Scientists recognize neural circuit associated with reciprocally controlling weight gain and despondency

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• Source: Baylor College of Medicine


• Date: 27 Mar,2021

Research has found that obesity and mental disorders such as depression and anxiety seem to often go together. Researchers at Baylor College of Medicine and cooperating institutions are providing new insights into this association by identifying and characterizing a novel neural circuit that mediates the reciprocal control of feeding and mental conditions in mouse models.

Similar to human patients, mice who consumed a high-fat diet not only became obese, but also stressed and depressed, a condition mediated by a defective brain circuit. When the researchers genetically or pharmacologically adjusted specific disruptions they’d observed within this circuit, the mice became less anxious and depressed and later lost excess body weight.

Interestingly, weight loss wasn’t the result of lack of appetite, but of the animals’ change of food preference. Before the treatment, the mice obviously preferred to consume a high-fat diet, but after the treatment they turned their preference toward a healthier diet with reduced fat and abundant carbohydrates and protein. The findings, published in the journal Molecular Psychiatry, for the first time, not only show a key regulatory mechanism for coinciding obesity and mental disorders, but also suggest the possibility of a pharmacological treatment.

Reports indicate that 43% of adults with depression are obese and that adults with mental illness are more likely to develop obesity than those who are mentally healthy. Factors such as hormonal dysregulation, genetic deficiency and inflammation have been proposed to be involved in the connection between obesity and mental disorders. Here we provide evidence that supports the involvement of a neural component.”

Dr. Qi Wu, corresponding author, a Pew Scholar for Biomedical Sciences, Kavli Scholar and assistant professor in pediatrics-nutrition at Baylor’s Children’s Nutrition Research Center

To investigate the neuronal circuits which could be involved in reciprocally regulating weight gain and depression or anxiety, the researchers supplied mice with a high-fat diet. As expected, the animals became obese. They also developed depression and anxiety. In these mice, the group analyzed the role of neuronal circuits.

“We discovered in normal mice which two groups of brain cells, dBNST and AgRP neurons located in separate brain areas, form a circuit or link to each other by extending cellular projections,” said co-first author Dr. Guobin Xia, postdoctoral associate in the Wu laboratory. “This newly discovered circuit was malfunctioning in mice that were both obese and depressed.”

“Using genetic approaches, we identified specific genes and other mediators which were changed and mediated the circuit’s malfunction in the heavy and depressed mice,” said co-first writer Dr. Yong Han, postdoctoral associate in the Wu lab.

“Importantly, genetically restoring the neural defects to ordinary eliminated the high fat diet-induced anxiety and depression and also reduced body weight,” Xia said. “We were amazed to see that the animals lost weight, not because they lost their appetite, but because genetically-aided readjustment of the mental states changed their feeding taste from high-fat to low-fat food.”

“Bearing in mind translational applications of our findings into the clinic, we investigated the potential for restoring the publication circuit pharmacologically,” Wu said. “We found that the combination of two clinically-approved medications, zonisamide and granisetron, profoundly reduced depression and anxiety in mice and encouraged weight loss by synergistically acting upon two different molecular targets within our newly identified brain circuit. We consider that our results provide convincing support for further research and future clinical trials testing the worth of a cocktail therapy combining zonisamide and granisetron (or a variety of the derivatives) to take care of metabolic-psychiatric diseases.”