Amylin–leptin coadministration stimulates central histaminergic signaling in rats

Combined amylin + leptin (AMN + LEP) can reduce diet induced obesity and is very effective in combating LEP resistance. The purpose of this study was to evaluate the effect of AMN + LEP on central histaminergic signaling in lean and obese rats. Male rats were administered LEP (300 μg/kg/d), AMN (100 μg/kg/d), AMN + LEP or vehicle (SAL, 0.9% normal saline), via a subcutaneous mini-osmotic pump or single injection (LEP, 300 μg/kg and AMN, 100 μg/kg) for acute studies. AMN + LEP administration increased expression of histamine H1 receptor (HIR) and histidine decarboxylase (HDC) mRNA in the hypothalamus. Increased levels of H1R were seen in arcuate (Arc) and ventromedial hypothalamus (VMH) as well as the area postrema (APOS) and nucleus of solitary tract (NTS) following AMN + LEP administration. APOS and NTS also showed expression of immediate early gene c-FOS in the hindbrain in AMN + LEP-treated rats. We confirmed previous evidence indicating that AMN + LEP increased STAT-3 protein phosphorylation in Arc and VMH. Finally, by in vivo microdialysis, we observed an increase in methyl HIS levels in the VMH of AMN, LEP and AMN + LEP-treated rats. Taken together, these observations are consistent with an important role that neuronal HIS may play in mediating the potent effects of AMN + LEP on food intake and body weight.

► Amylin and leptin interaction increases hypothalamic histamine.
► Combined amylin+leptin can very effectively reduce caloric intake and body weight.
► HIS H1 receptor and histidine decarboxylase enzyme are upregulated in key brain areas involved in regulation of food intake.