title: Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue.
abstract: We report an unexpected link between aging, thermogenesis and weight gain via the orphan G protein-coupled receptor GPR3. Mice lacking GPR3 and maintained on normal chow had similar body weights during their first 5 months of life, but gained considerably more weight thereafter and displayed reduced total energy expenditure and lower core body temperature. By the age of 5 months GPR3 KO mice already had lower thermogenic gene expression and uncoupling protein 1 protein level and showed impaired glucose uptake into interscapular brown adipose tissue (iBAT) relative to WT littermates. These molecular deviations in iBAT of GPR3 KO mice preceded measurable differences in body weight and core body temperature at ambient conditions, but were coupled to a failure to maintain thermal homeostasis during acute cold challenge. At the same time, the same cold challenge caused a 17-fold increase in Gpr3 expression in iBAT of WT mice. Thus, GPR3 appears to have a key role in the thermogenic response of iBAT and may represent a new therapeutic target in age-related obesity.
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Tony
authors.initials: T
authors.lastname: Jourdan
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Gergő
authors.initials: G
authors.lastname: Szanda
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2N-17, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Fong
authors.initials: F
authors.lastname: Ming Mo
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: Douglas
authors.initials: D
authors.lastname: Osei-Hyiaman
authors.affiliation: Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, 5625 Fishers Lane, RM 2S-18, MSC-9413, Bethesda, Maryland 20892-9413, U.S.A.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001692:Biological Transport; D001831:Body Temperature; D003080:Cold Temperature; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics*; D022722:Thermogenesis / Q000235:genetics*; D000071256:Uncoupling Protein 1; D015430:Weight Gain
chemical_list: C494613:GPR3 protein, mouse; D007473:Ion Channels; D024101:Mitochondrial Proteins; D043562:Receptors, G-Protein-Coupled; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005947:Glucose