Weight loss restores glucose tolerance for many with obesity. However, most individuals regain weight, which further worsens glucose tolerance beyond that of obesity itself. We have previously shown that weight gain and weight loss increase CD8+ T-cell exhaustion and macrophage activation, which may directly affect glucose tolerance following weight regain. Exercise training improves glucose tolerance, reduces T-cell exhaustion, and reduces inflammation, but its protective role during weight cycling remains unclear. This study aimed to test the hypothesis that exercise training can improve glucose tolerance, attenuate CD8+ T-cell exhaustion, and reduce macrophage inflammation following weight cycling. Male C57Bl/6 mice were placed on cycles of low-fat and/or high-fat diets for 27 weeks to elicit lean, obese, and weight cycled (WC) groups. One additional WC group underwent voluntary wheel running during weight loss (WCEx). Body weight was tracked weekly, and body composition and glucose tolerance were evaluated at week 26. At week 27, CD8+ T-cells and macrophages were isolated from epididymal adipose tissue and analysed via flow cytometry. One-way ANOVA with Tukey’s HSD post hoc testing was used to assess group differences. Obese, WC, and WCEx had significantly elevated body weight and fat mass compared to the lean group. As expected, glucose tolerance was worse in the WC than obese group. However, there was no significant difference between the WC and WCEx groups. Interestingly, there were significantly less exhausted CD8+ and CD8+ memory T-cells in the WCEx group vs. the obese and WC groups. However, macrophage IL-6 and TNF increased in WC and WCEx vs. the obese group without differences between WC and WCEx. These results suggest that adding exercise to diet-induced weight loss attenuates CD8+ memory T-cell exhaustion, but not glucose intolerance or macrophage inflammation following weight regain. This study was funded by an American College of Sports Medicine Research Endowment Award (#4039) 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.
Oforka et al. (Fri,) studied this question.