Treating Obesity (And Brain) With Liraglutide

Obesity leads to altered energy metabolism and reduced insulin sensitivity of cells. The so-called “anti-obesity drugs” are increasingly used to treat obesity and have caused tremendous interest, especially in the USA. 

Researchers at the Max Planck Institute for Metabolism Reseat reduced insulin sensitivity affects learning of sensory associations. A single dose of the anti-obesity drug liraglutide was able to normalise these changes and restore the underlying brain circuit function.

To control our behaviour, the brain must be able to form associations. This involves, for example, associating a neutral external stimulus with a consequence following the stimulus (e.g., the hotplate glows red — you can burn your hand). 

In this way, the brain learns what the implication of our handling of the first stimulus are. Associative learning is the basis for forming neural connections and gives stimuli their motivational force. It is essentially controlled by a brain region called the dopaminergic midbrain. This region has many receptors for the body’s signaling molecules, such as insulin, and can thus adapt our behaviour to the physiological needs of our body.

But what happens when the body’s insulin sensitivity is reduced due to obesity? Does this change our brain activity, our ability to learn associations and thus our behaviour? Researchers at the Max Planck Institute for Metabolism Research have now measured how well the learning of associations works in participants with normal body weight (high insulin sensitivity, 30 volunteers) and in participants with obesity (reduced insulin sensitivity, 24 volunteers), and if this learning process is influenced by the anti-obesity drug liraglutide.

Low insulin sensitivity reduces the brain’s ability to associate sensory stimuli.

In the evening, they injected the participants with either the drug liraglutide or a placebo in the evening. Liraglutide is a so-called GLP-1 agonist, which activates the GLP-1 receptor in the body, stimulating insulin production and producing a feeling of satiety. It is often used to treat obesity and type 2 diabetes and is given once a day. The next morning, the subjects were given a learning task that allowed the researchers to measure how well associative learning works. They found that the ability to associate sensory stimuli was less pronounced in participants with obesity than in those of normal weight, and that brain activity was reduced in the areas encoding this learning behavior.

After just one dose of liraglutide, participants with obesity no longer showed these impairments, and no difference in brain activity was seen between participants with normal weight and obesity. In other words, the drug returned the brain activity to the state of normal-weight subjects.

Sources:

Ruth Hanssen, Lionel Rigoux, Bojana Kuzmanovic, Sandra Iglesias, Alina C. Kretschmer, Marc Schlamann, Kerstin Albus, Sharmili Edwin Thanarajah, Tamara Sitnikow, Corina Melzer, Oliver A. Cornely, Jens C. Brüning, Marc Tittgemeyer. Liraglutide restores impaired associative learning in individuals with obesity. Nature Metabolism, 2023; DOI: 10.1038/s42255-023-00859-y 

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