title: Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice.
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.
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Felipe C G
authors.initials: FC
authors.lastname: Reis
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Jéssica L O
authors.initials: JL
authors.lastname: Branquinho
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Bruna B
authors.initials: BB
authors.lastname: Brandão
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Beatriz A
authors.initials: BA
authors.lastname: Guerra
authors.affiliation: Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Ismael D
authors.initials: ID
authors.lastname: Silva
authors.affiliation: Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Frontini
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomou
authors.affiliation: Department of Clinical and Experimental Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Sartini
authors.affiliation: Department of Clinical and Experimental Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: Departament of Physiology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: William T
authors.initials: WT
authors.lastname: Festuccia
authors.affiliation: Department of Biochemistry, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.|Department of Biochemistry and Tissue Biology, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D020123:Sirolimus
keywords: adipose tissue; aging; dicer; dietary restriction; insulin resistance