Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity

Anna C. Simcocks, Kayte A. Jenkin, Lannie O’Keefe, Chrishan S. Samuel, Michael L. Mathai, Andrew J. McAinch, Deanne H. Hryciw

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague–Dawley rats were fed a high-fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague–Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9% saline/0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.

Original languageEnglish
Pages (from-to)203-216
Number of pages14
JournalEndocrine Connections
Volume8
Issue number3
DOIs
Publication statusPublished - Mar 2019

Keywords

  • Cannabinoid
  • GPR18
  • GPR55
  • High-fat diet
  • O-1602
  • O-1918
  • Obesity

Cite this

Simcocks, A. C., Jenkin, K. A., O’Keefe, L., Samuel, C. S., Mathai, M. L., McAinch, A. J., & Hryciw, D. H. (2019). Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity. Endocrine Connections, 8(3), 203-216. https://doi.org/10.1530/EC-18-0535
Simcocks, Anna C. ; Jenkin, Kayte A. ; O’Keefe, Lannie ; Samuel, Chrishan S. ; Mathai, Michael L. ; McAinch, Andrew J. ; Hryciw, Deanne H. / Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity. In: Endocrine Connections. 2019 ; Vol. 8, No. 3. pp. 203-216.
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abstract = "Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague–Dawley rats were fed a high-fat diet (40{\%} digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague–Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9{\%} saline/0.75{\%} Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.",
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Simcocks, AC, Jenkin, KA, O’Keefe, L, Samuel, CS, Mathai, ML, McAinch, AJ & Hryciw, DH 2019, 'Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity' Endocrine Connections, vol. 8, no. 3, pp. 203-216. https://doi.org/10.1530/EC-18-0535

Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity. / Simcocks, Anna C.; Jenkin, Kayte A.; O’Keefe, Lannie; Samuel, Chrishan S.; Mathai, Michael L.; McAinch, Andrew J.; Hryciw, Deanne H.

In: Endocrine Connections, Vol. 8, No. 3, 03.2019, p. 203-216.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jenkin, Kayte A.

AU - O’Keefe, Lannie

AU - Samuel, Chrishan S.

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AU - McAinch, Andrew J.

AU - Hryciw, Deanne H.

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