ABSTRACT
Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.
Subject(s)
Adaptor Proteins, Vesicular Transport , Coenzyme A Ligases , Diet, High-Fat , Energy Metabolism , Mitochondria , Thermogenesis , Animals , Adaptor Proteins, Vesicular Transport/metabolism , Adaptor Proteins, Vesicular Transport/genetics , Male , Mitochondria/metabolism , Mice , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/genetics , Mice, Inbred C57BL , Obesity/metabolism , Obesity/genetics , Adipocytes/metabolism , Adipose Tissue, Beige/metabolism , Insulin Resistance , Fatty Acids/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Protein Transport , Oxidation-Reduction , Signal Transduction , 3T3-L1 Cells , Mice, KnockoutABSTRACT
Buyang Huanwu decoction (BYHWD), a classical prescription for ischemic stroke, has been reported to promote angiogenesis after focal ischemia. However, the mechanisms of the contribution of BYHWD on angiogenesis are still unclear. Connexin 43 (Cx43) played important roles in the functions of neurogliovascular unit. Therefore, the aim of this study was to explore the potential role of Cx43 in angiogenesis of the ischemic brain after BYHWD treatment. Middle cerebral artery occlusion (MCAO) was used to establish the model of focal ischemia. BYHWD was administrated intragastrically twice a day after MCAO with or without Gap26 (a specific Cx43 inhibitor). Western blot, neurological deficits, immunofluorescent staining, and Evans blue dye were used to confirm the role of Cx43 in angiogenesis after BYHWD treatment. The expression levels of total Cx43 and phosphorylated Cx43 were upregulated by BYHWD and peaked at 7 days post MCAO. Inhibition of Cx43 with Gap26 significantly attenuated the protective role of BYHWD in neurological behavior. BYHWD treatment promoted angiogenesis demonstrated by increased microvascular density, upregulated vascular endothelial growth factor (VEGF), and angiopoietin-1 (Ang-1), while inhibition of Cx43 with Gap26 attenuated these effects of BYHWD. In addition, Gap26 inhibited the beneficial effect of BYHWD on blood-brain barrier (BBB) integrity. These results suggested that Cx43 mediated the angiogenesis of BYHWD via VEGF and Ang-1 after focal ischemic stroke.