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

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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.

• Document type: Journal article
• Source: AGING-US; v. 8, n. 6, p. 1201-1222, JUN 2016.
• Web of Science Citations: 16

Abstract

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)

• FAPESP's process: 10/52557-0 - Identification of mechanisms responsible for beneficial effects of calorie restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/01316-7 - Dicer, miRNAs and the control of mitochondrial function in the context of aging and caloric restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/24109-6 - The role of Dicer in adipose tissue in aging, stress response and in the effects of caloric restriction in mice
• Grantee: Felipe Castellani Gomes dos Reis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral