Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats.
Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats.
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作者：
de Lange P;Cioffi F;Senese R;Moreno M;Lombardi A;Silvestri E;De Matteis R;Lionetti L;Mollica MP;Goglia F;Lanni A
众所周知，高脂肪饮食(HFD)会导致胰岛素抵抗。在此之前，我们发现3，5-二碘甲腺原氨酸(T2)在4周的HFD中同时给予大鼠，可以防止体重和脂肪质量的增加。在这里，我们调查了T2是否以及如何预防HFD诱导的胰岛素抵抗。我们使用多种技术，包括基因组和蛋白质组图谱、免疫印迹、瞬时转染法和酶活性分析，研究了T2与脂质和葡萄糖动态平衡相关的生化指标。在这里，我们表明，在大鼠中，高脂饲料喂养诱导了胰岛素抵抗(正如预期的)，而T2注射阻止了它的发生。T2通过快速刺激肝脏脂肪酸氧化、降低肝脏甘油三酯水平和改善血脂状况来做到这一点，同时防止骨骼肌脂肪堆积。在机制水平上，1)转基因研究表明T2不通过甲状腺激素受体β发挥作用；2)AMP激活的蛋白激酶不参与T2的作用；3)在肾衰大鼠中，T2迅速增加肝细胞核sirtuin 1的活性；5)靶向过氧化物酶体增殖物激活受体-γ共激活物(PGC-1α)和固醇调节元件结合蛋白(SREBP)-1c的SIRT1被去乙酰化，线粒体生物发生相关基因上调，成脂基因下调，PPARα/δ诱导的基因上调，而参与肝脏糖异生的基因下调。肝脏蛋白质图谱的蛋白质组学分析支持这些变化。T2，通过激活SIRT1，触发一系列事件，导致改善血脂状况，防止脂肪堆积，最终防止饮食诱导的胰岛素抵抗。
High-fat diets (HFDs) are known to induce insulin resistance. Previously, we showed that 3,5-diiodothyronine (T2), concomitantly administered to rats on a 4-week HFD, prevented gain in body weight and adipose mass. Here we investigated whether and how T2 prevented HFD-induced insulin resistance. We investigated the biochemical targets of T2 related to lipid and glucose homeostasis over time using various techniques, including genomic and proteomic profiling, immunoblotting, transient transfection, and enzyme activity analysis. Here we show that, in rats, HFD feeding induced insulin resistance (as expected), whereas T2 administration prevented its onset. T2 did so by rapidly stimulating hepatic fatty acid oxidation, decreasing hepatic triglyceride levels, and improving the serum lipid profile, while at the same time sparing skeletal muscle from fat accumulation. At the mechanistic level, 1) transfection studies show that T2 does not act via thyroid hormone receptor β; 2) AMP-activated protein kinase is not involved in triggering the effects of T2; 3) in HFD rats, T2 rapidly increases hepatic nuclear sirtuin 1 (SIRT1) activity; 4) in an in vitro assay, T2 directly activates SIRT1; and 5) the SIRT1 targets peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC-1α) and sterol regulatory element–binding protein (SREBP)-1c are deacetylated with concomitant upregulation of genes involved in mitochondrial biogenesis and downregulation of lipogenic genes, and PPARα/δ-induced genes are upregulated, whereas genes involved in hepatic gluconeogenesis are downregulated. Proteomic analysis of the hepatic protein profile supported these changes. T2, by activating SIRT1, triggers a cascade of events resulting in improvement of the serum lipid profile, prevention of fat accumulation, and, finally, prevention of diet-induced insulin resistance.