RESUMO
In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to ß-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure.
Assuntos
Metabolismo Energético , Palmitoil-CoA Hidrolase/metabolismo , Tecido Adiposo Marrom/metabolismo , Agonistas Adrenérgicos/farmacologia , Sequência de Aminoácidos , Animais , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Espaço Intracelular/metabolismo , Gotículas Lipídicas/metabolismo , Camundongos , Mitocôndrias/metabolismo , Oxirredução , Palmitoil-CoA Hidrolase/química , Palmitoil-CoA Hidrolase/genética , Fosforilação/efeitos dos fármacos , Agregados Proteicos , Serina/metabolismo , Termogênese/efeitos dos fármacosRESUMO
BACKGROUND: Refractory surface of wound and dermal chronic ulcer are largely attributed to poor neovascularization. We have previously shown that E2F1 suppresses VEGF expression in the ischemic heart, and that genetic deletion of E2F1 leads to better cardiac recovery. However, whether E2F1 has a role in dermal wound healing is currently not known. METHODS AND RESULTS: Skin wounds were surgically induced in E2F1-null (E2F1-/-) mice and WT littermates. E2F1-/- displayed an accelerated wound healing including wound closure, dermal thickening and collagen deposition, which was associated with an increased endothelial cell proliferation and greater vessel density in the border zone of the wound. Furthermore, more macrophages were recruited to the skin lesions and the level of VEGF expression was markedly higher in E2F1-/- than in WT mice. CONCLUSIONS: E2F1 hinders skin wound healing by suppressing VEGF expression, neovascularization, and macrophage recruitment. Strategies that target E2F1 may enhance wound healing.
