The findings demonstrated for the first time that there is a GLP-1-brain-immune axis that controls inflammation across the body independent of weight loss, even in peripheral organs devoid of GLP1 receptors.
"As the scientific community deservingly celebrates GLP-1 agonists and their impact, there are many unknowns left,” commented Dr Anne-Claude Gingras, Director of the LTRI and Vice-President of Research at Sinai Health. “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."
The work is far from complete, however. The team is now trying to pinpoint the brain cells that interact with GLP-1. They are also looking at various mouse models of inflammation, including heart disease, atherosclerosis, and liver and kidney inflammation, to establish whether the beneficial effects of GLP-1 in each case are indeed mediated through the brain.
Drucker said that understanding how GLP-1 dampens inflammation may open new avenues for reducing the complications associated with type 2 diabetes and obesity.
The findings were reported in the paper, ‘Central glucagon-like peptide 1 receptor activation inhibits toll-like receptor agonist-induced inflammation’, published in Cell Metabolism. To access this paper, please click here
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