Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity

• DOI: 10.1016/j.molmet.2023.101713
• Publication Date: 2023-03-26T05:18:44Z
• Authors: Alba Clara Fernán...; Nicola Forte; Letizia Palomba; Lea Tunisi; Fabiana Piscitelli; Roberta Imperatore; Alfonso Di Costanzo; Vincenzo Di Marzo; Luigia Cristino
• Keywords: Energy homeostasis

Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology regulating energy homeostasis complex behaviors linked to arousal. Under conditions chronic or acute leptin signaling deficiency, such as in obesity short-term food deprivation, respectively, OX-A become hyperactive promote hyperarousal seeking. However, this leptin-dependent mechanism still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) known be implicated consumption promoting hyperphagia obesity, we others demonstrated that strong inducer 2-AG biosynthesis. Here, investigated hypothesis that, under (6 h fasting wt mice) (in ob/ob hypothalamic reduction, OX-A-induced enhancement levels leads production 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), bioactive lipid belonging class lysophosphatidic acids (LPAs), which then regulates synaptic plasticity disassembling α-MSH anorexigenic inputs via GSK-3β-mediated Tau phosphorylation, ultimately affecting intake.We combined cell-type-specific morphological (CLEM confocal microscopy), biochemical, pharmacological, electrophysiological techniques dissect leptin- OX-A/2-AGP-mediated molecular pathways GSK-3β-controlled pT231-Tau at POMC obese wild-type (wt) lean littermate mice an vitro model mHypoN41 (N41).2-AGP overproduced hypothalamus leptin-deficient, 6 food-deprived mice, promotes intake reducing α-MSH-expressing acid type-1 receptor (LPA1-R) activation, accumulation projections. This effect due activation Pyk2-mediated pTyr216-GSK3β pathway contributes further elevating release obesity. Accordingly, found correlation between 2-AGP serum human subjects.Hypothalamic feeding are endowed with 2-AGP-mediated according their inherent functional activities necessity adapt changes nutritional status. These findings reveal new involved regulation, could targeted treat related disturbances.