A Meadows1,2, J H Lee1, C-S Wu1, Q Wei1,3, G Pradhan1, M Yafi2, H-C Lu4, Y Sun1,5. 1. USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. 2. Division of Pediatric Endocrinology, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA. 3. Division of Endocrinology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China. 4. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. 5. Huffington Center on Aging, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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.
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.
Authors: Markus Waldeck-Weiermair; Cristina Zoratti; Wolfgang F Graier; Karin Osibow; Nariman Balenga; Edith Goessnitzer; Maria Waldhoer; Roland Malli Journal: J Cell Sci Date: 2008-04-29 Impact factor: 5.285
Authors: Christopher M Henstridge; Nariman A B Balenga; Lesley A Ford; Ruth A Ross; Maria Waldhoer; Andrew J Irving Journal: FASEB J Date: 2008-08-29 Impact factor: 5.191
Authors: José María Moreno-Navarrete; Victoria Catalán; Lauren Whyte; Adenis Díaz-Arteaga; Rafael Vázquez-Martínez; Fernando Rotellar; Rocío Guzmán; Javier Gómez-Ambrosi; Marina R Pulido; Wendy R Russell; Mónica Imbernón; Ruth A Ross; María M Malagón; Carlos Dieguez; José Manuel Fernández-Real; Gema Frühbeck; Ruben Nogueiras Journal: Diabetes Date: 2011-12-16 Impact factor: 9.461
Authors: Muhammad Farooq Rai; Linda J Sandell; Toby N Barrack; Lei Cai; Eric D Tycksen; Simon Y Tang; Matthew J Silva; Robert L Barrack Journal: Cartilage Date: 2018-09-03 Impact factor: 4.634
Authors: Bruno A Marichal-Cancino; Alfonso Fajardo-Valdez; Alejandra E Ruiz-Contreras; Monica Mendez-Díaz; Oscar Prospero-García Journal: Curr Neuropharmacol Date: 2017 Impact factor: 7.363
Authors: Mikael Bjursell; Erik Ryberg; Tingting Wu; Peter J Greasley; Mohammad Bohlooly-Y; Stephan Hjorth Journal: PLoS One Date: 2016-12-12 Impact factor: 3.240