Adiponectin production is required for intermittent prednisone effects on muscle performance. (A) Serum adipokine arrays identified adiponectin as a top upregulated hit after weekly prednisone regimens in both normal and HFD conditions. (B and C) After 12 wk of treatment, total and HMW adiponectin levels were elevated in fat tissue and circulation of mice on normal and HFDs. (D) WB confirmation of HMW adiponectin trends in adipose tissue. (E) Weekly prednisone upregulated adiponectin to a modestly lower level than rosiglitazone. However, compared to rosiglitazone, treatment significantly upregulated muscle Adipor1, underscoring the treatment effects on the fat–muscle axis. (F–H) Body-wide ablation of adiponectin (Adipoq-KO) blocked the effects of weekly prednisone on nutrient oxidation (G) and adiposity and exercise tolerance (H) seen in the Adipoq-WT littermates. Line plots, single values with min-max boxplots and connected medians; histograms, single values and mean ± SEM. All panels report data verified in at least two independent experiments. n = 5 mice/group (A–C and H), 3 mice/group (D, E, and G). *, P < 0.05; **, P < 0.01; ***, P < 0.001; (B–E) one-way Welch’s ANOVA with Tukey multiple comparison; (H) two-way ANOVA. Source data are available for this figure: SourceData F3.