An α7 Nicotinic Acetylcholine Receptor-Selective Agonist Reduces Weight Gain and Metabolic Changes in a Mouse Model of Diabetes
An α7 Nicotinic Acetylcholine Receptor-Selective Agonist Reduces Weight Gain and Metabolic Changes in a Mouse Model of Diabetes
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DOI：
10.1124/jpet.109.154633
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Bencherif, Merouane
中科院分区：
文献类型：
--
作者：
Marrero, Mario B.;Lucas, Rudolf;Bencherif, Merouane
2型糖尿病已成为一个普遍的公共卫生问题。该疾病的病因尚未完全确定，但似乎涉及外周和中枢神经系统通路的异常，以及突出的炎症成分。由于已知烟碱乙酰胆碱受体（nAChR）与抗炎途径相互作用，并参与食欲和体重的控制，以及脂质和能量代谢，我们研究了它们在调节与疾病相关的生物学参数中的作用。在2型糖尿病模型中，即纯合子瘦素抵抗db/db肥胖小鼠，我们测量了新型α 7 nAChR选择性激动剂[5-甲基-N-[2-（吡啶-3-基甲基）-1-氮杂双环[2.2.2]辛-3-基]噻吩-2-甲酰胺（TC-7020）]对体重、葡萄糖和脂质代谢以及促炎细胞因子的影响。TC-7020的口服给药减少了体重增加和食物摄入，降低了升高的葡萄糖和糖化血红蛋白水平，并降低了升高的甘油三酯和促炎细胞因子肿瘤坏死因子-α的血浆水平。这些变化被α 7-选择性拮抗剂methylylycaconitine逆转，证实了α 7 nAChR的参与。Janus激酶2（JAK 2）抑制剂α-氰基-（3，4-二羟基）-N-苄基肉桂酰胺（AG-490）也阻断了体重增加、摄食量减少和葡萄糖水平正常化的预防作用，表明这些作用涉及α 7 nAChR与JAK 2-信号转导子和转录激活子3信号通路的连接。结果表明，α 7 nAChR在调节与糖尿病相关的生物学参数方面发挥着核心作用，并支持靶向这些受体作为新的治疗策略的潜力。
Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel alpha 7 nAChR-selective agonist [5-methyl-N-[2-(pyridin3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-alpha. These changes were reversed by the alpha 7-selective antagonist methyllycaconitine, confirming the involvement of alpha 7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of alpha 7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that alpha 7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.