Creatine-naïve AGAT-/- mice have low body weight and altered composition rescuable by dietary creatine. (A) Creatine-naïve KO mice had low body weight associated with reduced water, fat and lean mass (***P < 0.001; n = 14 male and 14 female per group). (B) These changes were not proportional because the linear relationship between % body fat and % total water was significantly altered in KO mice (P < 0.0001 for slope). Dietary supplementation with 0.5% creatine for 1 week abolished the fat-water relationship, which was rescued to WT values after 7 weeks of dietary creatine and was unaltered by homoarginine (HA) supplementation (C). Values for body weight (D), fat mass (E), lean mass (F), and total water (G) in the same mice before and after 1-week and 7-week creatine supplementation or 10-day homoarginine supplementation are shown in WT (open circles) and KO (triangles). Lean mass and total water were rapidly changing, suggesting an osmotic role for creatine, whereas fat mass only changed with chronic dietary creatine. Each data point represents mean ± SD for n = 7–10 mice except HA wild-type (n = 4), ** denotes P < 0.01, *** P < 0.001, **** P < 0.0001 compared with pre-treatment values.