Leptin-regulated endocannabinoids are involved in maintaining food intake


Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance1. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as α-melanocyte-stimulating hormone2,3, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y4. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors6, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y7. CB1 cannabinoid receptors8 and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus9, and marijuana10 and anandamide11,12 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Food intake in CB1-/- mice and their CB1+/+ littermates in the absence and presence of the CB1 receptor antagonist SR141716A.
Figure 2: Hypothalamic levels of anandamide and 2-arachidonoyl glycerol (2-AG).
Figure 3: Hypothalamic levels of anandamide (AEA), 2-arachidonoyl glycerol (2-AG) and palmitoyl ethanolamide (PEA).
Figure 4: Effect of SR141716A on food intake in NPY-deficient mice.
Figure 5: Effect of SR141716A on food intake in obese mice.


  1. 1

    Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Schwartz, M. W. et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Seeley, R. J. et al. Melanocortin receptors in leptin effects. Nature 390, 349–351 (1997).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–534 (1995).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Erickson, J. C., Clegg, K. E. & Palmiter, R. D. Sensitivity to leptin and susceptibility to seizures in mice lacking neuropeptide Y. Nature 381, 415–421 (1996).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Herkenham, M. et al. Characterization and localization of cannabinoid receptors in rats: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583 (1991).

    CAS  Article  Google Scholar 

  9. 9

    Gonzalez, S. et al. Identification of endocannabinoids and cannabinoid CB1 receptor mRNA in the pituitary gland. Neuroendocrinology 70, 137–145 (1999).

    CAS  Article  Google Scholar 

  10. 10

    Mechoulam, R., Hanus, L. & Fride, E. Towards cannabinoid drugs—revisited. Prog. Med. Chem. 35, 199–243 (1998).

    CAS  Article  Google Scholar 

  11. 11

    Williams, C. M. & Kirkham, T. C. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology 143, 315–317 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Hao, S., Avraham, Y., Mechoulam, R. & Berry, E. M. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur. J. Pharmacol. 392, 147–156 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Zimmer, A., Zimmer, A. M., Hohmann, A. G., Herkenham, M. & Bonner, T. I. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl Acad. Sci. USA 96, 5780–5785 (1999).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Járai, Z. et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl Acad. Sci. USA 96, 14136–14141 (1999).

    ADS  Article  Google Scholar 

  15. 15

    Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240–244 (1994).

    CAS  Article  Google Scholar 

  16. 16

    Lopez, M. et al. Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus. Biochem. Biophys. Res. Commun. 269, 41–45 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Sahu, A. Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets for leptin signaling in the hypothalamus. Endocrinology 139, 795–798 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Sugiura, T. et al. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoyl-ethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur. J. Biochem. 240, 53–62 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Funahashi, H. et al. The effect of leptin on feeding-regulating neurons in the rat hypothalamus. Neurosci. Lett. 264, 117–120 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Bisogno, T. et al. Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J. Neurochem. 72, 2113–2119 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Colombo, G. et al. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716A. Life Sci. 63, PL113–PL117 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Chaperon, F., Soubrie, P., Puech, A. J. & Thiebot, M.-H. Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology 135, 324–332 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Bouaboula, M. et al. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor. 1. Evidence for a new model of receptor/ligand interactions. J. Biol. Chem. 272, 22330–22339 (1997).

    CAS  Article  Google Scholar 

  26. 26

    White, R. & Hiley, C. R. The actions of the cannabinoid receptor antagonist, SR141716A, in rat isolated mesenteric artery. Br. J. Pharmacol. 125, 689–696 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Sakarai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).

    Article  Google Scholar 

  28. 28

    Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S. & Maratos-Flier, E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396, 670–674 (1998).

    ADS  CAS  Article  Google Scholar 

  29. 29

    Di Marzo, V. et al. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur. J. Biochem. 264, 258–267 (1999).

    CAS  Article  Google Scholar 

Download references


We thank A. Zimmer for heterozygote breeding pairs for the CB1-/-and CB1+/+ mice. This study was supported by grants from the NIH to G.K. Z.J. and S.B. were supported by fellowships from Sanofi Research (Montpellier, France) and the Martin Rodbell visiting program, respectively. V.D.M. was the recipient of a Human Frontier Science Program short-term fellowship.

Author information



Corresponding author

Correspondence to George Kunos.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Di Marzo, V., Goparaju, S., Wang, L. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001). https://doi.org/10.1038/35071088

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing