Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
Mol Psychiatry. 2023 May;28(5):1857-1867. doi: 10.1038/s41380-023-01981-9. Epub 2023 Feb 10.
Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.
抗精神病药物（AP）是治疗各种精神疾病的有效方法，但过度体重增加和随后代谢疾病的发展仍然是其使用的严重副作用。食物摄入量的增加导致 AP 引起的体重增加，但潜在的分子机制仍不清楚。在以前的研究中，我们发现神经肽 Agrp 和核受体亚家族 5 组 A 成员 2（Nr5a2）在 AP 诱导的多食后在下丘脑显著上调。虽然 Agrp 特异性表达于下丘脑弓状核，在食欲刺激中起关键作用，但 Nr5a2 表达于中枢神经系统和外周组织，但其在摄食行为中的作用尚不清楚。在这项研究中，我们研究了下丘脑 Nr5a2 在 AP 诱导的多食和体重增加中的作用。在下丘脑细胞系中，奥氮平治疗导致 Nr5a2 和 Agrp 的基因表达呈剂量依赖性增加。在小鼠中，NR5A2 的药理学抑制减少了奥氮平诱导的多食和体重增加，而在弓状核中 Nr5a2 的敲低部分逆转了奥氮平诱导的多食。染色质免疫沉淀研究首次表明，NR5A2 直接结合 Agrp 启动子区域。最后，单细胞 RNA seq 数据的分析证实 Nr5a2 和 Agrp 在弓状核中的一部分神经元中共同表达。总之，我们将 Nr5a2 确定为 AP 诱导摄食的关键机制驱动因素。这些发现可以为未来不激活多食和体重增加的 AP 的临床开发提供信息。
