Peripheral Cannabinoid-1 Receptor Blockade Restores Hypothalamic Leptin Signaling

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2017 Oct 17

PMID 29031713

Citations 39

Authors

Joseph Tam

Gergo Szanda

Adi Drori

Ziyi Liu

Resat Cinar

Yoshihiro Kashiwaya

Marc L Reitman

George Kunos

Affiliations

Soon will be listed here.

Abstract

Objective: In visceral obesity, an overactive endocannabinoid/CB receptor (CBR) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CBR blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CBR antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined.

Methods: We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.

Results: Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY than with POMC ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY mice kept on a high-fat diet.

Conclusions: Peripheral CBR blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC.

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References

Horvath T, Sarman B, Garcia-Caceres C, Enriori P, Sotonyi P, Shanabrough M . Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A. 2010; 107(33):14875-80. PMC: 2930476. DOI: 10.1073/pnas.1004282107. View

Coons A . Fluorescent antibody methods. Gen Cytochem Methods. 1958; 1:399-422. View

Osei-Hyiaman D, Depetrillo M, Pacher P, Liu J, Radaeva S, Batkai S . Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005; 115(5):1298-305. PMC: 1087161. DOI: 10.1172/JCI23057. View

Denis R, Joly-Amado A, Webber E, Langlet F, Schaeffer M, Padilla S . Palatability Can Drive Feeding Independent of AgRP Neurons. Cell Metab. 2015; 22(4):646-57. PMC: 5024566. DOI: 10.1016/j.cmet.2015.07.011. View

Seeley R, Yagaloff K, Fisher S, Burn P, Thiele T, van Dijk G . Melanocortin receptors in leptin effects. Nature. 1997; 390(6658):349. DOI: 10.1038/37016. View

Ottaway N, Mahbod P, Rivero B, Norman L, Gertler A, DAlessio D . Diet-induced obese mice retain endogenous leptin action. Cell Metab. 2015; 21(6):877-82. PMC: 4456263. DOI: 10.1016/j.cmet.2015.04.015. View

Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M . The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003; 112(3):423-31. PMC: 166293. DOI: 10.1172/JCI17725. View

Elias C, Aschkenasi C, Lee C, Kelly J, Ahima R, Bjorbaek C . Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron. 1999; 23(4):775-86. DOI: 10.1016/s0896-6273(01)80035-0. View

Yamada T, Katagiri H, Ishigaki Y, Ogihara T, Imai J, Uno K . Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: neuronal involvement in food-intake regulation. Cell Metab. 2006; 3(3):223-9. DOI: 10.1016/j.cmet.2006.02.001. View

10.

Argueta D, DiPatrizio N . Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol Behav. 2017; 171:32-39. PMC: 5296283. DOI: 10.1016/j.physbeh.2016.12.044. View

11.

Moreira F, Grieb M, Lutz B . Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract Res Clin Endocrinol Metab. 2009; 23(1):133-44. DOI: 10.1016/j.beem.2008.09.003. View

12.

Matias I, Vergoni A, Petrosino S, Ottani A, Pocai A, Bertolini A . Regulation of hypothalamic endocannabinoid levels by neuropeptides and hormones involved in food intake and metabolism: insulin and melanocortins. Neuropharmacology. 2007; 54(1):206-12. DOI: 10.1016/j.neuropharm.2007.06.011. View

13.

Weigle D, Duell P, Connor W, Steiner R, Soules M, Kuijper J . Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab. 1997; 82(2):561-5. DOI: 10.1210/jcem.82.2.3757. View

14.

Xu A, Ste-Marie L, Kaelin C, Barsh G . Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology. 2006; 148(1):72-80. DOI: 10.1210/en.2006-1119. View

15.

Cristino L, Busetto G, Imperatore R, Ferrandino I, Palomba L, Silvestri C . Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci U S A. 2013; 110(24):E2229-38. PMC: 3683753. DOI: 10.1073/pnas.1219485110. View

16.

Faouzi M, Leshan R, Bjornholm M, Hennessey T, Jones J, Munzberg H . Differential accessibility of circulating leptin to individual hypothalamic sites. Endocrinology. 2007; 148(11):5414-23. DOI: 10.1210/en.2007-0655. View

17.

Meek T, Matsen M, Damian V, Cubelo A, Chua Jr S, Morton G . Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology. 2014; 155(11):4157-67. PMC: 4197991. DOI: 10.1210/en.2014-1169. View

18.

Cheung C, Clifton D, Steiner R . Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology. 1997; 138(10):4489-92. DOI: 10.1210/endo.138.10.5570. View

19.

Wang Y, Tache Y, Sheibel A, Go V, Wei J . Two types of leptin-responsive gastric vagal afferent terminals: an in vitro single-unit study in rats. Am J Physiol. 1997; 273(2 Pt 2):R833-7. DOI: 10.1152/ajpregu.1997.273.2.R833. View

20.

Sohn J, Elmquist J, Williams K . Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 2013; 36(9):504-12. PMC: 3769497. DOI: 10.1016/j.tins.2013.05.003. View