Deletion of α7 Nicotinic Acetylcholine Receptor in POMC Neurons Impairs Energy Balance and Leptin-Induced Anorexigenic Response in Male Mice.

Recent studies demonstrate that α7 nicotinic acetylcholine receptors (α7nAChR) in hypothalamic neurons, including pro-opiomelanocortin (POMC) neurons, modulate energy homeostasis. This study aimed to explore how the α7nAChR subunit in hypothalamic POMC neurons affects food intake and energy balance in mice. This study used site-specific knockout mice for α7nAChR in POMC neurons (Control: α7nAChRfl/fl; Knockout: α7nAChRfl/flPOMCCre) generated via the Cre-LoxP system. Body weight (BW) and body weight gain (BWG) were measured. We measured energy expenditure by respirometry and assessed glycemic homeostasis using an intraperitoneal glucose tolerance test (ipGTT) and an insulin tolerance test (ipITT). Food intake was measured after intraperitoneal injection of saline (0.9%), leptin (5 μg/g BW), or the selective α7nAChR agonist PNU-282987 (1 mg/kg BW). Afterward, fasted mice were injected intraperitoneally with saline (0.9%), leptin (2.5 μg/g BW), or PNU-282987 (1 mg/kg BW), and subsequently euthanized. RT-qPCR and Western blotting analyses were performed. The α7nAChRfl/flPOMCCre males were initially lighter but had higher BWG. The opposite was observed in females. α7nAChRfl/flPOMCCre male mice showed increased epididymal fat, serum leptin levels, and food intake. Knockout male mice showed no major impairment in glucose homeostasis and signaling. Furthermore, the leptin-induced anorectic response was delayed, with reduced hypothalamic anorectic proteins and a trend toward reduced pCREBSer133 after an acute leptin stimulus. PNU-282987 treatment increased pCREBSer133 content and Pcsk1 gene expression in vitro. The α7nAChR expressed in POMC neurons seems to contribute to energy and glycemic homeostasis and to the hypothalamic leptin-induced anorectic response mediated by CREB phosphorylation.