Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.
Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.
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肠促胰岛素和糖皮质激素作用的分子整合可逆转免疫代谢功能障碍和肥胖
DOI：
10.1016/j.cmet.2017.08.023
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发表时间：
2017
期刊：
影响因子：
29
通讯作者：
Strom TM
中科院分区：
文献类型：
--
作者：
Quarta C;Clemmensen C;Yang B;Joseph SS;Lutter D;Graf E;García-Cáceres C;Legutko B;Fischer K;Brommage R;Zizzari P;Franklin BS;Krueger M;Koch M;Vettorazzi S;Hofmann SM;Bakhti M;Bastidas-Ponce A;Lickert H;Strom TM
慢性炎症被认为与饮食诱导肥胖的发病机制有关。然而，治疗肥胖症和相关的免疫代谢并发症的治疗选择很少。糖皮质激素通常用于炎症性疾病的治疗，但其多效性会导致有害的代谢副作用。我们开发了一种新的胰升糖素样肽-1(GLP-1)-地塞米松共激动剂，其中GLP-1选择性地将地塞米松输送到GLP-1受体表达细胞。GLP-1-地塞米松通过靶向下丘脑控制进食和增加能量消耗，使肥胖小鼠的体重减轻高达25%。这一策略逆转了下丘脑和全身炎症，同时改善了葡萄糖耐量和胰岛素敏感性。对GLP-1受体的选择性偏好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影响。因此，GLP-1导向的糖皮质激素药理学代表了饮食诱导的免疫代谢紊乱和由此导致的肥胖的安全和有效的治疗选择。
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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
García-Cáceres C;Quarta C;Varela L;Gao Y;Gruber T;Legutko B;Jastroch M;Johansson P;Ninkovic J;Yi CX;Le Thuc O;Szigeti-Buck K;Cai W;Meyer CW;Pfluger PT;Fernandez AM;Luquet S;Woods SC;Torres-Alemán I;Kahn CR;Götz M;Horvath TL;Tschöp MH
通讯作者：
Tschöp MH
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
16.2
作者：
Harder, H;Nielsen, L;Astrup, A
通讯作者：
Astrup, A