Pnoc-KO Mouse

Pnoc, short for prepronociceptin, is associated with the regulation of feeding behavior and energy homeostasis. It is expressed in certain neurons, and the neuropeptides derived from it may be involved in neural communication related to these processes [1,2,3]. Pnoc -expressing neurons are part of a GABAergic population in the arcuate nucleus of the hypothalamus (ARC), distinct from well-known feeding regulatory neurons like AgRP or POMC neurons [1].

In mice, selective ablation of Pnoc -expressing neurons in the ARC (PNOCARC neurons) upon high-fat-diet (HFD) exposure promotes the activation of anorexigenic POMC neurons, reduces feeding, and protects from obesity, while having no effect on normal chow consumption [1]. This indicates that PNOCARC neurons play a role in diet-induced hyperphagia and obesity. Also, the activity of PNOCARC neurons is necessary for HFD-induced inhibition of POMC neurons, and is mediated by GABA release [2]. Moreover, loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the ARC causes hyperphagia and obesity, and restoring Lepr expression in these neurons reduces body weight [3].

In conclusion, Pnoc-expressing neurons, especially PNOCARC neurons, are crucial mediators in leptin-controlled energy homeostasis and diet-induced hyperphagia. The study of Pnoc using gene-knockout (KO) or conditional-knockout (CKO) mouse models has significantly contributed to understanding its role in obesity-related disease conditions, highlighting its potential as a target for obesity therapeutics [1,2,3].

References:

1. Jais, Alexander, Paeger, Lars, Sotelo-Hitschfeld, Tamara, Kloppenburg, Peter, Brüning, Jens C. 2020. PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding. In Neuron, 106, 1009-1025.e10. doi:10.1016/j.neuron.2020.03.022. https://pubmed.ncbi.nlm.nih.gov/32302532/

2. Sotelo-Hitschfeld, Tamara, Minère, Marielle, Klemm, Paul, Fenselau, Henning, Brüning, Jens Claus. 2024. GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia. In Cell reports, 43, 114343. doi:10.1016/j.celrep.2024.114343. https://pubmed.ncbi.nlm.nih.gov/38865247/

3. Solheim, Marie H, Stroganov, Sima, Chen, Weiyi, Steuernagel, Lukas, Brüning, Jens C. 2025. Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis. In Cell, , . doi:10.1016/j.cell.2025.04.001. https://pubmed.ncbi.nlm.nih.gov/40273910/