Drugs against obesity act as a brake to prevent excessive food intake. They act not only at the digestive level but also in the brain. How? Tracing the impact of glucagon analogs (GLP-1), better known as the Ozempic family, is one of the scientific goals. Now, Casey Halpern's laboratory has conducted an experiment in which they have managed to identify the passage of tirzepatide (marketed as Mounjaro) through the brain of a person with obesity.
The head of Stereotactic and Functional Neurosurgery at the University of Pennsylvania has conducted a study to detect the influence of this drug on the brain networks that control dysregulated eating. His team has implanted electrodes in the patient's brain, a very invasive procedure, and has drawn several conclusions that are now published in Nature Medicine.
Although it is a "unique observation," as Halpern explains to this medium, the findings represent the first research in humans on the impact of tirzepatide on brain activity, specifically in the nucleus accumbens, a region associated with pleasure, motivation, and reward.
Francisco J. Tinahones, Head of the Endocrinology and Nutrition Service at the Virgen de la Victoria Hospital in Malaga, values this experiment, which he suggests approaching with "caution." He comments that it is the first time that it has been demonstrated that a drug that is a dual agonist of GLP-1 and GIP acts on a key region of the pleasure and food motivation mesolimbic circuit. "This neurophysiological approach had not been done before. It was known that in many patients with binge eating, this area of the brain that regulates pleasure and motivation could be altered," he clarifies.
Detecting the Key Electrical Signal
Halpern investigates the mechanisms of human brain circuits related to mental illnesses such as addiction, eating disorders, OCD, and obesity. To do this, he uses innovations from his laboratory to develop specific neuromodulatory interventions ranging from transcranial magnetic stimulation and deep brain stimulation to MRI-guided focused ultrasound.
On this occasion, he has used the implantation of electrodes in the brain, a very invasive procedure. In this way, they have identified a key electrical "signal" (called delta-theta power) in the nucleus accumbens. "This observation suggests that changes in low-frequency signals in the nucleus accumbens may be associated with changes in the intensity of food concern," explains Halpern. When the signal is present, "it could indicate that suppressing appetite and controlling cravings is more difficult, which can lead to dysregulated eating behavior," details the American researcher. On the contrary, when the signal is absent, appetite and cravings could be easier to control.
"The signal may represent the anticipatory state of the brain in response to a reward or be related to the urge to obtain one," Halpern continues. "We have observed similar activity in the nucleus accumbens of mice seeking high-fat foods in a behavioral model of binge eating."
Preventive Window and Study Limitations
One of the milestones of this work is the detection of the biomarker seven weeks before the "most severe outbreak" of food concern. This finding could undoubtedly represent "a possible window for preventive intervention, acting as an early warning signal," points out the researcher. This would help in designing strategies for controlling food in patients who become accustomed to the drug.
Tinahones lists the limitations of the work, which Halpern also acknowledges. "It is a case study; these results cannot be generalized to the obese population. Although it is true that it opens a path to conduct a more comprehensive study to demonstrate that this effect is indeed widespread in other subjects," the Spanish researcher points out.
Another obstacle he points out is the reproducibility of the work. "The neurophysiological study is very invasive and not very applicable to the clinic since deep microelectrodes are placed in the brain. Perhaps with other electroencephalography studies, we could find alterations and see if they are reversed with tirzepatide."
Asked about this issue, Halpern responds that there are researchers, including his team, exploring the possibility of detecting this signal from deep brain regions through a scalp electroencephalogram or other non-invasive methods. "This type of detection is far from trivial, so considerable work is needed to examine its feasibility," emphasizes the author of the study.
A Step to Encourage the Scientific Community
However, the University of Pennsylvania researcher confirms that "currently we do not plan to conduct a larger clinical trial on this topic, as it is a serendipitous finding." Therefore, he assumes that his step has left a door open to "encourage the scientific community to continue researching, as it highlights how little we know about the action of these networks in the human brain."
Halpern insists that it must be clarified inhumans, "beyond mouse models," how drugs from the GLP receptor family control appetite and impulses is important. "Anecdotal reports of reduced cravings or opioid or alcohol consumption after the administration of GLP-1 receptor agonists have certainly sparked enthusiasm for this possibility," comments Halpern, while pointing out that "these drugs have not been optimized, designed, or approved for these indications, and careful controlled studies in humans are needed."