The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain.

Autor:	Li L; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX., Yoo ES; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea., Li X; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX., Wyler SC; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX., Chen X; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX., Wan R; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX., Arnold AG; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX., Birnbaum SG; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX.; Peter O'Donnell Jr. Brain Institute, The University of Texas Southwestern Medical Center, Dallas, TX., Jia L; Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX., Sohn JW; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea., Liu C; The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.; Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2021 Jul 05; Vol. 218 (7). Date of Electronic Publication: 2021 May 12.
DOI:	10.1084/jem.20202484
Abstrakt:	Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice. Competing Interests: Disclosures: The authors declare no competing interests exist. (© 2021 Li et al.)
Databáze:	MEDLINE
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