title: Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity.
abstract: OBJECTIVE
  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.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.|Division of Pediatric Endocrinology, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Meadows
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: C-S
authors.initials: CS
authors.lastname: Wu
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.|Division of Endocrinology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wei
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Pradhan
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yafi
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
authors.forename: H-C
authors.initials: HC
authors.lastname: Lu
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.|Huffington Center on Aging, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D001823:Body Composition; D004195:Disease Models, Animal; D004435:Eating; D004734:Energy Metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000473:pathology*; D010805:Physical Conditioning, Animal; D043882:Receptors, Cannabinoid / Q000378:metabolism / Q000502:physiology*
chemical_list: C526692:GPR55 protein, mouse; D043882:Receptors, Cannabinoid