Scientists solve the mystery of a brain “switch” that can trigger weight loss in opposite ways
Scientists have uncovered why two seemingly opposite ways of targeting the same brain receptor can both promote weight loss. In mice, activating the GIP receptor in the brainstem reduced appetite, while blocking it in the hypothalamus removed a kind of “brake” on fullness signals. The discovery helps explain why very different obesity drugs can achieve similar results and suggests that carefully…
Cambridge scientists have deciphered why activating or inhibiting the same brain receptor can either promote or inhibit weight loss. The study, published in Nature Metabolism, suggests that the effect hinges on which part of the brain is targeted. When the receptor is activated in the brainstem, appetite is curbed. Conversely, inhibiting the same receptor in the hypothalamus triggers weight loss via a distinct mechanism.
The prevalence of obesity affects more than a billion individuals globally, increasing the risk of diseases such as type 2 diabetes, cardiovascular issues, and cancer. While weight loss can mitigate some of these risks, achieving significant weight loss through diet and exercise alone is often challenging. Recent weight loss medications target specific receptors associated with appetite.
For instance, drugs like Wegovy and Ozempic activate the glucagon-like peptide 1 receptor (GLP-1R), while others act on the glucose-dependent insulinotropic polypeptide receptor (GIPR) in conjunction with GLP-1R. Scientists at the University of Cambridge's Institute of Metabolic Science conducted experiments on mice to unravel the mystery.
The findings indicate that GIPR agonists primarily function in the brainstem, reducing appetite and leading to reduced body weight. On the other hand, GIPR antagonists primarily operate in the hypothalamus, where they function as a sort of "brake" that diminishes the brainstem's response to fullness signals. Blocking the receptor alleviates this brake, thereby enhancing the signal's impact.
The research also suggests that blocking GIPR may synergize with emerging medicines targeting the amylin receptor, potentially making them more effective in treating obesity. Study leader Dr. Jo Lewis proposed that understanding the brain circuits responsive to these medications and how they function could lead to the development of more effective obesity drugs with fewer side effects, and possibly enhance the efficacy of combination therapies.
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