Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21
Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21
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DOI：
10.1002/psc.2408
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发表时间：
2012-06-01
影响因子：
2.1
通讯作者：
Tschoep, Matthias H.
中科院分区：
文献类型：
--
作者：
Mueller, Timo D.;Sullivan, Lorraine M.;Tschoep, Matthias H.
瘦素作为体重调节介质的发现为肥胖症的治疗带来了极大的兴奋。不幸的是，瘦素单一疗法不足以逆转啮齿动物或人类的肥胖。最近的研究结果表明，胰淀素能够恢复瘦素敏感性，并且与瘦素结合使用时，可以增强肥胖啮齿动物和人类的体重减轻。然而，由于这种联合疗法的独特性仍不清楚，我们评估了瘦素与其他减肥诱导激素的共同给药是否同样可以恢复饮食诱导肥胖（DIO）小鼠的瘦素反应性。因此，我们在此报告了一系列高效且持续作用的位点特异性增强瘦素类似物的设计和表征，当与Exendin-4或成纤维细胞生长因子21（FGF21）联合给药时，DIO小鼠在初始体重减轻30％后恢复瘦素反应性。与 exendin-4 或 FGF21 单一疗法相比，使用任一组合均能增强体重减轻，并且单独使用瘦素足以维持减轻的体重。相比之下，当在相当的时间内仅通过热量限制引起相同的体重减轻时，瘦素单一疗法被证明是无效的。因此，我们发现下丘脑对体重减轻的反调节反应（通过下丘脑刺鼠相关肽（AgRP）水平的变化进行评估）是由热量限制触发的，但通过 Exendin-4 治疗而减弱。我们的结论是，瘦素重新敏化需要药物治疗，但似乎并不局限于独特的信号通路。我们的研究结果提供了临床前证据，表明高活性、长效的瘦素类似物与其他减肥药物联合使用时具有附加功效。版权所有 (C) 2012 欧洲肽协会和 John Wiley & Sons, Ltd.
The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents. Copyright (C) 2012 European Peptide Society and John Wiley & Sons, Ltd.