High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila.
High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila.
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DOI：
10.1016/j.cmet.2010.09.014
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发表时间：
2010-11-03
期刊：
影响因子：
29
通讯作者：
Oldham S
中科院分区：
文献类型：
--
作者：
Birse RT;Choi J;Reardon K;Rodriguez J;Graham S;Diop S;Ocorr K;Bodmer R;Oldham S
高脂饮食（HFD）引起的肥胖是糖尿病和心血管疾病的主要原因，但其潜在的遗传机制知之甚少。在这里，我们使用果蝇来测试假设，HFD引起的肥胖和相关的心脏并发症有早期的进化起源，涉及营养传感信号转导通路。我们发现，HFD喂养的苍蝇表现出增加甘油三酯（TG）脂肪和胰岛素/葡萄糖稳态的改变，类似于哺乳动物的反应。HFD还引起心脏脂质积聚、心脏收缩力降低、传导阻滞和严重的结构病理，使人联想到糖尿病性心肌病。值得注意的是，HFD引起的这些代谢和心脏毒性表型通过抑制胰岛素-TOR信号传导而被阻断。值得注意的是，通过TSC 1 -2、4 EBP、F0 X 0）降低胰岛素-TOR活性或增加心肌中的脂肪酶表达足以有效地减轻由HFD诱导的心脏脂肪积累和功能障碍。我们得出结论，由于HFD引起的胰岛素-TOR信号转导失调是介导对代谢和心脏功能的不利影响的原因。
High Fat Diet (HFD)-induced obesity is a major contributor to diabetes and cardiovascular disease, but the underlying genetic mechanisms are poorly understood. Here, we use Drosophila to test the hypothesis that HFD-induced obesity and associated cardiac complications have early evolutionary origins involving nutrient-sensing signal transduction pathways. We find that HFD-fed flies exhibit increased triglyceride (TG) fat and alterations in insulin/glucose homeostasis, similar to mammalian responses. A HFD also causes cardiac lipid accumulation, reduced cardiac contractility, conduction blocks and severe structural pathologies, reminiscent of diabetic cardiomyopathies. Remarkably, these metabolic and cardiotoxic phenotypes elicited by HFD are blocked by inhibiting insulin-TOR signaling. Remarkably, reducing insulin-TOR activity by TSC1-2, 4EBP, FOXO) or increasing lipase expression in the myocardium suffices to efficiently alleviate cardiac fat accumulation and dysfunction induced by HFD. We conclude that deregulation of insulin-TOR signaling due to a HFD is responsible for mediating the detrimental effects on metabolism and heart function.
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影响因子：
9.8
作者：
Grönke S;Müller G;Hirsch J;Fellert S;Andreou A;Haase T;Jäckle H;Kühnlein RP
通讯作者：
Kühnlein RP
DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
4.6
作者：
Cherbas, L;Hu, X;Cherbas, P
通讯作者：
Cherbas, P
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R
DOI：
10.1083/jcb.200408161
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Manning BD
通讯作者：
Manning BD