Study finds new roles for gut hormone GLP-1 in the brain

A research team led by Daniel Drucker, 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, has discovered a gut-brain-immune network that controls inflammation across the body and affects organ health.

The findings, published in Cell Metabolism, centre on the effects of glucagon-like peptide-1 (GLP-1) receptor agonists, or activators, which clinicians use to treat Type 2 diabetes and which have recently proven highly effective for weight loss.

“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,” said Drucker, who holds the BBDC-Novo Nordisk Chair in Incretin Biology.

“We know from clinical studies that GLP-1 does all this amazing stuff in people, but we don’t fully know how it works,” said Drucker.

To help answer this question, Drucker’s team looked at how GLP-1 drugs reduce inflammation, which is common in chronic metabolic diseases. Inflammation occurs when 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.

Many researchers assumed that GLP-1 drugs dampen inflammation by interacting with GLP-1 receptors on immune cells. This is the case in the gut, where large numbers of immune cells are activated by GLP-1. But in other organs, the number of immune cells containing GLP-1 receptors is negligible, indicating another mechanism may 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,” said Drucker, whose earlier research showed how the GLP-1 gut hormone works at the molecular level and paved the way for several diabetes and weight-loss drugs, including Ozempic and Wegovy.

Drucker and his team had a hint that the brain might be involved for two reasons: GLP-1 receptors are abundant there, and the brain and the immune system communicate with all organs in the body.

Chi Kin Wong, first author on the study and a postdoctoral scientist in the Drucker lab, 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 their 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 showed 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 GLP-1 receptors, said Drucker.

Drucker has received some of the world’s most prestigious awards in the life sciences for his many findings on GLP-1, including the 2023 VinFuture Emerging Innovation Prize and the 2023 Wolf Prize in Medicine. As well, GLP-1-based diabetes drugs that emerged from Drucker’s early research were named 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,” said Anne-Claude Gingras, 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.”

Drucker’s 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 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.

He added that the recognition of GLP-1 biology as Science’s 2023 Breakthrough of the Year “highlights the expanding clinical impact of GLP-1, and the tremendous potential for basic scientific discovery to continuously improve human health.”

The research was funded by the Canadian Institutes for Health Research and Novo Nordisk Inc.