Postnatal administration of leptin antagonist mitigates susceptibility to obesity under high‐fat diet in αMUPA male mice

Perturbations in postnatal leptin signaling have been associated with altered susceptibility to diet‐induced obesity (DIO), under high‐fat‐diet (HFD), albeit with contradicting evidence. Previous studies have shown that Alpha murine urokinase‐type plasminogen activator (αMUPA) mice have a higher and longer postnatal leptin surge compared with their wild types (WT), as well as lower body weight and food intake under regular diet (RD). Here we explore αMUPA’s propensity to DIO and the effect of attenuating postnatal leptin signaling, using leptin antagonist, on energy homeostasis under both RD and HFD. Four‐day‐old αMUPA pups were treated on alternate days until P‐18 with either vehicle or leptin antagonist (LA; 10 or 20 mg d −1 kg −1 ) and weaned into RD or HFD. Compared with RD‐fed αMUPA males, HFD‐fed αMUPA males showed higher energy intake, even when corrected for bodyweight difference, and became hyperinsulinemic and obese. Additionally, HFD‐fed αMUPA males gained bodyweight at a higher rate than their WTs due mainly to strain‐differences in energy expenditure. LA administration did not affect strain differences under RD, but attenuated αMUPA’s hyperinsulinemia and DIO under HFD, most likely by mediating energy expenditure. Together with our previous findings, these results suggest that αMUPA’s leptin surge underlies its higher susceptibility to obesity under HFD, highlighting the role of leptin‐related developmental processes in inducing obesity under post weaning obesogenic environment, at least in αMUPA males. This study, therefore, supports the use of αMUPA mice for elucidating developmental mechanisms of obesity and the efficacy of early‐life manipulations via leptin surge axis in attenuating DIO. Support or Funding Information From the Union’s Seventh Framework Program FP7‐REGPOT‐2012‐2013‐1, Agreement no. 316157The effect of high‐fat diet (HFD) compared with regular diet (RD) on energy homeostasis of saline‐treated αMUPA and FVB/N wild‐type male pups. (A) Body weight; (B) body weight and composition at nine months of age; (C) energy balance. Abbreviations: FFM, fat‐free mass. N, 6–7 mice per treatment. Non‐matching lowercase letters indicate statistically significant differences among groups. *, statistically significant difference from zero, P<0.05. Results are presented as mean ± SEM.The effect of leptin antagonist (LA) compared with saline on αMUPA under regular (RD) and high‐fat (HFD) diets, also compared HFD‐fed saline‐treated WT. Bodyweight (A) and composition at 9 mo of age (B); (C) Energy balance. Abbreviations: FFM, fat‐free mass; LA‐10, 10 mg·day‐1·kg‐1 of LA injections; LA‐20, 20 mg·day‐1·kg‐1 of LA injections. d, Day; Δ, change. Nonmatching letters indicate differences among groups. * and # difference from zero, P < 0.05 and P < 0.01.