OBJECTIVE: To identify the role of hyperleptinaemia in mediating the effects of early postnatal overfeeding in a rat strain known to be prone to manipulations of the early environment which result in predispositions for obesity and associated metabolic and cardiovascular disturbance in later life. DESIGN: Wistar rats were reared in normal litters (NL, 10-12 pups) or small litters (SL, four pups) from postnatal day 3 and killed for determination of body composition and plasma leptin and insulin concentrations on day 7 or day 21 after having been treated with recombinant leptin (2´50 (pmol/g)/day) or saline from day 1. RESULTS: Rearing in SL doubled the body fat content and plasma leptin levels in comparison to NL pups by 21 days of age. Under leptin-treatment throughout suckling age, NL pups remained leptin responsive, ie the difference in body fat content was progressively reduced relative to the controls. Until 7 days of age, despite the body fat content of untreated SL pups being 2-fold higher and their plasma leptin level 7-fold higher than that of NL pups, leptin treatment caused the same percentage decreases in body fat in SL than in NL pups. But in contrast to NL pups, the SL pups became leptin resistant thereafter. Plasma insulin levels in 7-day-old leptin-treated SL pups were 3-fold higher than in untreated littermates and 5-fold higher than in the NL groups. CONCLUSION: Prophylactic leptin treatment does not prevent hyperinsulinaemia and excessive fat deposition in SL pups. On the other hand, selective hyperleptinaemia during suckling age does not trigger leptin resistance and obesity in NL pups. Rather than hyperleptinaemia per se, other factors associated with early postnatal overnutrition, for example, the concurrent hyperinsulinaemia, seem to play a pivotal role for the development of leptin-resistance and life-long obesity risk in SL rats. International Journal of Obesity (2001) 25, 1168-1174 | 
