Hypothalamic nesfatin-1 mediates feeding behavior via MC3/4R-ERK signaling pathway after weight loss in obese Sprague-Dawley rats

Nesfatin-1 is an anorexic peptide derived from nucleobindin 2 (NUCB2). An increase in hypothalamic nesfatin-1 inhibits feeding behavior and promotes weight loss. However, the effects of weight loss on hypothalamic nesfatin-1 levels are unclear. In this study, obese rats lost weight in three ways: Calorie Restriction diet (CRD), Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). We found an increase in nesfatin-1 serum and cerebrospinal fluid levels after weight loss in obese Sprague-Dawley (SD) rats. Moreover, weight loss also increased hypothalamic melanocortin 3/4 receptor (MC3/4R) and extracellular regulated kinase phosphorylation (p-ERK) signaling. Third ventricle administration of antisense morpholino oligonucleotide (MON) against the gene encoding NUCB2 inhibited hypothalamic nesfatin-1 and p-ERK signaling, increased food intake and reduced body weight loss in SG and RYGB obese rats. Third ventricle administration of SHU9119 (MC3/4R blocker) blocked hypothalamic MC3/4R, inhibited p-ERK signaling, increased food intake and reduced body weight loss in SG and RYGB obese rats. These findings indicate that weight loss leads to an increase in hypothalamic nesfatin-1. The increase in hypothalamic nesfatin-1 participates in regulating feeding behavior through the MC3/4R-ERK signaling especially after SG and RYGB.