Evaluation of leptin treatment on maintenance of body weight loss in diet-induced obese mice

AIMS: To evaluate the therapeutic potential of leptin treatment for weight loss maintenance preclinically, through a systematic evaluation of leptin efficacy (a) following a period of weight loss stability (as in published clinical studies), and (b) across a range of circulating leptin concentrations achieved through a variety of different weight loss conditions. MATERIALS/METHODS: Body weight and plasma leptin reduction were achieved via caloric restriction in diet-induced obese (DIO) male mice. The effect of r-Leptin (pulsatile exposure) or Fc-Leptin (continuous exposure), administered centrally or systemically, on the prevention of weight regain was tested in a variety of conditions aimed at lowering circulating leptin levels: following 10% or 20% weight loss, with or without a prior weight loss stabilization period, or dietary fat reduction from 60% to 30%. RESULTS: Leptin treatment (physiological to pharmacological dose ranges) did not prevent weight regain in the 10% weight loss (30% leptin lowering) model with or without a weight loss stabilization period. In contrast, liraglutide was effective in maintaining weight loss. Continuous high CNS leptin exposure targeting up to 35 nM (585 ng/mL) in CSF via intracerebroventricular infusion maintained weight loss in non-obese chow-fed mice but was ineffective in DIO mice. Lowering circulating leptin to non-obese mouse concentrations via either achieving greater weight loss (20%) or reducing dietary fat content (60% to 30%) was also not sufficient to reveal a leptin benefit on weight regain. CONCLUSIONS: Leptin treatment is not sufficient to maintain caloric restriction-induced weight loss in preclinical models and does not support the theory that leptin resistance in obesity is due to excessive leptin production and saturation of leptin signalling.