Nmnat2 deficiency in the arcuate nucleus or paraventricular nucleus induces Sarm 1‐independent neuron loss and liraglutide‐reversible obesity

, 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.