Lauren T. Seabrook and Lindsay Naef
University of Calgary
Seabrook, L. T*., Naef, L*., Baimel, C., Judge, A. K., Kenney, T., Ellis, M., Tayyab, T., Armstrong, M., Qiao, M., Floresco, S. B., & Borgland, S. L. (2022). Disinhibition of the orbitofrontal cortex biases decision-making in obesity. * Co-first Nature neuroscience, 10.1038/s41593-022-01210-6. Dec 15 2022.
Mechanistic insights on how mice fed a high-fat diet have altered decision making could help define new therapeutical targets.
Diet-induced obesity is a major health concern because it is often associated with comorbidities including type 2 diabetes, stroke, cancer, and depression. Studies show that increased consumption of processed foods rich in sugar, fats, and salts can alter an individual’s ability to control their caloric intake, leading to overconsumption and higher body weight. New research led by Lauren Seabrook and Lindsay Naef at the University of Calgary provides insight to understand how obesogenic food alters neural circuits to bias behavior toward eating beyond satiety.
Using mice, the researchers investigated the effects of a high-fat diet on the lateral orbitofrontal cortex (lOFC) a key brain region that guides decision-making related to food intake, and made three exciting discoveries.
First, they measured the activity of a subset of neurons called pyramidal neurons, and found they were more active in mice fed a high-fat diet.
Second, they showed that the behaviour of obese mice was altered in ways that promote overeating. Normally a food reward can be devalued with satiety (feeling full) or by pairing the food with sickness (food poisoning). This devaluation was altered in obese mice, who continued feeding past satiety and in the presence of a taste that was paired to sickness.
Third, the researchers were able to show that a specific neurotransmitter, GABA, acts to inhibit activity in the lOFC during food devaluation. Decreasing GABAaergic tone in lean mice promoted overeating behaviour, while increasing GABAergic tone in obese mice promoted food devaluation.
Taken together, these findings provide new and exciting avenues to treat obesity by targeting the decision-making centers of the brain. Currently in Canada there are four medications used for the treatment of overweight and obesity, yet none of them specifically target brain mechanisms to alter food choices. These findings provide a novel target for potential therapeutics.
This research was funded by a Koopmans Research Award, Mathison Centre for Research and Education Neural Circuits research grant, Canadian Institutes of Health Research operating grant (CIHR, FDN-147473) and a Canada Research Chair Tier 1 (950-232211) to Stephanie Borgland. Lauren Seabrook was supported by a Harley Hotchkiss Doctoral Scholarship in Neuroscience. Lindsay Naef was supported by postdoctoral awards from Les Fonds de la Recherche en Sante du Quebec, Alberta Innovates Health Solutions and CIHR.
About Lauren T Seabrook & Lindsay Naef.
Lauren T Seabrook and Lindsay Naef performed this research as a PhD student at the University of Calgary, in the laboratory of Dr. Stephanie Borgland. As co-first authors of the publication, she and Dr. Lindsay Naef performed most of the experiments, data analysis, and contributed significantly to the writing and editing of the manuscript. Dr. Naef currently works at Novo Nordisk.