2015 Apr 13. pii: jbc.M115.646885. [Epub ahead of print]
Palomba L1, Silvestri C2, Imperatore R2, Morello G3, Piscitelli F3, Martella A3, Cristino L3, Di Marzo V4.
Abstract
The adipocyte-derived, anorectic hormone, leptin, was recently shown to owe part of its regulatory effects on appetite-regulating hypothalamic neuropeptides to the elevation of ROS levels in arcuate nucleus (ARC) neurons. Leptin is also known to exert a negative regulation on hypothalamic endocannabinoid levels and hence on cannabinoid CB1 receptor activity. Here we investigated the possibility of a negative regulation by CB1 receptor of leptin-mediated ROS formation in the ARC. Through pharmacological and molecular biology experiments we report data showing that leptin-induced ROS accumulation is: 1) blunted by arachidonyl-2′-chloroethylamide (ACEA) in a CB1-dependent manner, in both the mouse hypothalamic cell line mHypoE-N41 and ARC neuron primary cultures; 2) likewise blocked by a peroxisome proliferator-activated receptor-γ (PPAR-γ)agonist, troglitazone, in a manner inhibited by T0070907, a PPAR-γ antagonist, which also inhibited ACEA effect on leptin; 3) blunted under conditions of increased endocannabinoid tone due to either pharmacological or genetic inhibition of endocannabinoid degradation in mHypoE-N41 and primary ARC neuronal cultures from MAGL-/- mice, respectively; 4) associated with reduction of both PPAR-γ and catalase activity, which are reversed by both ACEA and troglitazone. We conclude that CB1 activation reverses leptin-induced ROS formation, and hence possibly some of the ROS-mediated effects of the hormone, by preventing PPAR-γ inhibition by leptin, with subsequent increase of catalase activity. This mechanism might underlie in part CB1 orexigenic actions under physiopathological conditions accompanied by elevated hypothalamic endocannabinoid levels.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
KEYWORDS:
cannabinoid; cannabinoid receptor type 1 (CB1); hypothalamus; leptin; reactive oxygen species (ROS)
- PMID:
- 25869131
- [PubMed – as supplied by publisher]