Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice Aline Cordeiro, Luana Lopes de Souza, Lorraine Soares Oliveira, Larissa Costa Faustino, Letı ´cia Araga ˜o Santiago, Flavia Fonseca Bloise, Tania Maria Ortiga-Carvalho, Norma Aparecida dos Santos Almeida 1 and Carmen Cabanelas Pazos-Moura Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Cidade Universita ´ ria - Ilha do Funda ˜ o, Avenida Carlos Chagas Filho, 373, Centro de Cie ˆ ncias da Sau ´ de, Bloco G, CEP: 21941-902, Rio de Janeiro, RJ, Brazil 1 Department of Physiological Sciences, Rural Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil Correspondence should be addressed to C C Pazos-Moura Email cpazosm@biof.ufrj.br Abstract Sirtuin 1 (SIRT1), a NAD C -dependent deacetylase, has been connected to beneficial effects elicited by calorie restriction. Physiological adaptation to starvation requires higher activity of SIRT1 and also the suppression of thyroid hormone (TH) action to achieve energy conservation. Here, we tested the hypothesis that those two events are correlated and that TH may be a regulator of SIRT1 expression. Forty-eight-hour fasting mice exhibited reduced serum TH and increased SIRT1 protein content in liver and brown adipose tissue (BAT), and physiological thyroxine replacement prevented or attenuated the increment of SIRT1 in liver and BAT of fasted mice. Hypothyroid mice exhibited increased liver SIRT1 protein, while hyperthyroid ones showed decreased SIRT1 in liver and BAT. In the liver, decreased protein is accompanied by reduced SIRT1 activity and no alteration in its mRNA. Hyperthyroid and hypothyroid mice exhibited increases and decreases in food intake and body weight gain respectively. Food-restricted hyperthyroid animals (pair-fed to euthyroid group) exhibited liver and BAT SIRT1 protein levels intermediary between euthyroid and hyperthyroid mice fed ad libitum. Mice with TH resistance at the liver presented increased hepatic SIRT1 protein and activity, with no alteration in Sirt1 mRNA. These results suggest that TH decreases SIRT1 protein, directly and indirectly, via food ingestion control and, in the liver, this reduction involves TRb. The SIRT1 reduction induced by TH has important implication to integrated metabolic responses to fasting, as the increase in SIRT1 protein requires the fasting-associated suppression of TH serum levels. Key Words " Sirtuin1 (SIRT1) " thyroid hormones " fasting " calorie restriction " thyroid hormone receptor b Journal of Endocrinology (2013) 216, 181–193 Introduction Calorie deprivation has been proved to extend life span and reduce the rate of aging in several organisms, from yeast to rodents and primates (Weindruch & Walford 1982, Lin et al. 2000, Colman et al. 2009). It was described in some species that the mechanism by which calorie restriction promotes extended life span was dependent on Journal of Endocrinology Research A CORDEIRO and others Thyroid hormone downregulates SIRT1 216 :2 181–193 http://joe.endocrinology-journals.org Ñ 2013 Society for Endocrinology DOI: 10.1530/JOE-12-0420 Printed in Great Britain Published by Bioscientifica Ltd.