Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit

Authors: XIA, GUOBIN - Children'S Nutrition Research Center (CNRC); HAN, YONG - Children'S Nutrition Research Center (CNRC); MENG, FANTAO - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Children'S Nutrition Research Center (CNRC); SRISAI, DOLLADA - Vanderbilt University; FARIAS, MONICA - Children'S Nutrition Research Center (CNRC); DANG, MINGHAO - University Of Texas Medical Branch; PALMITER, RICHARD - University Of Washington; XU, YONG - Children'S Nutrition Research Center (CNRC); WU, QI - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular Psychiatry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/12/2021
Publication Date: 3/26/2021
Citation: Xia, G., Han, Y., Meng, F., He, Y., Srisai, D., Farias, M., Dang, M., Palmiter, R.D., Xu, Y., Wu, Q. 2021. Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit. Molecular Psychiatry. https://doi.org/10.1038/s41380-021-01053-w.
DOI: https://doi.org/10.1038/s41380-021-01053-w

Interpretive Summary: Anxiety/depression symptoms are the top comorbidity of obesity, that jointly form a vicious cycle disrupting the mental and metabolic health for >70% obese patients (i.e. >100 million in the US and ~500 million worldwide). So far there is no effective treatment for this global healthcare issue. In this article, we discovered how the brain exerts a reciprocal control of feeding of high-fat foods and psychological states. Similar to human patients, mice that consumed a high-fat diet not only became obese, but also anxious and depressed, a condition mediated by a defective brain circuit. When the disruptions were genetically or pharmacologically corrected within this neural circuit, the mice became less anxious and depressed and later lost excess body weight. More importantly, we successfully established a cocktail therapy using FDA-approved drugs for effectively treatment of this comorbidity. This new regimen displayed striking preclinical results that not only eradicate anxiety/depression but also reverse most of the obesity symptoms via a surprising effect to make the subjects voluntarily switching their diet choice from high-fat foods to a low-fat, carb/protein-enriched healthy diet.

Technical Abstract: The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto a5-containing GABAA receptors and serotonergic afferents onto 5-HT3 receptors. Chronic treatment with a high-fat diet (HFD) significantly blunts the hyperexcitability of AgRP neurons in response to not only hunger but also anxiety and depression-like stimuli. Such HFD-mediated desensitization reduces GABAergic outputs from AgRP neurons to downstream MC4RdBNST neurons, resulting in severe mental dysregulation. Genetic enhancement of the GABAAR-a5 or suppression of the 5-HT3R within the MC4RdBNST neurons not only abolishes HFD-induced anxiety and depression but also robustly reduces body weight by suppression of food intake. To gain further translational insights, we revealed that combined treatment of zonisamide (enhancing the GABAAR-a5 signaling) and granisetron (a selective 5-HT3R antagonist) alleviates mental dysfunction and yields a robust reversal of diet-induced obesity by reducing total calorie intake and altering food preference towards a healthy low-fat diet. Our results unveil a neural mechanism for reciprocal control of appetite and mental states, which culminates in a novel zonisamide-granisetron cocktail therapy for potential tackling the psychosis-obesity comorbidity.