Activation of cyclooxygenase-2 signaling mediates liraglutide-induced adipose lipolytic activity

Pharmacological benefits of glucagon like peptide-1 receptor agonist (GLP-1RA) were mainly contributed to body weight reduction. This study aims to identify the novel mechanisms by which liraglutide improves adipose tissue homeostasis through cyclooxygenase (COX)-2 signaling. Liraglutide's impact on metabolic parameters in vivo was assessed in high-fat diet (HFD)-induced obese mice received liraglutide (1 mg/kg/day) treatment. In vitro experiments were conducted with differentiated adipocytes, and non-targeted metabolomics sequenced to identify key metabolites and COX-2 involvement during cold exposure. Liraglutide improved metabolic insulin resistance, accompanied with reduction of body weight and individual fat weight. Liraglutide suppressed adipocyte hypertrophy whereas induced lipolytic activity, including upregulation of browning-related markers PGC1α, UCP1, and ATGL in obese adipose tissues and differentiated 3T3-L1 adipocytes. Metabolomics analysis revealed elevated activation of COX-2 signaling, including increasing levels of COX-2 signaling and prostaglandin levels in subcutaneous adipose tissue from liraglutide-treated obese mice. COX-2 inhibition abolished liraglutide's effects on adipogenesis and lipolysis, and impaired adaptive thermogenesis in response to cold. In conclusions, liraglutide suppressed adipocyte hypertrophy dependent on upregulation of COX-2 activity. Targeting COX-2 pathway in adipose tissue was one of clinical concerns when obese patient treated with GLP-1RA.