A recent Northwestern Medicine study has identified novel neural circuits modulated by the diabetes and obesity-management drugs semaglutide and tirzepatide that help suppress appetite, according to findings published in The Journal of Clinical Investigation.
The study, led by Lisa Beutler, MD, PhD, assistant professor of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine, improves the understanding of the molecular mechanisms influenced by these drugs and could help refine the development of future targeted therapies for treating diabetes and obesity.
Incretin receptor agonists are a class of drugs that mimic the effects of incretin hormones — glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — to stimulate insulin secretion and regulate blood sugar levels. At pharmacologic dosing, they also signal to the brain the feeling of prolonged fullness and satiety, resulting in weight loss.
These drugs, more commonly known as GLP-1 and GLP-1/GIP receptor agonist drugs (marketed as semaglutide and tirzepatide), have been commonly prescribed for the treatment of diabetes, and more recently, the management of obesity.
Nonetheless, the neural mechanisms by which these drugs regulate appetite and what areas of the brain these drugs specifically interact with has remained poorly understood.
“We’ve known for several years now that the way these drugs induce weight loss is by actions on the brain and largely by curbing appetite, but the brain’s obviously an incredibly complicated organ and a big question has been where in the brain these drugs might act,” Beutler said.
In the current study, Beutler’s team aimed to better understand how GLP-1 and GIP receptor agonist drugs affect the activity of AgRP neurons, a subset of neurons localized in the brain’s hypothalamus that are known to regulate appetite.
Using in vivo fiber photometry, the scientists studied AgRP neuronal activity in mice that had fasted and then treated them with a GLP-1 receptor agonist or a GIP-1 receptor agonist.
In mice receiving the GLP-1 receptor agonist or the GIP-1 receptor agonist, the investigators found that AgRP activity was suppressed, indicating fullness or satiety.
According to Beutler, additional research has shown that AgRP neurons protect the body from starvation: when the body loses weight and is in a negative energy balance state, these neurons become active to promote food intake. Semaglutide and tirzepatide counteract this response.
“You have these drugs that both activate brain stem neurons to tell you you’re full and silence AgRP neurons that should then become active and tell your brain, ‘you need to eat, you are losing weight.’ So, you have this double whammy where you suppress appetite and you prevent the rebound hunger that comes with that,” Beutler said.
Surprisingly, the scientists also found that GIP-1 alone, and not GLP-1, is essential for transmitting signals to AgRP neurons to promote gut-brain communication.
“Not only does targeting this GIP-1 receptor really inhibit these neurons, but it’s actually important in day-to-day feeding and gut-brain communication about meals,” Beutler said.
Moving forward, Beutler said her team aims to further investigate where in the brain GIP is sensed to transmit these signals that lead to AgRP neuron inhibition.
“We don’t think that this effect that GIP has on AgRP neurons is direct because GIP receptors aren’t actually expressed in AgRP neurons. This is an indirect circuit effect and we’re trying to figure out where that circuit starts,” Beutler said.
Beutler said the findings can also help inform the development of targeted treatments for long-term obesity management, as well as treatment strategies that avoid targeting other regions of the brain.
“The goal is to develop more efficacious drugs that are tolerated better and are more targeted to avoid the need for decades-long treatment with these drugs that target multiple brain regions,” Beutler said.
Hayley McMorrow, a student in the Northwestern University Interdepartmental Neuroscience (NUIN) program, was the lead author of the study.
Co-authors include Andrew Cohen, a student in the Driskill Graduate Program in Life Sciences (DGP), and Nikolas Hayes, a student in the NUIN program.
This work was supported by the American Diabetes Association Pathway to Stop Diabetes Award (12-22-ACE-31) and by National Institute of Health grants P30-DK020595, K08-DK118188 and R01-DK128477.
