The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin.
The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin.
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DOI：
10.1038/oby.2012.67
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发表时间：
2012-08
期刊：
影响因子：
6.9
通讯作者：
Pocai, Alessandro
中科院分区：
文献类型：
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作者：
Kosinski, Jennifer R.;Hubert, James;Carrington, Paul E.;Chicchi, Gary G.;Mu, James;Miller, Corey;Cao, Jin;Bianchi, Elisabetta;Pessi, Antonello;SinhaRoy, Ranabir;Marsh, Donald J.;Pocai, Alessandro
氧合酶调节蛋白是一种餐后由肠道L细胞分泌的多肽，与胰高血糖素样肽-1受体(GLP1R)和胰高血糖素受体(GCGR)均具有弱亲和力。在人类和啮齿动物体内外周服用OXM可以减轻体重，减少食物摄入量，增加能量消耗。已有研究表明，OXM仅通过GLP1R激动剂调节能量摄入。由于高血糖素减少了啮齿动物和人类的食物摄入量，我们研究了GCGR的激活是否与OXM的减肥效果有关。我们鉴定了一种等量的GLP1R选择性多肽激动剂，它与奥昔洛韦只有一个残基(Q3→E，OXMQ3E)不同，但在体外没有显著的GCGR激动剂活性，刺激肝糖原分解的能力降低了约100倍。OXM和OXMQ3E对肥胖小鼠的慢性治疗表明，OXM具有优越的减肥和降脂效果，其降血糖活性与相应的GLP1R选择性激动剂相当。在GLP1R−/−小鼠身上的研究以及OXM和GCGR拮抗剂的联合给药表明，OXM的减肥作用需要GLP1R和GCGR的激活。我们的数据为OXM的作用机制提供了新的见解，并提示GCGR的激活参与了OXM的减肥作用。
Oxyntomodulin (OXM) is a peptide secreted postprandially from the L-cells of the gut that has a weak affinity for both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Peripheral administration of OXM in humans and rodents causes weight loss reducing food intake and increasing energy expenditure. It has been suggested that OXM modulates energy intake solely through GLP1R agonism. Because glucagon decreases food intake in rodents and humans, we examined whether activation of the GCGR is involved in the body weight-lowering effects of OXM. We identified an equipotent GLP1R-selective peptide agonist that differs from OXM by only one residue (Q3→E, OXMQ3E), but has no significant GCGR agonist activity in vitro and ~100-fold reduced ability to stimulate liver glycogenolysis. Chronic treatment of obese mice with OXM and OXMQ3E demonstrated that OXM exhibits superior weight loss and lipid-lowering efficacy, and antihyperglycemic activity that is comparable to the corresponding GLP1R-selective agonist. Studies in Glp1r−/− mice and coadministration of OXM and a GCGR antagonist revealed that the antiobesity effect of OXM requires activation of both GLP1R and GCGR. Our data provide new insight into the mechanism of action of OXM and suggest that activation of GCGR is involved in the body weight-lowering action of OXM.
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影响因子：
4.8
作者：
Maida, Adriano;Lovshin, Julie A.;Drucker, Daniel J.
通讯作者：
Drucker, Daniel J.
影响因子：
4.8
作者：
Dakin, CL;Small, CJ;Bloom, SR
通讯作者：
Bloom, SR
影响因子：
4.8
作者：
Dakin, CL;Gunn, I;Bloom, SR
通讯作者：
Bloom, SR
影响因子：
82.9
作者：
Scrocchi, LA;Brown, TJ;Drucker, DJ
通讯作者：
Drucker, DJ
DOI：
10.1038/nrendo.2010.187
发表时间：
2010-12
期刊：
Nature reviews. Endocrinology
影响因子：
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作者：
通讯作者：
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