Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects

Abstract

Dietary restriction (DR) improves health and prolongs lifespan in part by upregulating type III endoribonuclease DICER in adipose tissue. In this study, we aimed to specifically test which missing dietary component was responsible for DICER upregulation. Methods: We performed a nutrient screen in mouse preadipocytes and validated the results in vivo using different kinds of dietary interventions in wild type or genetically modified mice and worms, also testing the requirement of DICER on the effects of the diets. Results: We found that sulfur amino acid restriction (i.e., methionine or cysteine) is sufficient to increase Dicer mRNA expression in preadipocytes. Consistently, while DR increases DICER expression in adipose tissue of mice, this effect is blunted by supplementation of the diet with methionine, cysteine, or casein, but not with a lipid or carbohydrate source. Accordingly, dietary methionine or protein restriction mirrors the effects of DR. These changes are associated with alterations in serum adiponectin. We also found that DICER controls and is controlled by adiponectin. In mice, DICER plays a role in methionine restriction-induced upregulation of Ucpl in adipose tissue. In C. elegans, DR and a model of methionine restriction also promote DICER expression in the intestine (an analog of the adipose tissue) and prolong lifespan in a DICER-dependent manner. Conclusions: We propose an evolutionary conserved mechanism in which dietary sulfur amino acid restriction upregulates DICER levels in adipose tissue leading to beneficial health effects29124135CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305069/2015-2; 304995/2014-288887.143923/2017-002017/01184-9; 2017/07975-8; 2017/22057-5; 2015/03292-8; 2012/07259-7; 2016/02207-0; 2010/52557-0; 2015/01316-7; 2012/50558-5; 2015/19530-5We thank Elzira Elisabeth Saviani and Emanoel Cabral for valuable technical support. We thank the National Institute of Science and Technology on Photonics Applied to Cell Biology (INFABIC) at the Universidade Estadual de Campinas to provide access to microscopes, the Caenorhabditis Genetics Center (CGC) for worms and Dr. Amy Pasquinelli for the dcr-1 RNAi clone. CGC is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). We thank Carmen Perrone for sharing the composition of the methionine restriction diet, for valuable discussion and for sharing samples of rats exposed to methionine restriction. This study was funded by grants of the Fundação de Amparo à Pesquisa do Estado de São Paulo ( 2017/01184-9 , 2017/07975-8 , 2017/22057-5 , 2015/03292-8 , 2012/07259-7 , 2016/02207-0 , 2010/52557-0 , 2015/01316-7 , 2012/50558-5 and 2015/19530-5 ), Conselho Nacional de Desenvolvimento Científico e Tecnológico ( 305069/2015-2 and 304995/2014-2 ) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - German Academic Exchange Service ( PROBRAL - 88887.143923/2017-00 )