Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.

中文翻译：

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Incretin和糖皮质激素作用的分子整合逆转了免疫代谢功能障碍和肥胖症。

已经提出慢性炎症有助于饮食诱导的肥胖症的发病机理。但是，很少有治疗方法可用于治疗肥胖症和相关的免疫代谢并发症。糖皮质激素常规用于炎性疾病的治疗，但是其多效性导致有害的代谢副作用。我们开发了一种胰高血糖素样肽1（GLP-1）-地塞米松共激动剂，其中GLP-1将地塞米松选择性地递送至表达GLP-1受体的细胞。GLP-1-地塞米松通过控制下丘脑的进食控制和增加能量消耗，使肥胖小鼠的体重降低了25％。该策略可逆转下丘脑和全身性炎症，同时改善葡萄糖耐量和胰岛素敏感性。对GLP-1受体的选择性偏爱绕过了地塞米松对葡萄糖处理，骨骼完整性和下丘脑-垂体-肾上腺轴活动的有害作用。因此，针对饮食诱导的免疫代谢紊乱和由此产生的肥胖症，GLP-1指导的糖皮质激素药理学是一种安全有效的治疗选择。