GLP-1 Medications Targeting the Brain to Reduce Systemic Inflammation

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Breakthrough Discovery: GLP-1 Medications Targeting the Brain to Reduce Systemic Inflammation

Breakthrough Discovery: GLP-1 Medications Targeting the Brain to Reduce Systemic Inflammation

Recently, Science magazine named GLP-1 class medications as the top scientific breakthrough of 2023.

These medications, originally designed to benefit individuals with type 2 diabetes and obesity, have demonstrated broad health benefits in clinical trials, including the prevention of cardiovascular and cerebrovascular diseases.

The journey from the discovery of GLP-1 to its role in treating diabetes and obesity has been a long and winding one, spanning over 40 years and involving hundreds of researchers from the academic and pharmaceutical sectors.

Four scientists, Svetlana Mojsov, Joel Habener, Daniel Drucker, and Jens Juul Holst, played a pivotal role in laying the foundation and revealing the structure and function of GLP-1.

For years, GLP-1 receptor agonists have been considered to have occasional “side effects” beyond weight reduction, improving metabolic health.

However, the regulatory mechanisms within the body remained unclear.

In a groundbreaking study published in the journal Cell Metabolism on December 18, 2023, Daniel Drucker’s team began unraveling this mystery, revealing a connection that starts in the brain.

The research suggests that the activation of GLP-1 receptors (GLP-1R) in the brain inhibits inflammation induced by Toll-like receptor agonists. This study introduces the concept of a GLP-1-brain-immune axis, demonstrating its ability to independently control systemic inflammation, even in peripheral organs lacking GLP-1 receptors.

Breakthrough Discovery: GLP-1 Medications Targeting the Brain to Reduce Systemic Inflammation

Represented by semaglutide, a GLP-1 receptor agonist (GLP-1RA) simulates the intestinal hormone GLP-1, regulating blood sugar levels and appetite, and is used to treat type 2 diabetes and obesity.

Professor Daniel Drucker emphasizes the intriguing aspect of GLP-1 medications, as they not only control blood sugar and weight but also appear to reduce complications of chronic metabolic diseases, such as heart failure, stroke, and fatty liver. While clinical studies have showcased these miraculous effects in the human body, the precise mechanisms remained elusive.

Daniel Drucker’s early research on GLP-1 hormones provided an understanding of how they work at the molecular level, paving the way for various GLP-1 medications. Currently, his focus is on investigating how GLP-1 medications reduce inflammation, a common factor in chronic metabolic diseases. Inflammation is the process where the immune system identifies and clears foreign substances like viruses and bacteria, promoting healing. However, in chronic forms, it can persist without external causes, leading to organ damage.

GLP-1 receptor agonists (GLP-1RA) exhibit anti-inflammatory effects associated with chronic complications of type 2 diabetes. While GLP-1RA directly alleviates T-cell-mediated intestinal and systemic inflammation within the intestinal epithelial lymphocytes’ GLP-1 receptors, it remained uncertain how GLP-1RA inhibits systemic inflammation in the absence of widespread immune expression of GLP-1R.

Considering the presence of immune cells in most organs, a hypothesis emerged that GLP-1RA inhibits inflammation by interacting with GLP-1R on immune cells. While a substantial number of immune cells are activated by GLP-1 in the intestine, other organs show negligible expression of GLP-1R, suggesting an alternative mechanism.

Surprisingly, many organs where GLP-1 seems to act don’t express much GLP-1R. The research team speculated the involvement of the brain based on two key reasons: high abundance of GLP-1R in the brain and the continuous information exchange between the brain and the immune system throughout the body.

In this study, the research team induced sepsis in mice by injecting bacterial cell wall components, causing widespread inflammation leading to organ damage. Notably, GLP-1 receptor agonists (GLP-1RA) could reduce inflammation only when GLP-1R in the brain was not blocked. The ability of GLP-1RA to reduce inflammation was lost when GLP-1R in the mouse brain was pharmacologically inhibited or genetically knocked out.

Specifically, GLP-1R activation alleviated Toll-like receptor agonist-induced induction of plasma tumor necrosis factor-alpha (TNF-α), a process not mediated by GLP-1R in hematopoietic or endothelial cells but requiring GLP-1R in the central nervous system. In the microbial-induced sepsis model, GLP-1RA also needed GLP-1R in the brain to mitigate sepsis-related adverse reactions, including nausea, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation led to a decrease in TNF-α through α1-adrenergic, δ-opioid, and κ-opioid receptor signaling pathways. These findings expand the emerging concept of a brain-immune network and propose a new gut-brain GLP-1R axis to inhibit peripheral inflammation.

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Professor Daniel Drucker states that this research result establishes the existence of a GLP-1-brain-immune axis, capable of independently controlling systemic inflammation, even in peripheral organs lacking GLP-1R.

However, this work is far from complete. The research team is actively working to identify the brain cells interacting with GLP-1. They are also studying various inflammatory mouse models, including heart disease, atherosclerosis, liver, and kidney inflammation, to determine whether GLP-1’s beneficial effects in these diseases are indeed mediated through the brain.

Professor Daniel Drucker emphasizes that understanding how GLP-1 inhibits inflammation may open new pathways to reduce complications associated with type 2 diabetes and obesity. Science’s recognition of GLP-1 medications as the top scientific breakthrough of 2023 underscores the expanding clinical impact of GLP-1 and the enormous potential of basic scientific discoveries in improving human health.

While GLP-1 receptor agonists (GLP-1RA) have significant potential beyond weight loss, they pose more challenges than they solve. Professor Daniel Drucker and his team persistently strive to unravel the mechanisms of these medications, and this latest research deepens our understanding of the complex brain-immune network regulating metabolism.

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