A new study from the lab of Shangang Zhao, PhD, shows increased susceptibility of older mice to side effects when treated with liraglutide (a GLP-1 receptor agonist to treat obesity and metabolic disease). From this study, on-off cycles of this drug cause acceleration of frailty and sarcopenia. Dr. Zhao is an Assistant Professor in the Department of Medicine, Division of Endocrinology and an investigator with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Repeated Withdrawal of a GLPR Agonist Induces Hyperleptinemia and Deteriorates Metabolic Health in Obese Aging UM-HET3 Mice
Nisi Jiang, Jiyuan Yin, Noah Lawrence, Jieyi Meng, Laurence T Maeyens, Ziying Xu, Xin Li, Mbolle Ekane, Ariana Chaudhary, Pengju Cao, Guannan Li, Carolina Solis-Herrera, Yi Zhu, Shangang Zhao
Aging Cell. 2025 Oct;24(10):e70210. doi: 10.1111/acel.70210. Epub 2025 Sep 17.
Abstract:
GLP-1-based therapy is highly effective in combating aging-associated metabolic diseases. However, the metabolic effects of frequent withdrawal from this therapy in aged, obese mice have not been previously studied. In this study, aged obese UM-HET3 mice were assigned to three groups: Group 1 received no liraglutide treatment (Lira OFF); Group 2 underwent 3 cycles of treatment followed by withdrawal (Lira ON/OFF); and Group 3 remained on continuous treatment (Lira ON). As expected, mice in Group 3 showed reduced body weight and food intake, along with improved metabolic health. In contrast, mice in Group 2 developed hyperleptinemia and visceral fat expansion, leading to impaired metabolic health. Importantly, although these mice regained their fat mass after each treatment cycle, they failed to restore lean mass, an unfavorable shift in body composition that may increase vulnerability to aging-related sarcopenia. These findings suggest that continuous GLP-1-based therapy is necessary to sustain metabolic benefits, while intermittent use may promote age-associated sarcopenia and metabolic decline.
Keywords: leptin; liraglutide; repeated withdrawal; sarcopenia; weight cycling.