A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia.,Nature Communications

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A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia.
Nature Communications ( IF 14.7 ) Pub Date : 2018-12-10 , DOI: 10.1038/s41467-018-07684-y
Anabel Perez-Gomez _{1,

2} , Maria Carretero _{1,

2} , Natalie Weber ₃ , Veronika Peterka ₃ , Alan To _{1,

2} , Viktoriya Titova _{1,

2} , Gregory Solis _{1,

2} , Olivia Osborn ₃ , Michael Petrascheck _{1,

2}

Affiliation

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.

中文翻译：

表型秀丽隐杆线虫筛选鉴定出抗精神病药物引起的食欲过盛的选择性抑制剂。

抗精神病 (AP) 药物用于治疗精神疾病，但与体重显着增加和代谢疾病有关。食物摄入量增加（食欲过盛）似乎是 AP 导致体重增加的驱动力，但其机制尚不清楚。在这里，我们报告给线虫施用 AP 会通过一种与基础食物摄入在遗传上不同的机制诱导食欲亢进。我们利用这一发现来筛选可抑制 AP 诱导的线虫和小鼠食欲亢进的辅助药物。在小鼠中，AP 诱导的食欲亢进与独特的下丘脑基因表达特征相关，该特征可通过辅助药物治疗消除。使用秀丽隐杆线虫对该特征进行遗传分析，确定了 AP 诱导的食欲亢进所需的两个转录因子：nhr-25/Nr5a2 和 nfyb-1/NFYB。我们的研究表明，可以选择性地抑制 AP 引起的食欲亢进，而不影响基础食物摄入量，从而允许新的药物发现策略来对抗 AP 引起的代谢副作用。

更新日期：2018-12-10

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