Abstract

Objective: We examined whether chronic leptin treatment of diet-induced obese (DIO) rats promotes or alleviates the susceptibility to continued high-fat (HF) feeding. Secondly, we examined if voluntary wheel running (WR) is beneficial in reducing the trajectory of weight gain in HF-raised leptin resistant rats.

Research Design and Methods: Sprague-Dawley rats were chow or HF fed for five months, and then hypothalamic leptin overexpression was induced through central administration of rAAV-leptin while continuing either chow or HF diet. Two weeks later, half of the rats in each group were provided access to running wheels for 38 days, whilst maintained on either chow or HF.

Results: In chow-raised rats, either WR or leptin reduced the trajectory of weight gain, and the combined effect of both treatments was additive. In HF-raised leptin-resistant rats, leptin overexpression first transiently reduced weight gain, but then accelerated the weight gain 2-fold over controls. WR in HF-raised was 6-fold less than in chow raised rats and did not affect the weight gain. Surprisingly, WR plus leptin completely prevented the weight gain. This synergy was associated with enhanced hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression in the WR plus leptin compared with leptin-treated sedentary HF counterparts. This enhanced STAT3 signaling associated with the combination treatment occurred only in HF-raised, leptin-resistant, and not in chow-raised, leptin-responsive rats.

Conclusions: Chronic leptin treatment in diet-induced obese rats accelerates dietary obesity. However, leptin combined with WR prevents further dietary weight gain. Thus, this combination therapy may be a viable anti-obesity treatment.