Yu Huimin, Feng Ning, Zhong Wuling, Han Yumo, Cheng Yalan, Zhang Zhentong, Wang Yingqi, Gao Peidong, Huang Rui, Zhang Cong, Liu Zongyang, Dong Jieya, He Zhishui, Lai Hejin, Shen Ziru, Zhai Qiwei
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
FASEB J. 2025 Feb 28;39(4):e70400. doi: 10.1096/fj.202402546R.
Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) plays an important role in maintaining axon integrity, and the arcuate nucleus (ARC), and paraventricular nucleus (PVN) are crucial nuclei in the control of energy balance. However, the effect of Nmnat2 deficiency in ARC and PVN is still unclear. Nmnat2 or Nmnat2 , Sarm1 mice were bilaterally injected with AAV-CMV-GFP-Cre once into the ARC, PVN, or lateral parabrachial nucleus (LPBN) to obtain Nmnat2 , Nmnat2 , Nmnat2 , Nmnat2 , SKO, Nmnat2 , SKO, or Nmnat2 , SKO mice. Syn1-Cre mice were bilaterally injected with AAV-EF1a-flex-taCasp3-TEVp once into the ARC or PVN to specifically induce neuron loss. Metabolic changes were measured in the mice intraperitoneally injected with or without liraglutide, a glucagon-like peptide-1 (GLP-1) analog. Neuron loss and neuron activation were monitored by immunofluorescence. Deletion of Nmnat2 in ARC or PVN of mice leads to neuron loss, increased food intake, and obesity in a Sarm1-independent manner. Intraperitoneal injection of liraglutide activates neurons in PVN and LPBN, and attenuates hyperphagia and obesity induced by Nmnat2 deletion or apoptosis of Syn1-positive neurons in ARC or PVN, but has no significant effect on neuron loss. Nmnat2 deficiency in LPBN leads to death within 2 weeks, which can be markedly rescued by Sarm1 deficiency. These data show that deletion of Nmnat2 in ARC or PVN in adult mice leads to Sarm1-independent neuron loss, and liraglutide-reversible hyperphagia and obesity. These findings also elucidate the integrated role of ARC or PVN for downregulating food intake, the requirement of LPBN for survival, and the ARC- or PVN-independent effect of GLP-1 on food intake.
烟酰胺单核苷酸腺苷酸转移酶2（Nmnat2）在维持轴突完整性方面发挥着重要作用，而弓状核（ARC）和室旁核（PVN）是控制能量平衡的关键核团。然而，ARC和PVN中Nmnat2缺乏的影响仍不清楚。将Nmnat2或Nmnat2、Sarm1基因敲除小鼠双侧注射一次携带AAV-CMV-GFP-Cre的病毒至ARC、PVN或外侧臂旁核（LPBN），以获得Nmnat2、Nmnat2、Nmnat2、Nmnat2、SKO、Nmnat2、SKO或Nmnat2、SKO小鼠。将Syn1-Cre小鼠双侧注射一次携带AAV-EF1a-flex-taCasp3-TEVp的病毒至ARC或PVN，以特异性诱导神经元丢失。对腹腔注射或未注射胰高血糖素样肽-1（GLP-1）类似物利拉鲁肽的小鼠进行代谢变化测量。通过免疫荧光监测神经元丢失和神经元激活。小鼠ARC或PVN中Nmnat2的缺失导致神经元丢失、食物摄入量增加和肥胖，且不依赖于Sarm1。腹腔注射利拉鲁肽可激活PVN和LPBN中的神经元，并减轻由Nmnat2缺失或ARC或PVN中Syn1阳性神经元凋亡诱导的食欲亢进和肥胖，但对神经元丢失无显著影响。LPBN中Nmnat2缺乏导致小鼠在2周内死亡，而Sarm1缺乏可显著挽救这一情况。这些数据表明，成年小鼠ARC或PVN中Nmnat2的缺失导致不依赖于Sarm1的神经元丢失，以及利拉鲁肽可逆的食欲亢进和肥胖。这些发现还阐明了ARC或PVN在下调食物摄入量方面的综合作用、LPBN对生存的需求，以及GLP-1对食物摄入量的不依赖于ARC或PVN的作用。
