GLP-1/Glucagon Coagonism Restores Leptin Responsiveness in Obese Mice Chronically Maintained on an Obesogenic Diet
GLP-1/Glucagon Coagonism Restores Leptin Responsiveness in Obese Mice Chronically Maintained on an Obesogenic Diet
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DOI：
10.2337/db13-1609
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发表时间：
2014-04-01
期刊：
影响因子：
7.7
通讯作者：
Mueller, Timo D.
中科院分区：
文献类型：
--
作者：
Clemmensen, Christoffer;Chabenne, Joseph;Mueller, Timo D.
我们最近报道了饮食诱导的肥胖（DIO）小鼠使用优化的聚乙二醇化（PEG）-瘦素类似物与exendin-4或FGF-21的组合来恢复瘦素反应。然而，瘦素作用的恢复需要停止高脂饮食（HFD）暴露。在这里，我们评估是否一个单一的肽具有平衡的凝血胰高血糖素样肽1（GLP-1）和胰高血糖素受体可以恢复瘦素反应DIO小鼠维持HFD。DIO小鼠用PEG-GLP-1/胰高血糖素（每4天30 nmol/kg）处理以诱导类似于15%的体重减轻，之后将其随机分配以继续PEG-GLP-1/胰高血糖素治疗或重新分配以接受每日补充的PEG-瘦素（185 nmol/kg/天）。与单独的PEG-GLP-1/胰高血糖素相比，向PEG-GLP-1/胰高血糖素中添加PEG-瘦素导致类似于18%的更大体重减轻，并且伴随着食物摄入的进一步减少和葡萄糖和脂质代谢的改善。PEG-瘦素补充的有益作用发生在初始体重减轻后，类似于我们先前报道的在减少膳食脂肪沿着PEG-瘦素和exendin-4或FGF 21共治疗后的效果。总之，我们报告了GLP-1/胰高血糖素凝血功能恢复维持HFD小鼠的瘦素反应性，从而强调了这种多药疗法治疗肥胖和糖尿病的转化价值。
We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an similar to 15% body weight loss, upon which they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an similar to 18% greater weight loss as compared with PEG-GLP-1/glucagon alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes.