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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #415474
Research Project: Microbiota and Nutritional Health

Location: Children's Nutrition Research Center

Title: Hyperleptinemia contributes to antipsychotic drug–associated obesity and metabolic disorders

Author
item ZHAO, SHANGANG - University Of Texas Southwestern Medical Center
item LIN, QIAN - University Of Texas Southwestern Medical Center
item XIONG, WEI - University Of Texas Health Science Center
item LI, LI - University Of Texas Southwestern Medical Center
item STRAUB, LEON - University Of Texas Southwestern Medical Center
item ZHANG, DINGHONG - University Of California
item ZAPATA, RIZALDY - University Of California
item ZHU, QINGZHANG - University Of Texas Southwestern Medical Center
item SUN, XUE-NAN - University Of Texas Southwestern Medical Center
item ZHANG, ZHUZHEN - Wuhan University
item FUNCKE, JAN-BERND - University Of Texas Southwestern Medical Center
item LI, CHAO - University Of Texas Southwestern Medical Center
item CHEN, SHIUHWEI - University Of Texas Southwestern Medical Center
item ZHU, YI - Children'S Nutrition Research Center (CNRC)
item JIANG, NISI - University Of Texas Southwestern Medical Center
item LI, GUANNAN - University Of Texas Southwestern Medical Center
item XU, ZIYING - University Of Texas Southwestern Medical Center
item WYLER, STEVEN - University Of Texas Southwestern Medical Center
item WANG, MAY-YUN - University Of Texas Southwestern Medical Center
item JULI, BAI - University Of Texas Southwestern Medical Center
item HAN, XIANLIN - University Of Texas Southwestern Medical Center
item KUSMINSKI, CHRISTINE - University Of Texas Southwestern Medical Center
item ZHANG, ZINGYAN - University Of Texas Health Science Center
item AN, ZHIQIANG - University Of Texas Health Science Center
item ELMQUIST, JOEL - University Of Texas Southwestern Medical Center
item OSBORN, OLIVIA - University Of California
item LIU, CHEN - University Of Texas Southwestern Medical Center
item SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Science Translational Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/17/2023
Publication Date: 11/22/2023
Citation: Zhao, S., Lin, Q., Xiong, W., Li, L., Straub, L., Zhang, D., Zapata, R., Zhu, Q., Sun, X., Zhang, Z., Funcke, J., Li, C., Chen, S., Zhu, Y., Jiang, N., Li, G., Xu, Z., Wyler, S.C., Wang, M., Juli, B., Han, X., Kusminski, C.M., Zhang, Z., An, Z., Elmquist, J.K., Osborn, O., Liu, C., Scherer, P.E. 2023. Hyperleptinemia contributes to antipsychotic drug–associated obesity and metabolic disorders. Science Translational Medicine. 15. Article 723. https://doi.org/10.1126/scitranslmed.ade8460.
DOI: https://doi.org/10.1126/scitranslmed.ade8460

Interpretive Summary: Unwanted side effects such as weight gain and insulin resistance are well-known consequences of certain antipsychotic drugs. This paper shows that two such drugs, olanzapine and risperidone, elicited a rise in leptin in mice that both preceded and contributed to treatment-induced obesity and insulin resistance. Addition of a leptin-neutralizing antibody to the treatment regimen prevented much of these metabolic effects and additionally attenuated drug-induced local and systemic inflammation.

Technical 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.capability in mice.