Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity
Objective: Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signalin...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-06-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823000479 |
| _version_ | 1797833131650187264 |
|---|---|
| author | Alba Clara Fernández-Rilo Nicola Forte Letizia Palomba Lea Tunisi Fabiana Piscitelli Roberta Imperatore Alfonso Di Costanzo Vincenzo Di Marzo Luigia Cristino |
| author_facet | Alba Clara Fernández-Rilo Nicola Forte Letizia Palomba Lea Tunisi Fabiana Piscitelli Roberta Imperatore Alfonso Di Costanzo Vincenzo Di Marzo Luigia Cristino |
| author_sort | Alba Clara Fernández-Rilo |
| collection | DOAJ |
| description | Objective: Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signaling deficiency, such as in obesity or short-term food deprivation, respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking. However, this leptin-dependent mechanism is still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) is known to be implicated in food consumption by promoting hyperphagia and obesity, and we and others demonstrated that OX-A is a strong inducer of 2-AG biosynthesis. Here, we investigated the hypothesis that, under acute (6 h fasting in wt mice) or chronic (in ob/ob mice) hypothalamic leptin signaling reduction, OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lipid belonging to the class of lysophosphatidic acids (LPAs), which then regulates hypothalamic synaptic plasticity by disassembling α-MSH anorexigenic inputs via GSK-3β-mediated Tau phosphorylation, ultimately affecting food intake. Methods: We combined cell-type-specific morphological (CLEM and confocal microscopy), biochemical, pharmacological, and electrophysiological techniques to dissect the leptin- and OX-A/2-AGP-mediated molecular pathways regulating GSK-3β-controlled pT231-Tau production at POMC neurons of obese ob/ob and wild-type (wt) lean littermate mice and in an in vitro model of POMC neurons such as mHypoN41 neurons (N41). Results: 2-AGP is overproduced in the hypothalamus of obese leptin-deficient, or lean 6 h food-deprived mice, and promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections. This effect is due to the activation of the Pyk2-mediated pTyr216-GSK3β pathway and contributes to further elevating OX-A release in obesity. Accordingly, we found a strong correlation between OX-A and 2-AGP levels in the serum of obese mice and of human subjects. Conclusions: Hypothalamic feeding pathways are endowed with 2-AGP-mediated synaptic plasticity according to their inherent functional activities and the necessity to adapt to changes in the nutritional status. These findings reveal a new molecular pathway involved in energy homeostasis regulation, which could be targeted to treat obesity and related disturbances. |
| first_indexed | 2024-04-09T14:18:38Z |
| format | Article |
| id | doaj.art-9264eccabc294d96960ef6595ab4fb4d |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-09T14:18:38Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-9264eccabc294d96960ef6595ab4fb4d2023-05-05T04:40:33ZengElsevierMolecular Metabolism2212-87782023-06-0172101713Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesityAlba Clara Fernández-Rilo0Nicola Forte1Letizia Palomba2Lea Tunisi3Fabiana Piscitelli4Roberta Imperatore5Alfonso Di Costanzo6Vincenzo Di Marzo7Luigia Cristino8Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, ItalyInstitute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy; Heart and Lung Research Institute and Institute for Nutrition and Functional Foods with Centre NUTRISS, Université Laval, Quebec City, CanadaUniversity of Urbino “Carlo Bo”, Urbino, ItalyInstitute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, ItalyInstitute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, ItalyUniversity of Sannio, Benevento, ItalyCentre for Research and Training in Medicine of Aging, Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, ItalyInstitute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy; Heart and Lung Research Institute and Institute for Nutrition and Functional Foods with Centre NUTRISS, Université Laval, Quebec City, Canada; Corresponding author. Heart and Lung Research Institute and Institute for Nutrition and Functional Foods with Centre NUTRISS, Université Laval, Quebec City, Canada.Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy; Corresponding author. Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy.Objective: Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signaling deficiency, such as in obesity or short-term food deprivation, respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking. However, this leptin-dependent mechanism is still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) is known to be implicated in food consumption by promoting hyperphagia and obesity, and we and others demonstrated that OX-A is a strong inducer of 2-AG biosynthesis. Here, we investigated the hypothesis that, under acute (6 h fasting in wt mice) or chronic (in ob/ob mice) hypothalamic leptin signaling reduction, OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lipid belonging to the class of lysophosphatidic acids (LPAs), which then regulates hypothalamic synaptic plasticity by disassembling α-MSH anorexigenic inputs via GSK-3β-mediated Tau phosphorylation, ultimately affecting food intake. Methods: We combined cell-type-specific morphological (CLEM and confocal microscopy), biochemical, pharmacological, and electrophysiological techniques to dissect the leptin- and OX-A/2-AGP-mediated molecular pathways regulating GSK-3β-controlled pT231-Tau production at POMC neurons of obese ob/ob and wild-type (wt) lean littermate mice and in an in vitro model of POMC neurons such as mHypoN41 neurons (N41). Results: 2-AGP is overproduced in the hypothalamus of obese leptin-deficient, or lean 6 h food-deprived mice, and promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections. This effect is due to the activation of the Pyk2-mediated pTyr216-GSK3β pathway and contributes to further elevating OX-A release in obesity. Accordingly, we found a strong correlation between OX-A and 2-AGP levels in the serum of obese mice and of human subjects. Conclusions: Hypothalamic feeding pathways are endowed with 2-AGP-mediated synaptic plasticity according to their inherent functional activities and the necessity to adapt to changes in the nutritional status. These findings reveal a new molecular pathway involved in energy homeostasis regulation, which could be targeted to treat obesity and related disturbances.http://www.sciencedirect.com/science/article/pii/S2212877823000479HypothalamusObesityα-MSHOrexin/hypocretin2-Arachidonoyl-glycerol2-AG |
| spellingShingle | Alba Clara Fernández-Rilo Nicola Forte Letizia Palomba Lea Tunisi Fabiana Piscitelli Roberta Imperatore Alfonso Di Costanzo Vincenzo Di Marzo Luigia Cristino Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity Molecular Metabolism Hypothalamus Obesity α-MSH Orexin/hypocretin 2-Arachidonoyl-glycerol 2-AG |
| title | Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity |
| title_full | Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity |
| title_fullStr | Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity |
| title_full_unstemmed | Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity |
| title_short | Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity |
| title_sort | orexin induces the production of an endocannabinoid derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity |
| topic | Hypothalamus Obesity α-MSH Orexin/hypocretin 2-Arachidonoyl-glycerol 2-AG |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823000479 |
| work_keys_str_mv | AT albaclarafernandezrilo orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT nicolaforte orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT letiziapalomba orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT leatunisi orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT fabianapiscitelli orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT robertaimperatore orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT alfonsodicostanzo orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT vincenzodimarzo orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity AT luigiacristino orexininducestheproductionofanendocannabinoidderivedlysophosphatidicacidelicitinghypothalamicsynapticlossinobesity |