Nmnat2 deficiency in the arcuate nucleus or paraventricular nucleus induces Sarm1-independent neuron loss and liraglutide-reversible obesity.

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.