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Chemogenetic inhibition of the lateral hypothalamus effectively reduces food intake in rats in a translational proof-of-concept study.

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اقرأ على الانترنت اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • المصدر:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • الموضوع:
      Clozapine*/analogs & derivatives ; Clozapine*/pharmacology ; Eating*/drug effects ; Hypothalamic Area, Lateral*/drug effects ; Dependovirus*/genetics ; Proof of Concept Study*; Animals ; Rats ; Male ; Exenatide/pharmacology ; Humans
    • نبذة مختصرة :
      Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.
      (© 2024. The Author(s).)
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    • Grant Information:
      K143816 National Research, Development and Innovation Office
    • Contributed Indexing:
      Keywords: Body weight; Clozapine-N-oxide; DREADD; Deschloroclozapine; Food-intake management; Obesity
    • الرقم المعرف:
      0 (clozapine N-oxide)
    • الموضوع:
      Date Created: 20240518 Date Completed: 20240518 Latest Revision: 20240521
    • الموضوع:
      20240521
    • الرقم المعرف:
      PMC11102470
    • الرقم المعرف:
      10.1038/s41598-024-62014-1
    • الرقم المعرف:
      38762561