Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice

Autor(es):Mostrar menos -

Reis, Felipe C. G. ; Branquinho, Jessica L. O. ; Brandao, Bruna B. ; Guerra, Beatriz A. ; Silva, Ismael D. ; Frontini, Andrea ; Thomou, Thomas ; Sartini, Loris ; Cinti, Saverio ; Kahn, C. Ronald ; Festuccia, William T. ; Kowaltowski, Alicia J. ; Mori, Marcelo A.

• Tipo de documento: Artigo Científico
• Fonte: AGING-US; v. 8, n. 6, p. 1201-1222, JUN 2016.
• Citações Web of Science: 16

Resumo

Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance. (AU)

• Processo FAPESP: 10/52557-0 - Identificação de mecanismos responsáveis pelos efeitos benéficos da restrição calórica
• Beneficiário: Marcelo Alves da Silva Mori
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/01316-7 - Dicer, miRNAs e o controle da função mitocondrial no contexto do envelhecimento e da restrição calórica
• Beneficiário: Marcelo Alves da Silva Mori
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/24109-6 - As contribuições de Dicer no tecido adiposo para o envelhecimento, para a resposta ao estresse e para os efeitos da restrição calórica em camundongos
• Beneficiário: Felipe Castellani Gomes dos Reis
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado