MC4R loss-of-function decreases wheel running independent of body weight. (A) Experimental timeline of VWR in WT and HOM rats, with tissues collected 6 h after final night of VWR. (B) Mean daily running distance, (C) cumulative running distance, and (D) body weights at week 0 and 4 of WT and HOM littermate rats without (sedentary) or with (runner) 4-wk free access to running wheels (n = 14/group). (E) Mean daily running distance, (F) cumulative running distance, and (G) body weights at week 0 and 12 of WT and loxTBMc4r littermate mice without (sedentary) or with (runner) 12-wk free access to running wheels (n = 6–7/group). (H) Mean daily running distance, (I) cumulative running distance, and (J) body weights at week 0 and 12 of lean WT and WTBWM mice (body-weight matched to loxTBMc4r mice; values for loxTBMc4r mice are depicted in I and J for comparison) with 12-wk free access to running wheels (n = 6–7/group). (K) Mean daily running distance, and (L) cumulative running distance of WT mice with ICV administration of vehicle or SHU9119 (5 ng/day) during 7-d free access to running wheels (n = 5–6/group). *p < 0.05, **P < 0.001 versus WT wheel-runner/vehicle; †p < 0.05 versus WTBWM wheel-runner; Different letters indicate significant difference as following: a,bp < 0.05, main effect of genotype.