RESUMO
Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD+-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions.
Assuntos
Tecido Adiposo Marrom , Sirtuínas , Camundongos , Animais , Tecido Adiposo Marrom/metabolismo , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Metabolismo Energético/fisiologia , Camundongos Knockout , RNA Mensageiro/metabolismo , Mamíferos/genética , Sirtuínas/genética , Sirtuínas/metabolismoRESUMO
Recent evidence has revealed a novel signaling mechanism through which brown adipose tissue (BAT)-derived exosomal microRNAs (miRNAs) influence hepatic gene expression. Here, we uncover neuronal control of these miRNAs and identify exosomal miR-132-3p as a regulator of hepatic lipogenesis under cold stress conditions. Norepinephrine, a sympathetic nervous system neurotransmitter mediating cold-induced BAT activation, altered the composition of brown adipocyte (BAC)-derived exosomal miRNAs; among them, miR-132-3p was significantly induced. The isolated BAC-derived exosomes suppressed expression of hepatic Srebf1, a predicted target of miR-132-3p. In an indirect co-culture system, BACs suppressed expression of hepatic Srebf1 and its target lipogenic genes; this effect was not seen with miR-132-3p-inhibited BACs. Srebf1 was experimentally validated as an miR-132-3p target. Cold stimuli consistently induced miR-132-3p expression in BAT and attenuated Srebf1 expression in the liver. Our results suggest that BAT-derived exosomal miR-132-3p acts as an endocrine factor that regulates hepatic lipogenesis for cold adaptation.
