Hyperleptinemia contributes to antipsychotic drug–associated obesity and metabolic disorders

Shangang Zhao, Qian Lin, Wei Xiong, Li Li, Leon Straub, Dinghong Zhang, Rizaldy Zapata, Qingzhang Zhu, Xue Nan Sun, Zhuzhen Zhang, Jan Bernd Funcke, Chao Li, Shiuhwei Chen, Yi Zhu, Nisi Jiang, Guannan Li, Ziying Xu, Steven C. Wyler, May Yun Wang, Juli BaiXianlin Han, Christine M. Kusminski, Ningyan Zhang, Zhiqiang An, Joel K. Elmquist, Olivia Osborn, Chen Liu, Philipp E. Scherer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug–induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug–treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug–associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.

Original languageEnglish (US)
Article numbereade8460
JournalScience translational medicine
Volume15
Issue number723
DOIs
StatePublished - Nov 15 2023

ASJC Scopus subject areas

  • General Medicine

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