title: Inactivation of the adrenergic receptor β2 disrupts glucose homeostasis in mice.
abstract: Three types of beta adrenergic receptors (ARβ1-3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arβ2 knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arβ1, and Arβ3 mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a high-fat diet (40% fat) for 6 weeks, ARβ2KO mice doubled their caloric intake, accelerated energy expenditure, and induced Ucp1 expression in a manner similar to WT controls, exhibiting a similar body weight gain and increase in the size of white adipocytes to the WT controls. However, ARβ2KO mice maintain fasting hyperglycemia as compared with WT controls despite very elevated insulin levels, but similar degrees of liver steatosis and hyperlipidemia. In conclusion, inactivation of the ARβ2KO pathway preserves cold- and diet-induced adaptive thermogenesis but disrupts glucose homeostasis possibly by accelerating hepatic glucose production and insulin secretion. Feeding on a high-fat diet worsens the metabolic imbalance, with significant fasting hyperglycemia but similar liver structure and lipid profile to the WT controls.
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Gustavo W
authors.initials: GW
authors.lastname: Fernandes
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Cintia B
authors.initials: CB
authors.lastname: Ueta
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Tatiane L
authors.initials: TL
authors.lastname: Fonseca
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Cecilia H A
authors.initials: CH
authors.lastname: Gouveia
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Lancellotti
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Patrícia C
authors.initials: PC
authors.lastname: Brum
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Christoffolete
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.affiliation: Presbyterian University Mackenzie - Biological ScienceCCBS, São Paulo, SP, BrazilInstitute of Science Biomedical - Morpho-Functional SciencesAv. Prof. Lineu Prestes, São Paulo, SP 04310-000, BrazilDepartment of Cell and Developmental BiologyInstitute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, BrazilDepartment of AnatomyInstitute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, SP 05508-000, BrazilSanta Casa - AFIP and PathologySchool of Medical Sciences, São Paulo, SP, BrazilSchool of Physical Education and SportUniversity of São Paulo, São Paulo, SP, BrazilFederal University of ABC - Human and Natural Sciences CenterRua Catequese, 242, Santo Andre, SP 09090-400, BrazilDivision of EndocrinologyDiabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida, USACiências Biológicas e da SaúdeUniversidade Presbiteriana Mackenzie - PPGDD - CCBS, Rua da Consolação, 930 prédio 16, 1 andar, São Paulo, SP 01302-907, Brazil miriamribeiro@mackenzie.br.
authors.forename: Miriam O
authors.initials: MO
authors.lastname: Ribeiro
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat / Q000009:adverse effects; D004280:Dobutamine / Q000494:pharmacology; D005215:Fasting / Q000097:blood; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006946:Hyperinsulinism / Q000097:blood; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D018343:Receptors, Adrenergic, beta-2; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D004280:Dobutamine; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D009638:Norepinephrine
keywords: adaptive thermogenesis; brown adipose tissue (BAT); obesity; β-adrenergic receptors