Being overweight not only affects physical fitness and health, but also the ability to learn, as an experiment has now confirmed. Accordingly, a reduced insulin sensitivity of the cells in people with obesity leads to a brain region linked to the hormone balance reacting in a changed way. As a result, the ability to learn associatively – linking different stimuli together – is impaired. The good news, however, is that "weight loss injections" with active ingredients such as semaglutide or liraglutide can reverse this impairment of learning, as the researchers found. These drugs act on the so-called GLP-1 receptor and thereby reduce the feeling of hunger, but also normalize insulin production. This in turn has a positive effect on the function of the brain network required for associative learning.
Our brain must be able to form associations so that we can learn to avoid danger and behave accordingly. For example, it links information about a situation or an object with a stimulus - for example, the pain when burning in a candle flame with the glow of the flame. This associative learning is therefore an important basis for our behavior and our reaction to the environment. However, this form of learning does not only include the reaction to external stimuli - information about our internal state - for example thirst, hunger and other information linked to our metabolic state - is linked to behavior via associative learning. For example, we learn that the feeling of hunger decreases after eating. The dopaminergic midbrain, which is closely linked to the reward system, plays a key role in this form of learning. There are numerous receptors for endogenous hormones such as insulin. Via connections to other brain areas, this brain area influences the formation of new synapses and nerve cell connections - and thus learning.
Learning tasks for people with and without overweight
However, studies show that many metabolic reactions are altered in people with obesity and that insulin sensitivity also decreases. Ruth Hanßen from the Max Planck Institute for Metabolism Research in Cologne and her colleagues have now investigated whether this may also influence the dopaminergic midbrain and thus the ability to engage in associative learning. Their study involved 24 subjects with obesity and reduced insulin sensitivity and 30 controls with normal body weight and good insulin sensitivity. The evening before the actual test, all participants received either an injection with 0.6 milligrams of the drug liraglutide or a saline solution as a placebo. Like the active ingredient semaglutide marketed under the drug names Osempic and Wegovy, liraglutide is a so-called GLP-1 agonist. These drugs mimic the body's own hormone GLP-1, which affects sugar metabolism and satiety. To do this, it docks onto the corresponding receptors in the brain. First and foremost, these active ingredients should help against diabetes and support weight loss in people with obesity. However, through their effect on the brainstem and midbrain, they could also influence associative learning - this is the assumption of Hanßen and her team.
To investigate this, the researchers had their test subjects complete a learning task the day after the injection. The participants heard a high or low tone and were asked to guess which of two objects they would then see – a house or a face. The correct answer was displayed after the test persons had decided. In the course of the 320 test runs, it became clear how quickly the participants learned which object was linked to which sound. It turned out that when the placebo was given, the normal-weight control subjects performed better on average than the obese test subjects. Brain scans using functional magnetic resonance imaging showed that their brain activity was also lower in the brain areas important for associative learning. “These results are fundamental. We show here that basic behaviors such as associative learning depend not only on external environmental conditions, but also on the metabolic state of the body," says senior author Marc Tittgemeyer from the Max Planck Institute for Metabolism Research. "So whether someone is overweight or not also determines how the brain learns to assign sensory signals and what kind of drive is created."
Liraglutide compensates for deficits
However, the result changed with the administration of liraglutide: Even the one-off administration of the weight-loss drug eliminated the differences between the two groups, and the test subjects with obesity now performed just as well as the control group, as the researchers report. In terms of brain activity, too, they were no longer able to determine any difference between normal-weight and overweight test subjects. From this, the team concludes that liraglutide restores the brain areas that are important for associative learning in the obese participants to a certain extent back to normal. Specifically, this was shown in the dopaminergic midbrain, but also in the extensions of this brain region, which reach into the nucleus accumbens and the prefrontal cortex. According to the researchers, this confirms the results of the learning tests - and shows that GLP-1 agonists such as liraglutide can also help against the negative effects of obesity and lower insulin sensitivity on the brain.
"While it is gratifying that the drugs available have a positive effect on brain activity in obesity, it is alarming that brain performance changes occur even in young people with obesity without any other diseases," emphasizes Hanßen. “The prevention of obesity should play a much larger role in our healthcare system in the future. Taking medication for life is a much worse option if we could avoid obesity and its complications through prevention.”
Source: Ruth Hanßen (Max Planck Institute for Metabolism Research, Cologne) et al., Nature Metabolism, doi: 10.1038/s42255-023-00859-y