Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain.
Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain.
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DOI：
10.1016/j.molmet.2020.101123
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发表时间：
2021-01
影响因子：
8.1
通讯作者：
Filippi BM
中科院分区：
文献类型：
--
作者：
Patel B;New LE;Griffiths JC;Deuchars J;Filippi BM
背侧迷走神经复合体（DVC）感知胰岛素并控制葡萄糖稳态、进食行为和体重。大鼠三天的高脂饮食（HFD）足以诱导DVC的胰岛素抵抗，并损害其调节摄食行为的能力。HFD喂养与DVC中动力蛋白相关蛋白1（Drp 1）依赖性线粒体分裂增加相关。我们研究了DVC中Drp1活性改变对摄食行为的影响。此外，我们的目的是揭示分子事件和神经元细胞群与DVC胰岛素敏感和抵抗。8周龄雄性Sprague道利大鼠接受DVC立体定向手术进行脑灌注，以促进胰岛素或病毒的局部给药，以表达突变形式的Drp 1或敲低DVC NTS中的诱导型一氧化氮合酶（iNOS）。高脂饮食喂养导致胰岛素抵抗和肥胖。我们发现DVC中Drp1的激活增加了大鼠的体重增加，而HFD喂养大鼠中Drp1的抑制减少了食物摄入、体重增加和脂肪组织。在DVC中表达活性Drp1的大鼠具有更高水平的iNOS，并且在HFD喂养的大鼠中敲低DVC iNOS导致食物摄入量、体重增加和脂肪组织减少。最后，抑制DVC星形胶质细胞中的线粒体分裂足以保护大鼠免受HFD依赖性胰岛素抵抗、暴食、体重增加和脂肪沉积。我们发现了大脑调节全身代谢的新分子和细胞靶点，这可以为对抗肥胖和糖尿病的新策略提供信息。
The dorsal vagal complex (DVC) senses insulin and controls glucose homeostasis, feeding behaviour and body weight. Three-days of high-fat diet (HFD) in rats are sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in the DVC. We investigated the effects that altered Drp1 activity in the DVC has on feeding behaviour. Additionally, we aimed to uncover the molecular events and the neuronal cell populations associated with DVC insulin sensing and resistance. Eight-week-old male Sprague Dawley rats received DVC stereotactic surgery for brain infusion to facilitate the localised administration of insulin or viruses to express mutated forms of Drp1 or to knockdown inducible nitric oxide synthase (iNOS) in the NTS of the DVC. High-Fat diet feeding was used to cause insulin resistance and obesity. We showed that Drp1 activation in the DVC increases weight gain in rats and Drp1 inhibition in HFD-fed rats reduced food intake, weight gain and adipose tissue. Rats expressing active Drp1 in the DVC had higher levels of iNOS and knockdown of DVC iNOS in HFD-fed rats led to a reduction of food intake, weight gain and adipose tissue. Finally, inhibiting mitochondrial fission in DVC astrocytes was sufficient to protect rats from HFD-dependent insulin resistance, hyperphagia, weight gain and fat deposition. We uncovered new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.
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影响因子：
64.5
作者：
Dietrich MO;Zimmer MR;Bober J;Horvath TL
通讯作者：
Horvath TL
影响因子：
8.1
作者：
Buckman LB;Thompson MM;Lippert RN;Blackwell TS;Yull FE;Ellacott KL
通讯作者：
Ellacott KL
DOI：
10.1074/jbc.m111.228817
发表时间：
2011-10-21
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Birkenfeld AL;Lee HY;Majumdar S;Jurczak MJ;Camporez JP;Jornayvaz FR;Frederick DW;Guigni B;Kahn M;Zhang D;Weismann D;Arafat AM;Pfeiffer AF;Lieske S;Oyadomari S;Ron D;Samuel VT;Shulman GI
通讯作者：
Shulman GI
影响因子：
7.7
作者：
Carvalho, MA;Ueno, M;Saad, MJA
通讯作者：
Saad, MJA
影响因子：
64.5
作者：
García-Cáceres C;Quarta C;Varela L;Gao Y;Gruber T;Legutko B;Jastroch M;Johansson P;Ninkovic J;Yi CX;Le Thuc O;Szigeti-Buck K;Cai W;Meyer CW;Pfluger PT;Fernandez AM;Luquet S;Woods SC;Torres-Alemán I;Kahn CR;Götz M;Horvath TL;Tschöp MH
通讯作者：
Tschöp MH