GLP-1–Mediated Targeting of Inflammation Corrects Obesogenic Memory in Male Mice

Obesity-induced biologic changes often persist after weight loss and are difficult to reverse, a phenomenon known as obesogenic memory. This enduring effect is associated with metabolic inflammation, particularly in adipose tissue. In this study, we characterized a mouse model of obesogenic memory and evaluated the efficacy of the unimolecular conjugate glucagon-like peptide 1 (GLP-1)/dexamethasone (GLP-1/Dexa), which selectively and safely delivers the anti-inflammatory drug dexamethasone to GLP-1 receptor (GLP-1R)–expressing cells. We report that this precision pharmacologic approach outperformed treatment with GLP-1 or dexamethasone alone, significantly reducing body weight, food intake, adiposity, and markers of adipose tissue inflammation in male mice with obesogenic memory. In addition, we identified the CCR2/CCL2 inflammatory pathway as an important mediator of glucose intolerance and adipose tissue inflammation associated with obesogenic memory. Our findings suggest that targeting inflammation via GLP-1R signaling may be a promising therapeutic strategy to alleviate obesogenic memory and improve the long-term clinical management of metabolic diseases. ARTICLE HIGHLIGHTS Weight loss defense mechanisms and inflammation challenge metabolic disease management, with few treatments available. We developed a mouse model of obesogenic memory and investigated the efficacy of a glucagon-like peptide 1/dexamethasone (GLP-1/Dexa) conjugate that safely and cell-selectively targets inflammation in GLP-1 receptor cells. GLP-1/Dexa offers a promising strategy to correct obesogenic memory and adipose tissue inflammation in male mice. CCR2 monocytes contribute to glucose intolerance associated with obesogenic memory and may be targeted by GLP-1/Dexa.