TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway.
TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway.
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DOI：
10.1016/j.molmet.2016.08.008
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发表时间：
2016-10
影响因子：
8.1
通讯作者：
Chakraborty A
中科院分区：
文献类型：
--
作者：
Ghoshal S;Zhu Q;Asteian A;Lin H;Xu H;Ernst G;Barrow JC;Xu B;Cameron MD;Kamenecka TM;Chakraborty A
肥胖和2型糖尿病（T2 D）导致各种危及生命的疾病，如冠心病、中风、骨关节炎、哮喘和神经变性。因此，正在进行广泛的研究，以确定可以在肥胖/T2 D中靶向的新途径。肌醇焦磷酸（5-IP7）生物合成酶肌醇六磷酸激酶-1（IP 6 K1）的缺失可保护小鼠免受高脂饮食（HFD）诱导的肥胖（DIO）和胰岛素抵抗。然而，该途径是否是肥胖/T2 D的有效药理学靶点尚不清楚。在这里，我们证明了TNP [N2-（m-Trifluorobenzyl），N6-（p-nitrobenzyl）purine]，一种pan-IP 6 K抑制剂，在DIO小鼠中具有强的抗肥胖和抗糖尿病作用。在各种饮食和温度条件下，在短期（2.5周）和长期（10周）TNP处理的DIO C57/BL 6 WT和IP 6 K1-KO小鼠中进行Q-NMR、GTT、ITT、食物摄入、能量消耗、QRT-PCR、ELISA、组织学和免疫印迹研究。TNP，当在HFD喂养开始时注射时，减慢DIO和胰岛素抵抗的起始。此外，当给予DIO小鼠时，TNP促进体重减轻并恢复代谢参数。然而，TNP不减少HFD喂养的IP 6 K1-KO小鼠的体重增加。TNP通过Akt激活特异性增强DIO小鼠的胰岛素敏感性。TNP主要通过增强脂肪组织中的产热能量消耗来减缓体重增加。因此，TNP对体重的影响被部分消除，而其对葡萄糖稳态的影响在热中性温度下被保留。肌醇焦磷酸途径的药理学抑制在肥胖症、T2 D和其他代谢疾病中具有很强的治疗潜力。在高脂喂养开始时，TNP对IP 6 K的药理学抑制减缓了小鼠DIO和胰岛素抵抗的起始。TNP，当治疗DIO小鼠时，促进体重减轻和恢复代谢稳态。TNP不降低IP 6 K1-KO小鼠中高脂饮食诱导的体重增加。TNP通过刺激Akt活性来促进胰岛素敏感性，而它主要通过增加产热能量消耗来减轻体重。长期TNP治疗不会显示有害的副作用。
Obesity and type 2 diabetes (T2D) lead to various life-threatening diseases such as coronary heart disease, stroke, osteoarthritis, asthma, and neurodegeneration. Therefore, extensive research is ongoing to identify novel pathways that can be targeted in obesity/T2D. Deletion of the inositol pyrophosphate (5-IP7) biosynthetic enzyme, inositol hexakisphosphate kinase-1 (IP6K1), protects mice from high fat diet (HFD) induced obesity (DIO) and insulin resistance. Yet, whether this pathway is a valid pharmacologic target in obesity/T2D is not known. Here, we demonstrate that TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine], a pan-IP6K inhibitor, has strong anti-obesity and anti-diabetic effects in DIO mice. Q-NMR, GTT, ITT, food intake, energy expenditure, QRT-PCR, ELISA, histology, and immunoblot studies were conducted in short (2.5-week)- and long (10-week)-term TNP treated DIO C57/BL6 WT and IP6K1-KO mice, under various diet and temperature conditions. TNP, when injected at the onset of HFD-feeding, decelerates initiation of DIO and insulin resistance. Moreover, TNP facilitates weight loss and restores metabolic parameters, when given to DIO mice. However, TNP does not reduce weight gain in HFD-fed IP6K1-KO mice. TNP specifically enhances insulin sensitivity in DIO mice via Akt activation. TNP decelerates weight gain primarily by enhancing thermogenic energy expenditure in the adipose tissue. Accordingly, TNP's effect on body weight is partly abolished whereas its impact on glucose homeostasis is preserved at thermoneutral temperature. Pharmacologic inhibition of the inositol pyrophosphate pathway has strong therapeutic potential in obesity, T2D, and other metabolic diseases. Pharmacologic inhibition of IP6K by TNP, at the onset of high fat feeding, decelerates initiation of DIO and insulin resistance in mice. TNP, when treated to DIO mice, promotes weight loss and restores metabolic homeostasis. TNP does not reduce high fat diet induced weight gain in IP6K1-KO mice. TNP promotes insulin sensitivity by stimulating Akt activity, whereas it reduces body weight primarily by enhancing thermogenic energy expenditure. Long-term TNP treatment does not display deleterious side effects.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Chakraborty A;Kim S;Snyder SH
通讯作者：
Snyder SH
影响因子：
64.5
作者：
Chakraborty A;Koldobskiy MA;Bello NT;Maxwell M;Potter JJ;Juluri KR;Maag D;Kim S;Huang AS;Dailey MJ;Saleh M;Snowman AM;Moran TH;Mezey E;Snyder SH
通讯作者：
Snyder SH
DOI：
10.1097/med.0b013e328337a81f
发表时间：
2010-04
期刊：
Current opinion in endocrinology, diabetes, and obesity
影响因子：
--
作者：
Cypess AM;Kahn CR
通讯作者：
Kahn CR
影响因子：
29
作者：
Cypess AM;Weiner LS;Roberts-Toler C;Franquet Elía E;Kessler SH;Kahn PA;English J;Chatman K;Trauger SA;Doria A;Kolodny GM
通讯作者：
Kolodny GM