Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Department of Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Nat Commun. 2018 Dec 10;9(1):5272. doi: 10.1038/s41467-018-07684-y.
Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.
抗精神病药物（AP）用于治疗精神疾病，但会导致明显的体重增加和代谢疾病。进食增加（多食）似乎是 AP 诱导体重增加的驱动力，但机制尚不清楚。在这里，我们报告称，AP 给药会通过一种与基础食物摄入在遗传上不同的机制诱导秀丽隐杆线虫的多食。我们利用这一发现来筛选辅助药物，以抑制秀丽隐杆线虫和小鼠中 AP 诱导的多食。在小鼠中，AP 诱导的多食与一种独特的下丘脑基因表达特征相关，该特征可被辅助药物治疗所消除。使用秀丽隐杆线虫对该特征进行的遗传分析确定了两个转录因子，nhr-25/Nr5a2 和 nfyb-1/NFYB，是 AP 诱导的多食所必需的。我们的研究表明，AP 诱导的多食可以被选择性抑制而不影响基础食物摄入，从而为对抗 AP 诱导的代谢副作用提供了新的药物发现策略。
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