Leptin-regulated endocannabinoids are involved in maintaining food intake
Abstract
Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.
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Following binding to central nervous system receptors such as CB1, endocannabinoids reduce anxiety and increase food intake.
“Following their binding to central nervous system receptors (e.g.CB1 receptors), endocannabinoids have been shown, e.g., to reduce anxiety (Marsicano et al., 2002;Lutz et al., 2015) and increase food intake (Di Marzo et al., 2001).”
From Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans (2016) · cites this paper as Di Marzo et al., 2001
Activation of the endocannabinoid system has been previously shown to increase acutely appetite and mood.
“Given that activation of the endocannabinoid system has been previously shown to increase acutely appetite and mood (Di Marzo et al., 2001;Lutz et al., 2015)”
From Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans (2016) · cites this paper as Di Marzo et al., 2001
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Ghrelin’s Role as a Major Regulator of Appetite and Its Other Functions in Neuroendocrinology
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- Authors
- Di Marzo, V., Goparaju, S. K., Wang, L., Liu, J., Bátkai, S., Járai, Z., Fezza, F., Miura, G. I., Palmiter, R. D., Sugiura, T., & Kunos, G.
- Affiliations
- Virginia Commonwealth University (US)
- National Institutes of Health (US)
- National Research Council (IT)
- Howard Hughes Medical Institute (US)
- Teikyo University (JP)
- Corresponding author
- Kunos, George
- Venue
- Nature
- Published
- 2001-04
- Volume
- 410
- Issue
- 6830
- Pages
- 822-825
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1491109154
- Cited by
- 1,559
- References
- 29
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 24 · 2023: 28 · 2022: 27 · 2021: 45 · 2020: 41 · 2019: 44 · 2018: 57 · 2017: 54 · 2016: 55 · 2015: 59 · 2014: 57 · 2013: 63 · 2012: 64
- FWCI
- 47.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, endocannabinoids, food intake regulation, CB1 receptor, anandamide, 2-arachidonoylglycerol, hypothalamus, energy balance, obesity, neuropeptide Y, melanocortin-4 receptor, leptin receptor, ob/ob mice, db/db mice, Zucker rats, SR141716A, dietary restriction
- MeSH terms
- Rimonabant, Animals, Appetite Regulation, Arachidonic Acids, Cannabinoids, Cerebellum, Eating, Female, Food, Glycerides, Hypothalamus, Lipoprotein Lipase, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Phospholipase D, Piperidines, Pyrazoles, Rats, Zucker, Receptors, Drug, Signal Transduction, Rats, Sprague-Dawley, Mice, Knockout, Leptin, Receptors, Cannabinoid, Mice, Rats, Receptors, Leptin, Cannabinoid Receptor Modulators, Endocannabinoids
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