Cravings and binges develop in the brain, and that’s where the new generation of weight-loss drugs work. This is what explains research published Monday in the scientific journal Nature medicine. Neurologists at the University of Pennsylvania had the rare opportunity to peer into the brains of four obese people suffering from the so-called binge eating disorder. One of them was being treated with tirzepatide. This weight loss drug has been shown to suppress neuronal activity in the nucleus accumbensa region associated with pleasure, motivation and reward. The drug demonstrated a short-term or incomplete effect, warranting further research.
The findings represent the first research in humans on the impact of this compound on brain activity. “Now we can begin to understand what the drugs are doing in this region of the brain,” explains Casey Halpern, a neurologist at the University of Pennsylvania and lead author of the study, in a conversation with this newspaper. The desire to eat, both for pleasure and to obtain energy, involves the complex interaction between different areas of the brain. Studying how these drugs change brain activity could help develop new treatments for eating disorders.
Weight loss drugs, like tirzepatide, promote weight loss in a surprising way that we don’t fully understand. The basic mechanism would be more or less this: when food reaches our intestine, incretins are naturally secreted, hormones whose main function is to stimulate insulin secretion and warn the brain that the food has already arrived, giving a feeling of satiety. The two most important incretins are GLP-1 and GIP. In people with type 2 diabetes and those who are obese, these hormones do not work as well. This is why they continue to eat, even if they are physically full.
“Incretin analogues mimic the effects of these molecules,” explains Andreea Ciudin, coordinator of the comprehensive obesity treatment unit at Vall Hebron University Hospital, in a message exchange. They trick your pancreas and brain into telling them you’ve already eaten, giving you a feeling of eternal satiety. The first generation of drugs, semaglutide (sold under brand names such as Ozempic or Wegovy) mimicked only one molecule, GLP1. “But the new compositions add the effect of GIP, creating a much more powerful double compound,” says the endocrinologist. This is the case of tirzeptad, included in commercial brands such as Mounjaro. “It’s the most effective drug available so far for weight loss,” he explains. Early versions of semaglutide resulted in an average loss of 15% of body weight. Tirzeptaide raises this percentage to 22%. “One hypothesis is that GIP acts at other levels in the brain, potentiating the effect of GLP1,” says the expert.
Until now, it was hypothesized that these molecules manipulate the neuronal mechanisms of pleasure and addiction. It had been demonstrated in mice. It had been observed in observational studies, such as the one published last year Nature, highlighting that there was a 50% lower risk of incidence or recurrence of alcohol use disorder among semaglutide users. This suggested a strong association, but did not prove causation.
This is what the present study does, analyzing the brain activity, recorded directly with electrodes, of four participants with severe obesity and difficulty controlling their eating habits. “The brain surgery to implant the electrodes is invasive, so it is extremely rare to study human brain activity in this way,” explains Halpern.
Initially, the study aimed to implant electrodes in people with binge eating disorders, to interact with the brain with the aim of stopping cravings before they occurred. But one of the four participants, a 60-year-old woman identified as “patient three,” was being treated with tirzepatide, so the neurologists decided to also observe how the drug acted in her brain and compare its activity with that of the rest of the patients. “This rare opportunity to study the underlying physiology of agonists in the brain may not happen again,” Halpern says, so he decided to take advantage of it.
In doing so, they found that episodes of intense worry about food and cravings were related to stronger low-frequency brain signals (called brain activity). delta-theta) in the nucleus accumbens. And consuming tirzepatide suppressed that signal, resulting in reduced appetite and weight loss. “This finding could be useful in treating a wide range of conditions related to impulse control, such as binge eating disorder,” the author notes.
Binge eating disorder was recognized as a mental illness in 2013, it is estimated that it affects 3% of the Spanish population, being the most common eating disorder in the adult population. Understanding the brain mechanisms that cause it could change how we approach it. “This may also mean a revolution in the field of mental health, eating disorders and addictions,” says Ciudin. “Perhaps many of these diagnoses are based on a biological alteration, then the replacement treatment is given and the pathology disappears”.
