A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity.
A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity.
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DOI：
10.2337/db16-0243
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发表时间：
2016-09
期刊：
影响因子：
7.7
通讯作者：
Verhoeven AJ
中科院分区：
文献类型：
--
作者：
Tol MJ;Ottenhoff R;van Eijk M;Zelcer N;Aten J;Houten SM;Geerts D;van Roomen C;Bierlaagh MC;Scheij S;Hoeksema MA;Aerts JM;Bogan JS;Dorn GW 2nd;Argmann CA;Verhoeven AJ
线粒体异常分裂在骨骼肌胰岛素抵抗的发病机制中起着关键作用。然而，融合-裂变动力学受内在组织特异性和营养敏感性过程的生理调节，这些过程可能对胰岛素敏感性具有不同甚至相反的影响。基于小鼠群体遗传学和体外功能试验的结合，我们在此描述了一个调节回路，其中过氧化物酶体增殖物激活受体γ（PPARγ），脂肪细胞主调节剂和噻唑烷二酮类抗糖尿病药物的受体，通过转录诱导Bnip 3控制线粒体网络片段化。短发夹RNA介导的Bnip 3在培养的脂肪细胞中的敲低将平衡向线粒体延长转移，导致呼吸能力受损、脂肪酸β-氧化相关的线粒体活性氧产生增加、胰岛素抵抗和三酰甘油储存减少。值得注意的是，选择性裂变/Drp 1抑制剂Mdivi-1模拟了Bnip 3敲除对脂肪线粒体生物能量学和葡萄糖处理的影响。我们进一步表明，Bnip 3在饮食诱导的肥胖症和瘦素缺乏的ob/ob小鼠模型的白色和棕色脂肪库中受到调节。最后，Bnip 3 −/−小鼠以减少的肥胖换取增加的肝脏脂肪变性，并对高脂肪喂养作出反应，从而发展出加重的全身胰岛素抵抗。总之，我们的数据概述了Bnip 3作为PPARγ介导的脂肪线粒体网络断裂的关键效应子，改善胰岛素敏感性和限制氧化应激。
Aberrant mitochondrial fission plays a pivotal role in the pathogenesis of skeletal muscle insulin resistance. However, fusion-fission dynamics are physiologically regulated by inherent tissue-specific and nutrient-sensitive processes that may have distinct or even opposing effects with respect to insulin sensitivity. Based on a combination of mouse population genetics and functional in vitro assays, we describe here a regulatory circuit in which peroxisome proliferator–activated receptor γ (PPARγ), the adipocyte master regulator and receptor for the thiazolidinedione class of antidiabetic drugs, controls mitochondrial network fragmentation through transcriptional induction of Bnip3. Short hairpin RNA–mediated knockdown of Bnip3 in cultured adipocytes shifts the balance toward mitochondrial elongation, leading to compromised respiratory capacity, heightened fatty acid β-oxidation-associated mitochondrial reactive oxygen species generation, insulin resistance, and reduced triacylglycerol storage. Notably, the selective fission/Drp1 inhibitor Mdivi-1 mimics the effects of Bnip3 knockdown on adipose mitochondrial bioenergetics and glucose disposal. We further show that Bnip3 is reciprocally regulated in white and brown fat depots of diet-induced obesity and leptin-deficient ob/ob mouse models. Finally, Bnip3−/− mice trade reduced adiposity for increased liver steatosis and develop aggravated systemic insulin resistance in response to high-fat feeding. Together, our data outline Bnip3 as a key effector of PPARγ-mediated adipose mitochondrial network fragmentation, improving insulin sensitivity and limiting oxidative stress.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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通讯作者：
Shaw RJ
影响因子：
8.2
作者：
Choo, HJ;Kim, JH;Ko, YG
通讯作者：
Ko, YG
影响因子：
3.5
作者：
Houten, Sander M.;Herrema, Hilde;Wanders, Ronald J. A.
通讯作者：
Wanders, Ronald J. A.
影响因子：
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作者：
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通讯作者：
Scherer, Philipp E.
影响因子：
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作者：
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通讯作者：
Nunnari, Jodi