Repeated Withdrawal of a GLPR Agonist Induces Hyperleptinemia and Deteriorates Metabolic Health in Obese Aging UM-HET3 Mice

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.