Ozempic does something unexpected to the brain’s hunger neurons

For decades, weight loss medications have yielded only modest results. However, the introduction of Ozempic and other GLP-1 therapies has led to substantial weight reduction of 10 to 15% or more. The mechanism behind their effectiveness remains unclear. Researchers at Yale University have now discovered an unexpected process that contradicts a well-established understanding of hunger circuits in the brain.

Traditionally, scientists believed that agouti-related peptide (AgRP) neurons, which fuel hunger, primarily work against weight loss. The new study indicates a significant shift in this understanding. During treatment with GLP-1 drugs like Ozempic, these neurons appear to be utilized to maintain fat loss. This revelation alters our comprehension of the mechanism involved in these medications and provides fresh insights into the biological basis of their long-term effects.

This could pave the way for more efficient drugs. The study, published in the Proceedings of the National Academy of Sciences (PNAS), was led by Mateus d'Ava, a neuroscience Ph.D. candidate focusing on the work of Tamas Horvath at Yale School of Medicine. Semaglutide, the active component of GLP-1 medications such as Ozempic, has proven to be one of the most successful drugs for obesity treatment.

The reason for its powerful and persistent effects has been less understood. Previous weight loss drugs could reduce appetite similarly to semaglutide but did not yield the same level of sustained weight loss. This discrepancy led the Yale team to suspect that semaglutide may have additional effects beyond simply reducing hunger.

Researchers had hypothesized that GLP-1 medications reduce weight by decreasing hunger-related neuron activity. However, they had not directly investigated the role of AgRP neurons during prolonged GLP-1 treatment in living organisms. The team aimed to identify what was missing from this explanation by examining the brain's response and adaptation during treatment.

They sought to uncover biological targets that could lead to more effective obesity therapies. Utilizing a mouse model, the researchers employed multiple experimental techniques while monitoring body weight, food intake, metabolism, and energy expenditure during semaglutide treatment. They also utilized genetic methods to selectively eliminate or silence AgRP hunger neurons.

This allowed the scientists to determine if those neurons were essential for semaglutide to sustain its effects over time. The results were surprising. In mice engineered to lack AgRP neurons, GLP-1 drugs were no longer capable of maintaining weight loss. Additional tests using electron microscopy, molecular biology, and electrophysiology revealed another unexpected finding.

Instead of being inhibited by semaglutide, AgRP neurons were activated. The researchers suggest this indicates a more complex response within the brain than previously recognized. When GLP-1 treatment induces a calorie deficit, the brain seems to counteract this by enhancing the activity of AgRP hunger neurons. These same neurons also play a role in coordinating fat loss.

In other words, cells once considered barriers to weight loss might actually become integral to the biological process that enables GLP-1 therapies to sustain fat loss. This discovery adds a previously unknown element to scientists' understanding of how these medications operate. While the experiments were conducted on mice, further research is required to ascertain if the same mechanism occurs in humans.

Nevertheless, identifying how GLP-1 medications influence the brain could provide crucial foundational knowledge for developing future obesity treatments. The identification of a previously unknown neural mechanism involved in sustaining weight loss offers new biological insights that could lead to even more effective therapies or reduced side effects, according to Mateus d'Ava.

Other contributors from Yale University include Roberto Collado-Pérez, a postdoctoral associate; Zhong-Wu Liu, assistant professor adjunct; Joseph Schlessinger, the William H. Prusoff Professor of Pharmacology; and Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine.