Coadministration of Dendrimer-Tesaglitazar with Semaglutide Increases Therapeutic Benefit and Blunts Weight Regain After GLP-1 Receptor Agonist Termination

Introduction: Current obesity treatment focuses heavily on glucagon like peptide-1 receptor agonists (GLP-1RAs), the benefits of which are primarily due to decreased caloric intake through appetite suppression. Although this allows for the benefit of rapid weight loss, it incurs a well-established effect of weight regain upon termination of GLP-1RA treatment due to a state of hyperphagia. Dendrimer conjugated Tesaglitazar (D-Tesa) leads to weight loss through browning of white adipose tissue, independent of appetite suppression. We hypothesize that D-Tesa mediated weight loss through white adipose tissue browning will provide a complimentary mechanism that can be used in parallel with GLP-1RAs to improve weight loss and cause lasting metabolic benefits even after termination of GLP-1RAs. Methods: 12-week-old male C57BL/6J mice are fed a high fat diet (HFD) for 16 weeks. Mice were then randomized into one of four groups: 1) vehicle (DI water P.O.; saline S.Q.), 2) D-Tesa monotherapy (20 µg/kg D-Tesa P.O., saline S.Q.), 3) semaglutide monotherapy (DI water P.O., 100 µg/kg semaglutide S.Q.), and 4) Combination treatment (20 µg/kg D-Tesa P.O., 100 µg/kg semaglutide S.Q.). Mice were treated and weighed daily for 5 weeks during the treatment period. After this treatment period, mice in groups 3 and 4 stopped receiving semaglutide to investigate the rebound of weight experienced after the GLP-1RA termination. Pulse wave velocity (PWV), blood pressure, and food intake were measured throughout the experiment. Quantitative NMR (qNMR) was conducted to determine body composition. Glucose and insulin tolerance tests were conducted at the end of the treatment and rebound periods. Results: Mice that received a combination of D-Tesa and semaglutide lost significantly more weight than mice that received D-Tesa or semaglutide monotherapy alone. Combination treated mice lost significantly more fat mass than semaglutide and D-Tesa monotherapy mice. D-Tesa and semaglutide monotherapy treated mice experienced a significant decrease in PWV, with combination treated mice having significantly improved PWV compared to monotherapy treated mice. During the rebound period, semaglutide monotherapy mice that stopped semaglutide rebounded to back to and beyond their initial body weight, due to hyperphagia that persisted 8 weeks after termination of semaglutide. Combination treated mice that stopped semaglutide but continued on D-Tesa did not experience this sustained hyperphagia which led to significantly lower body weight than vehicle and semaglutide treated mice after the rebound period. At the end of the rebound period, mice in the combination group that stopped semaglutide but continued on D-Tesa had significantly improved glucose tolerance, insulin sensitivity, and body composition compared to vehicle and semaglutide monotherapy mice that stopped semaglutide. Conclusion: Coadministration of D-Tesa with GLP-1RA therapy incurs a greater magnitude of benefit in weight loss and cardiovascular function than either D-Tesa or semaglutide monotherapy alone. Additionally, when continued on D-Tesa treatment after the termination of semaglutide, mice avoid prolonged hyperphagia, leading to less weight regain and sustained benefit of glucose tolerance and insulin sensitivity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.