Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake
Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake
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DOI：
10.1101/2023.01.04.522581
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发表时间：
2023-06
期刊：
影响因子：
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通讯作者：
Arianna Fozzato;L. New;Joanne C. Griffiths;B. Patel;S. Deuchars;B. M. Filippi
中科院分区：
文献类型：
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作者：
Arianna Fozzato;L. New;Joanne C. Griffiths;B. Patel;S. Deuchars;B. M. Filippi
棕色脂肪组织（BAT）摄取和代谢葡萄糖和甘油三酯以产生热量，并通过直接去甲肾上腺素能交感神经支配被中枢神经系统（CNS）激活。选择性CNS区域（如孤束核（NTS））中信号模块的失调与BAT活性改变、肥胖和糖尿病有关。高脂饮食（HFD）喂养增加NTS中的线粒体碎片，引发胰岛素抵抗、摄食过多和体重增加。在这里，我们试图确定NTS中线粒体动力学的变化是否会影响BAT葡萄糖摄取。我们的研究结果表明，短期HFD喂养降低了BAT摄取葡萄糖的能力，如PET/CT扫描所测量的。然而，抑制HFD喂养大鼠的NTS-星形胶质细胞中的线粒体片段化改善BAT葡萄糖摄取，同时降低血糖和胰岛素水平。与HFD喂养的大鼠相比，HFD喂养的动物，其中在NTS-星形胶质细胞中的线粒体断裂被抑制，具有较高水平的BAT的儿茶酚胺能神经支配，并且在BAT中不存在增大的白色脂肪滴的HFD依赖性浸润。在常规饲料喂养的大鼠中，增加NTS-星形胶质细胞中的线粒体碎片减少BAT葡萄糖摄取、儿茶酚胺能神经支配和β3-肾上腺素能受体水平。我们的数据表明，靶向NTS-星形胶质细胞中的线粒体动力学可能是一种有益的策略，可以增加葡萄糖的利用，并防止肥胖和糖尿病的发生。
Brown adipose tissue (BAT) uptakes and metabolises both glucose and triglycerides to produce heat and is activated by the central nervous system (CNS) through direct noradrenergic sympathetic innervation. Dysregulation of signalling modules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake. Our findings demonstrated that short-term HFD feeding reduces BAT’s ability to take up glucose, as measured by PET/CT scan. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats improved BAT glucose uptake while lowering blood glucose and insulin levels. Compared with HFD-fed rats, HFD fed animals, where mitochondrial fragmentation was inhibited in the NTS-astrocytes, had higher levels of catecholaminergic innervation of BAT, and did not present HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, catecholaminergic innervation and β3-adrenergic receptor levels. Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.