title: Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice.
abstract: Mechanistic target of rapamycin complex 1 (mTORC1) loss of function reduces adiposity whereas partial mTORC1 inhibition enhances fat deposition. Herein we evaluated how constitutive mTORC1 activation in adipocytes modulates adiposity in vivo. Mice with constitutive mTORC1 activation in adipocytes induced by tuberous sclerosis complex (Tsc)1 deletion and littermate controls were evaluated for body mass, energy expenditure, glucose and fatty acid metabolism, mitochondrial function, mRNA and protein contents. Adipocyte-specific Tsc1 deletion reduced visceral, but not subcutaneous, fat mass, as well as adipocyte number and diameter, phenotypes that were associated with increased lipolysis, UCP-1 content (browning) and mRNA levels of pro-browning transcriptional factors C/EBPβ and ERRα. Adipocyte Tsc1 deletion enhanced mitochondrial oxidative activity, fatty acid oxidation and the expression of PGC-1α and PPARα in both visceral and subcutaneous fat. In brown adipocytes, however, Tsc1 deletion did not affect UCP-1 content and basal respiration. Adipocyte Tsc1 deletion also reduced visceral adiposity and enhanced glucose tolerance, liver and muscle insulin signaling and adiponectin secretion in mice fed with purified low- or high-fat diet. In conclusion, adipocyte-specific Tsc1 deletion enhances mitochondrial activity, induces browning and reduces visceral adiposity in mice.
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Magdalon
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Chimin
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Belchior
authors.affiliation: Departmento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Rodrigo X
authors.initials: RX
authors.lastname: Neves
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05500900, Brazil.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Vieira-Lara
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Maynara L
authors.initials: ML
authors.lastname: Andrade
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Talita S
authors.initials: TS
authors.lastname: Farias
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: Bolsoni-Lopes
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Vivian A
authors.initials: VA
authors.lastname: Paschoal
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Yamashita
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05500900, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Departmento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508000, Brazil. Electronic address: william.festuccia@usp.br.
authors.forename: William T
authors.initials: WT
authors.lastname: Festuccia
mesh_terms: D052437:Adipocytes, Brown / Q000201:enzymology* / Q000648:ultrastructure; D052438:Adipocytes, White / Q000201:enzymology* / Q000648:ultrastructure; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000201:enzymology* / Q000648:ultrastructure; D050154:Adiposity / Q000235:genetics; D000818:Animals; D019069:Cell Respiration; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D004734:Energy Metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000201:enzymology* / Q000648:ultrastructure; D008066:Lipolysis; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure; D046912:Multiprotein Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D007328:Insulin; D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: Adiposity; Browning; Fatty acid oxidation; Mitochondria; UCP-1; mTOR