Alternate-day fasting (ADF) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are promising weight-loss interventions for metabolic syndrome, but the sustainability of their effects after treatment discontinuation remains unclear. Based on published data, we hypothesized that the anticipated weight gain from treatment cessation would be associated with worsened glucose tolerance. To test this hypothesis, we compared the effects of ADF and semaglutide on body weight, food intake, and glycemic control via an intraperitoneal glucose tolerance test (IPGTT) during and after treatment in a polygenic mouse model of metabolic syndrome. 17-week-old MS-NASH mice were randomly assigned to a control (C) diet, an ADF (A) diet, or daily semaglutide (S: 10 nmol/kg) treatment for 4 weeks, followed by a 4-day refeed period. ADF and semaglutide induced similar weight loss (-5.0 ± 0.6, -3.8 ± 0.7 g, respectively, both p < 0.05 vs. C) and reduced cumulative food intake compared to controls (C: 465 ± 8, A: 346 ± 8, S: 386 ± 9 kcal, p < 0.05 vs. C). There was no significant difference in 4-hour fasting blood glucose among groups at the end of treatment (C: 156 ± 6, A: 156 ± 6, S: 148 ± 5 mg/dL). However, mice treated with semaglutide exhibited improved glucose tolerance (IPGTT Area Under the Curve) relative to control and ADF mice on a fast day (C: 25970 ± 760, A: 26440 ± 1060, S: 21030 ± 340 mg*min/dL, p < 0.05 vs. C and vs. A). During the refeed period, ADF-treated mice regained 2.6 ± 0.3g, whereas semaglutide-treated mice regained only 1.1 ± 0.2g. Accordingly, ADF-treated mice consumed the most food throughout the refeed period, followed by semaglutide-treated mice, with controls exhibiting the lowest intake (C: 41.9 ± 1.3, A: 55.2 ± 2.3, S: 48.2 ± 1.3g, p < 0.05 for all comparisons). Surprisingly, glucose tolerance worsened for semaglutide-treated mice (23520 ± 310 mg*min/dL, p < 0.05 vs. pre-refeed) but improved for mice on ADF (22990 ± 580 mg*min/dL, p < 0.05 vs. pre-refeed) following treatment cessation. These results demonstrate the instability of weight-loss outcomes upon discontinuation of interventions such as ADF and semaglutide, and that weight rebound patterns do not necessarily align with post-treatment metabolic changes. This project was internally funded by Williams College. 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.
Sun et al. (2026) studied this question.