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-kappa B) 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. (C) 2020 The Authors. Published by Elsevier Inc.