A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests dopamine-driven learning processes are modified by metabolic signaling and that this effect “may contribute to the weight-reducing effects of liraglutide in obesity,” say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
“Liraglutide Can Normalize Learning of Associations”
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune'” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide (GIP).
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the Section of Medical Psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide Treatment Leveled Learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Tittgemyer and most of his co-authors had no disclosures. One co-author had several disclosures, which are detailed in the report. Kroemer had no disclosures.
Nat Metab. Published August 17, 2023. Full text
Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler
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