ArticleProceedings of the National Academy of Sciences of the United States of America2016
Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 86 citations in OpenAlex.
- Metabolic and Orexin-A Responses to Ketogenic Diet and Intermittent Fasting: A 12-Month Randomized Trial in Adults with Obesity.Nutrients · 2026Trial
- Acute assessment of subjective appetite and implicated hormones after a hypnosis-induced hallucinated meal: a randomized cross-over pilot trial.Reviews in endocrine & metabolic disorders · 2020Trial
- Beyond energy balance: 2-arachidonoylglycerol at the crossroads of obesity, inflammation, and metabolic dysfunction.Molecular biology reports · 2026Review
- Transcriptome profiling of human hypothalamic agouti-related protein and proopiomelanocortin neurons regulating energy homeostasis.Nature communications · 2026Article
- Counterbalancing O-GlcNAcylation and STAT3 Phosphorylation in Ventral Tegmental Area Dopaminergic Neurons Mediates Behavioral Adaptations to Acute Restraint Stress.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Signal transduction, dimerization, and therapeutic targeting of Orexin and receptor systems.Frontiers in pharmacology · 2025Review
- A biological rhythm in the hypothalamic system links sleep-wake cycles with feeding-fasting cycles.Scientific reports · 2024Article
- Hypothalamic cannabinoid signaling: Consequences for eating behavior.Pharmacology research & perspectives · 2024Review
- The Mechanism of the Gut-Brain Axis in Regulating Food Intake.Nutrients · 2023Review
- Dietary Fat Modulation of Gut Microbiota and Impact on Regulatory Pathways Controlling Food Intake.Nutrients · 2023Review
- Cannabinoid receptor type 1 (CBiScience · 2023Article
- Endocannabinoid-Binding Receptors as Drug Targets.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Antibiotic treatment inhibits paclitaxel chemotherapy-induced activity deficits in female mice.PloS one · 2023Article
- Review
- Assessing CBMethods in molecular biology (Clifton, N.J.) · 2023Article
- Metabolic Messengers: endocannabinoids.Nature metabolism · 2022Review
- Actions of feeding-related peptides on the mesolimbic dopamine system in regulation of natural and drug rewards.Addiction neuroscience · 2022Article
- Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes.Diabetes, metabolic syndrome and obesity : targets and therapy · 2022Review
- Orexin, serotonin, and energy balance.WIREs mechanisms of disease · 2022Review
- Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice.Nature communications · 2021Article
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Authors and funding
12 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In the hypothalamic arcuate nucleus (ARC), proopiomelanocortin (POMC) neurons and the POMC-derived peptide α-melanocyte-stimulating hormone (α-MSH) promote satiety. POMC neurons receive orexin-A (OX-A)-expressing inputs and express both OX-A receptor type 1 (OX-1R) and cannabinoid receptor type 1 (CB1R) on the plasma membrane. OX-A is crucial for the control of wakefulness and energy homeostasis and promotes, in OX-1R-expressing cells, the biosynthesis of the endogenous counterpart of marijuana's psychotropic and appetite-inducing component Δ(9)-tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB1R. We report that OX-A/OX-1R signaling at POMC neurons promotes 2-AG biosynthesis, hyperphagia, and weight gain by blunting α-MSH production via CB1R-induced and extracellular-signal-regulated kinase 1/2 activation- and STAT3 inhibition-mediated suppression of Pomc gene transcription. Because the systemic pharmacological blockade of OX-1R by SB334867 caused anorectic effects by reducing food intake and body weight, our results unravel a previously unsuspected role for OX-A in endocannabinoid-mediated promotion of appetite by combining OX-induced alertness with food seeking. Notably, increased OX-A trafficking was found in the fibers projecting to the ARC of obese mice (ob/ob and high-fat diet fed) concurrently with elevation of OX-A release in the cerebrospinal fluid and blood of mice. Furthermore, a negative correlation between OX-A and α-MSH serum levels was found in obese mice as well as in human obese subjects (body mass index > 40), in combination with elevation of alanine aminotransferase and γ-glutamyl transferase, two markers of fatty liver disease. These alterations were counteracted by antagonism of OX-1R, thus providing the basis for a therapeutic treatment of these diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.