Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity

Abstract

A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart. To better understand the interactions of CB1, CPT1 and PPARs in these tissues, 30 diet-induced obese (DIO) C57BL/6J male mice were obtained, weight-matched and divided into two groups (15 in each group): (i) DIO/vehicle mice (D-Veh) and (ii) DIO/SR141716 mice (D-SR) treated with SR141716 (or rimonabant, a selective CB1 receptor blocker) administered orally (10 mg/kg daily). Another 15 mice fed standard diet (STD) formed the STD/vehicle group (S-Veh). At the end of 3-week treatment, mean body weight was 28.4 ± 0.5, 36.5 ± 0.8, and 30.3 ± 1.2 g for the S-Veh, D-Veh, and D-SR group, respectively (p < 0.05; D-Veh vs. D-SR). Liver weight in the D-SR group was also decreased significantly compared to the D-Veh group (p < 0.05). Serum levels of total cholesterol, high-density lipoprotein cholesterol, leptin and adiponectin in the D-SR group were ameliorated compared to the D-Veh group (p < 0.05). Both qRT-PCR and Western blot assay revealed that CB1 expression levels were efficiently blocked by SR141716 in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscles and liver (D-SR vs. D-Veh; p < 0.05), whereas there was no significant difference between S-Veh and D-Veh mice (p > 0.05). Simultaneously with the reduction of CB1 expression in the D-SR group, the expression levels of CPT1A isoform (protein) in the liver and heart and CPT1B isoform (protein) in the SAT, VAT, liver and skeletal muscles were significantly increased (p < 0.05; D-SR vs. D-Veh). Interestingly, the CPT1A and CPT1B expression levels in heart were detected slightly. The expression levels of PPARα in the SAT, VAT, liver and skeletal muscles and PPARγ in the SAT and skeletal muscles in the D-SR group were significantly increased compared to the D-Veh mice (p < 0.05). However, the PPARβ expression level differed from that of PPARα and PPARγ. Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1. Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.

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Abbreviations

CB1:

cannabinoid type 1 receptor

CPT1:

carnitine palmitoyltransferase 1

DIO:

diet-induced obese (mice)

HDL-C:

high-density lipoprotein cholesterol

LDL-C:

low-density lipoprotein cholesterol

PPARs:

peroxisome proliferator-activated receptors

SAT:

subcutaneous adipose tissue

STD:

standard diet

TC:

total cholesterol

TG:

triglycerides

VAT:

visceral adipose tissue

References

  1. 1.

    Matias, I., Gonthier, M. P., Orlando, P., Martiadis, V., De, P. L., Cervino, C., Petrosino, S., Hoareau, L., Festy, F., and Pasquali, R. (2006) Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia, J. Clin. Endocr. Metab., 91, 3171–3180.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Mehrpouyabahrami, P., Chitrala, K. N., Ganewatta, M. S., Tang, C., Murphy, E. A., Enos, R. T., Velazquez, K. T., Mccellan, J., Nagarkatti, M., and Nagarkatti, P. (2017) Blockade of CB1 cannabinoid receptor alters gut microbio-ta and attenuates inflammation and diet-induced obesity, Sci. Rep., 7, 1–16.

    Article  CAS  Google Scholar 

  3. 3.

    Louet, J. F., Le May, C., Pegorier, J. P., Decaux, J. F., and Girard, J. (2001) Regulation of liver carnitine palmitoyl-transferase I gene expression by hormones and fatty acids, Biochem. Soc. Trans., 29, 310–316.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Musso, G., Gambino, R., and Cassader, M. (2009) Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD), Prog. Lipid Res., 48, 1–26.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Xu, H., Luo, J., Ma, G., Zhang, X., Yao, D., Li, M., and Loor, J. J. (2018) Acyl-CoA synthetase short-chain family member 2 (ACSS2) is regulated by SREBP-1 and plays a role in fatty acid synthesis in caprine mammary epithelial cells, J. Cell. Physiol., 233, 1005–1016.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Amengual, J., Petrov, P., Bonet, M. L., Ribot, J., and Palou, A. (2012) Induction of carnitine palmitoyl transferase 1 and fatty acid oxidation by retinoic acid in HepG2 cells, Int. J. Biochem. Cell B, 44, 2019–2027.

    Article  CAS  Google Scholar 

  7. 7.

    He, L., Kim, T., Long, Q., Liu, J., Wang, P., Zhou, Y., Ding, Y., Prasain, J., Wood, P. A., and Yang, Q. (2012) Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity, Circulation, 126, 1705–1716.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 8.

    Ratner, C., Madsen, A. N., Kristensen, L. V., Skov, L. J., Pedersen, K. S., Mortensen, O. H., Knudsen, G. M., Raun, K., and Holst, B. (2015) Impaired oxidative capaci-ty due to decreased CPT1b levels as a contributing factor to fat accumulation in obesity, Am. J. Physiol. Regul. Integr. Comp. Physiol., 308, R973–R982.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Braissant, O., Foufelle, F., Scotto, C., Dauca, M., and Wahli, W. (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribu-tion of PPAR-alpha, -beta, and -gamma in the adult rat, Endocrinology, 137, 354–366.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    O’Sullivan, S. E. (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors, Brit. J. Pharmacol., 152, 576–582.

    Article  CAS  Google Scholar 

  11. 11.

    Liu, L. Y., Alexa, K., Cortes, M., Schatzman-Bone, S., Kim, A. J., Mukhopadhyay, B., Cinar, R., Kunos, G., North, T. E., and Goessling, W. (2016) Cannabinoid receptor signaling regulates liver development and metabolism, Development, 143, 609–622.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Sun, Y., Alexander, S. P., Garle, M. J., Gibson, C. L., Hewitt, K., Murphy, S. P., Kendall, D. A., and Bennett, A. J. (2007) Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism, Brit. J. Pharmacol., 152, 734–743.

    Article  CAS  Google Scholar 

  13. 13.

    Palomer, X., Barroso, E., Zarei, M., Botteri, G., and Vazquez-Carrera, M. (2016) PPARβ/δ and lipid metabolism in the heart, Biochim. Biophys. Acta, 1861, 1569–1578.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Lehrke, M., and Lazar, M. A. (2006) The many faces of PPARgamma, Cell, 123, 993–999.

    Article  CAS  Google Scholar 

  15. 15.

    Duan, S. Z., Usher, M. G., and Mortensen, R. M. (2008) Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature, Circ. Res., 102, 283–294.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Zhang, Y. F., Yuan, Z. Q., Song, D. G., Zhou, X. H., and Wang, Y. Z. (2013) Effects of cannabinoid receptor 1 (brain) on lipid accumulation by transcriptional control of CPT1A and CPT1B, Anim. Genet., 45, 38–47.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Trillou, C. R., Arnone, M., Delgorge, C., Gonalons, N., Keane, P., Maffrand, J., and Soubrie, P. (2003) Anti-obesi-ty effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice, Am. J. Physiol. Regul. Integr. Comp. Physiol., 284, R345–R353.

    Article  CAS  Google Scholar 

  18. 18.

    Tam, J., Godlewski, G., Earley, B. J., Zhou, L., Jourdan, T., Szanda, G., Cinar, R., and Kunos, G. (2014) Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity, Am. J. Physiol. Endocr. Metab., 306, E457–E468.

    Article  CAS  Google Scholar 

  19. 19.

    Fu, L., Wei, L. W., Zhao, M. D., Zhu, J. L., Chen, S. Y., Jia, X. B., and Lai, S. J. (2016) Investigation of JAKs/STAT-3 in lipopolysaccharide-induced intestinal epithelial cells, Clin. Exp. Immunol., 186, 75–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. 20.

    Livak, K. J., and Schmittgen, T. D. (2001) Analysis of rela-tive gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method, Methods, 25, 402–408.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Katona, I., and Freund, T. F. (2012) Multiple functions of endocannabinoid signaling in the brain, Annu. Rev. Neurosci., 35, 529–558.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Lutz, B., Marsicano, G., Maldonado, R., and Hillard, C. J. (2015) The endocannabinoid system in guarding against fear, anxiety and stress, Nat. Rev. Neurosci., 16, 705–718.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 23.

    Lu, H. C., and Mackie, K. (2016) An introduction to the endogenous cannabinoid system, Biol. Psychiat., 79, 516–525.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Rinaldi-Carmona, M., Barth, F., Heaulme, M., Shire, D., Calandra, B., Congy, C., Martinez, S., Maruani, J., Neliat, G., and Caput, D. (1994) SR141716A, a potent and selec-tive antagonist of the brain cannabinoid receptor, FEBS Lett., 350, 240–244.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Tang, Y., Ho, G., Li, Y., Hall, M. A., Hills, R. L., Black, S. C., Liang, Y., and Demarest, K. T. (2012) Beneficial metabolic effects of CB1R anti-sense oligonucleotide treatment in diet-induced obese AKR/J mice, PLOS One, 7, e42134.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Leite, C. E., Mocelin, C. A., Petersen, G. O., Leal, M. B., and Thiesen, F. V. (2009) Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity, Pharmacol. Rep. Pr., 61, 217–224.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Saxena, S., Thimmaraju, K. V., Srivastava, P. C., Mallick, A. K., Das, B., Sinha, N., and Dalmia, K. (2015) Role of dyslipidaemia and lipid peroxidation in pregnancy induced hypertension, J. Clin. Sci. Res., 4, 205–212.

    Article  Google Scholar 

  28. 28.

    Silvestri, C., Ligresti, A., and Marzo, V. D. (2011) Peripheral effects of the endocannabinoid system in energy homeostasis: adipose tissue, liver and skeletal muscle, Rev. Endocr. Metab. Dis., 12, 153–162.

    Article  CAS  Google Scholar 

  29. 29.

    Maslov, L. N., and Karpov, R. S. (2017) Prospects for the use of cannabinoid receptor ligands for the treatment of metabolic syndrome and atherosclerosis: analysis of exper-imental and clinical data, Vestn. Ross. Akad. Med. Nauk, 72, 59–65.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Nogueiras, R., Veyratdurebex, C., Suchanek, P. M., Klein, M., Wittmann, G., Watanabe, M., and Liposits, Z. (2008) Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats, Diabetes, 57, 2977–2991.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    Osei-Hyiaman, D., Liu, J. L., Godlewski, G., Harvey-White, J., Jeong, W., Batkai, S., Marsicano, G., Lutz, B., Buettner, C., and Kunos, G. (2008) Hepatic CB1 receptor is required for development of diet-induced steatosis, dys-lipidemia, and insulin and leptin resistance in mice, J. Clin. Invest., 118, 3160–3169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Veiga, F., Graus-Nunes, F., Rachid, T. L., Barreto, A. B., Mandarim-de-Lacerda, C. A., and Souza-Mello, V. (2017) Anti-obesogenic effects of WY14643 (PPAR-alpha ago-nist): hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice, Biochimie, 140, 106–116.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Pagano, C., Pilon, C., Calcagno, A., Urbanet, R., Rossato, M., Milan, G., Bianchi, K., Rizzuto, R., Bernante, P., and Federspil, G. (2007) The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms, J. Clin. Endocr. Metab., 92, 4810–4819.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Wang, S., Dougherty, E. J., and Danner, R. L. (2016) PPARγ signaling and emerging opportunities for improved therapeutics, Pharmacol. Res., 111, 76–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Correspondence to L. Fu.

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Wei, L.W., Yuan, Z.Q., Zhao, M.D. et al. Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity. Biochemistry Moscow 83, 1279–1287 (2018). https://doi.org/10.1134/S0006297918100127

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Keywords

  • CB1
  • CPT1
  • PPARs
  • obesity
  • lipid metabolism