Constitutive Activation of the Nutrient Sensor mTORC1 in Myeloid Cells Induced by Tsc1 Deletion Protects Mice from Diet-Induced Obesity

Autor(es):Mostrar menos -

Paschoal, Vivian A. ^[1] ; Belchior, Thiago ^[1] ; Amano, Mariane T. ^[2] ; Burgos-Silva, Marina ^[2] ; Peixoto, Albert S. ^[1] ; Magdalon, Juliana ^{[1, 3]} ; Vieira, Thayna S. ^[1] ; Andrade, Maynara L. ^[1] ; Moreno, Mayara F. ^[1] ; Chimin, Patricia ^[4] ; Camara, Niels O. ^[2] ; Festuccia, William T. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 Sao Paulo - Brazil

^[3] Israelita Albert Einstein Hosp, BR-05652900 Sao Paulo - Brazil

^[4] Univ Estadual Londrina, Phys Educ & Sports Ctr, Dept Phys Educ, BR-86051990 Londrina, Parana - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR NUTRITION & FOOD RESEARCH; v. 62, n. 17 SEP 2018.
• Citações Web of Science: 2

Resumo

Scope: To test whether myeloid cells Tsc1 deletion and therefore constitutive activation of the nutrient sensor mTORC1 protects from high-fat diet (HFD)-induced obesity, glucose intolerance, and adipose tissue inflammation. Methods and results: Mice with Tsc1 deletion in myeloid cells (MTsc1KO) and littermate controls (MTsc1WT) were fed with HFD for 8 weeks and evaluated for body weight, glucose homeostasis, and adipose tissue inflammation. MTsc1KO mice were protected from HFD-induced obesity and glucose intolerance. MTsc1KO, however, displayed, independently of the diet, abnormal behavior, episodes of intense movement, and muscle spasms followed by temporary paralysis. To investigate whether obesity protection was due to myeloid cells Tsc1 deletion, bone marrow was transplanted from MTsc1WT and MTsc1KO into irradiated C57BL6/J mice. Mice transplanted with MTsc1KO bone marrow displayed reduced body weight gain, adiposity, and inflammation, and enhanced energy expenditure, glucose tolerance and adipose tissue M2 macrophage content upon HFD feeding, in the absence of abnormal behavior. In vitro, Tsc1 deletion increased in a mTORC1-dependent manner macrophage polarization to M2 profile and mRNA levels of fatty acid binding protein 4 and PPAR gamma. Conclusion: Constitutive mTORC1 activation in myeloid cells protects mice from HFD-induced obesity, adipose tissue inflammation, and glucose intolerance by promoting macrophage polarization to M2 pro-resolution profile and increasing energy expenditure. (AU)

• Processo FAPESP: 15/19530-5 - Caracterização do envolvimento do sensor de nutrientes mTOR no desenvolvimento de doenças metabólicas crônicas associadas à obesidade
• Beneficiário: William Tadeu Lara Festuccia
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/02270-2 - Novos mecanismos celulares, moleculares e imunológicos das lesões renais agudas e crônicas: busca por novas estratégias terapêuticas
• Beneficiário: Niels Olsen Saraiva Câmara
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/10783-7 - Envolvimento do complexo 1 da mTOR no controle da função de macrófagos durante resposta inflamatória crônica associada a obesidade e resistência a insulina
• Beneficiário: Vivian Almeida Paschoal
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/52191-6 - Envolvimento dos sensores de nutrientes mTOR e PPARgama no início, manutenção e término da inflamação associada à obesidade e resistência à insulina
• Beneficiário: William Tadeu Lara Festuccia
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/15354-7 - Envolvimento do tecido adiposo no desenvolvimento da obesidade e patologias associadas: investigação dos mecanismos moleculares e busca de novas alternativas terapêuticas
• Beneficiário: William Tadeu Lara Festuccia
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores