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Obesity has been recognized as a low-grade, chronic inflammatory disease that leads to an increase in obesity-associated disorders, including type 2 diabetes (T2D), fatty liver diseases and cancer. Glucagon-like peptide-1 (GLP-1) is an effective drug for T2D, and it not only has glucose-regulating effects but also has anti-inflammatory effects in obesity. In our previous study, we designed a novel GLP-1 analogue, (E X -4) 2 -Fc, which has been shown to reduce body weight and improve glucose tolerance in vivo. In this study, we observed that (E X -4) 2 -Fc also has anti-inflammatory functions in adipose tissue. After the treatment of diet-induced obesity (DIO) mice with (E X -4) 2 -Fc, we found that the inflammatory response in adipose tissue was significantly attenuated. (Ex-4) 2 -Fc can reduce obesity-associated proinflammatory cytokine levels and macrophage numbers in DIO mice. In addition, (E X -4) 2 -Fc treatment resulted in proinflammatory M1-type macrophages beginning to transform into anti-inflammatory M2-type macrophages. The inflammatory mitogen-activated protein kinase (MAPK) signalling pathway and nuclear factor kappa B (NF-κB) were altered in adipose tissue after (E X -4) 2 -Fc treatment. Leptin has been proven to be closely related to immunity, and we demonstrated that the effect of (E X -4) 2 -Fc on adipocyte inflammation was related to leptin. The data suggested that (E X -4) 2 -Fc could modulate the inflammatory response by inhibiting the expression of leptin in adipose tissue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies have shown that antidiabetic drugs can alter the gut microbiota. The hypoglycemic effects of the drugs can be attributed in part to certain species in the gut microbiome that help the drugs work more effectively. In addition, increasing energy expenditure via the induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Currently, glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) treatment for metabolic disorders such as obesity and type 2 diabetes has been widely studied. To determine the mechanism of a long‐acting GLP‐1 RA affects adipose tissue browning and the gut microbiome, we treated high‐fat diet mice with GLP‐1 RA and demonstrated that the drug can regulate adipose tissue browning. 16S rRNA and untargeted metabolomics assays suggested that it increased the abundance of bacterium Lactobacillus reuteri and decreased serum ceramide levels in mice. L. reuteri was negatively correlated with ceramide. We found that the mechanism of ceramide decline was alkaline ceramidase 2 (Acer2) overexpression. Moreover, L. reuteri can play a therapeutic synergistic role with GLP‐1 RA, suggesting that gut microbiota can be used as a part of the treatment of diabetes. [ABSTRACT FROM AUTHOR]