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Animal Models

Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity

International Journal of Obesity volume 40, pages 417–424 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Cannabinoid receptor 1 (CB1) is the best-characterized cannabinoid receptor, and CB1 antagonists are used in clinical trials to treat obesity. Because of the wide range of CB1 functions, the side effects of CB1 antagonists pose serious concerns. G-protein-coupled receptor 55 (GPR55) is an atypical cannabinoid receptor, and its pharmacology and functions are distinct from CB1. GPR55 regulates neuropathic pain, gut, bone, immune functions and motor coordination. GPR55 is expressed in various brain regions and peripheral tissues. However, the roles of GPR55 in energy and glucose homeostasis are unknown. Here we have investigated the roles of GPR55 in energy balance and insulin sensitivity using GPR55-null mice (GPR55−/−).

Methods:

Body composition of the mice was measured by EchoMRI. Food intake, feeding behavior, energy expenditure and physical activity of GPR55−/− mice were determined by indirect calorimetry. Muscle function was assessed by forced treadmill running test. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Adipose inflammation was assessed by flow cytometry analysis of adipose tissue macrophages. The expression of inflammatory markers in adipose tissues and orexigenic/anorexigenic peptides in the hypothalamus was also analyzed by real-time PCR.

Results:

GPR55−/− mice had normal total energy intake and feeding pattern (i.e., no changes in meal size, meal number or feeding frequency). Intriguingly, whereas adult GPR55−/− mice only showed a modest increase in overall body weight, they exhibited significantly increased fat mass and insulin resistance. The spontaneous locomotor activity of GPR55−/− mice was dramatically decreased, whereas resting metabolic rate and non-shivering thermogenesis were unchanged. Moreover, GPR55−/− mice exhibited significantly decreased voluntary physical activity, showing reduced running distance on the running wheels, whereas muscle function appeared to be normal.

Conclusions:

GPR55 has an important role in energy homeostasis. GPR55 ablation increases adiposity and insulin resistance by selectively decreasing physical activity, but not by altering feeding behavior as CB1.

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Acknowledgements

AM, JHL and CSW conducted the experiments, analyzed the data and wrote the manuscript. QW and GP conducted the experiments. MY supported the study and proofread the paper. HCL provided GPR55 mice, consulted on the study and proofread the paper. YS designed the experiments and wrote the manuscript. All authors read and approved the final manuscript. Indirect calorimetry was performed in the Mouse Metabolic Research Unit at the Children’s Nutrition Research Center, Baylor College of Medicine. We acknowledge the expert assistance of Mr Firoz Vohra and the MMRU Core Director Dr Marta Fiorotto. We thank Mr Michael R Honig at Houston’s Community Public Radio Station KPFT for his editorial assistance. This study was supported by USDA/CRIS grant ARS 3092-5-001-059 (YS), American Diabetes Association #1-15-BS-177 (YS), American Heart Association grants 12IRG9230004 and 14GRNT18990019 (YS), and was also partially supported by P30 DK56338 (YS).

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Author notes

  1. A Meadows, J H Lee and C-S Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA

    A Meadows, J H Lee, C-S Wu, Q Wei, G Pradhan & Y Sun

  2. Division of Pediatric Endocrinology, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA

    A Meadows & M Yafi

  3. Division of Endocrinology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China

    Q Wei

  4. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    H-C Lu

  5. Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA

    Y Sun

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  1. A Meadows
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Correspondence to Y Sun.

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Meadows, A., Lee, J., Wu, CS. et al. Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity. Int J Obes 40, 417–424 (2016). https://doi.org/10.1038/ijo.2015.209

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