The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-11-28 DOI:10.1038/s41467-024-54080-w

M. Pilar Valdecantos, Laura Ruiz, Cintia Folgueira, Patricia Rada, Beatriz Gomez-Santos, Maite Solas, Ana B. Hitos, Joss Field, Vera Francisco, Carmen Escalona-Garrido, Sebastián Zagmutt, María Calderon-Dominguez, Paula Mera, Irma Garcia-Martinez, Elsa Maymó-Masip, Diana Grajales, Rosa Alen, Alfonso Mora, Neira Sáinz, Irene Vides-Urrestarazu, Nuria Vilarrasa, José M. Arbones-Mainar, Carlos Zaragoza, María J. Moreno-Aliaga, Patricia Aspichueta, Sonia Fernández-Veledo, Joan Vendrell, Dolors Serra, Laura Herrero, Renate Schreiber, Rudolf Zechner, Guadalupe Sabio, David Hornigold, Cristina M. Rondinone, Lutz Jermutus, Joseph Grimsby, Ángela M. Valverde

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Abstract

Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery. These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways.

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GLP-1/胰高血糖素受体双重激动剂 G49 通过诱导代谢重构和器官间串联模拟减肥手术效果

减肥手术对治疗和缓解肥胖症和 2 型糖尿病很有效，但要避免手术后并发症，还需要能产生类似代谢适应性的药物治疗方法。在这里，我们展示了G49（一种oxyntomodulin（OXM）类似物和胰高血糖素/胰高血糖素样肽-1受体（GCGR/GLP-1R）双重激动剂）如何触发脂肪组织、胰腺和肝脏之间的器官间串联，这种串联是由白脂肪组织（WAT）以依赖GCGR的方式快速释放游离脂肪酸（FFAs）引发的。这种相互作用组会导致脂肪连素和成纤维细胞生长因子 21（FGF21）的升高，引起白脂肪组织变黑、棕色脂肪组织（BAT）活化、能量消耗（EE）增加和体重减轻。在代谢减肥手术后早期肥胖症患者的血浆中发现，在基础和餐后条件下，OXM 升高，G49 治疗后也有类似的代谢适应性。这些结果表明，G49 是与减肥手术荷尔蒙和新陈代谢途径共享的潜在药理学替代品。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.