The effect of leptin treatment on the development of obesity in overfed suckling Wistar rats

Abstract

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 (2Â50 (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.

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

“…In a previous study following the same protocol, 28 we also described no effects on body fat content. These results appear to be different from those of Schmidt et al 40 showing that daily subcutaneous administration of pharmacological doses of leptin (2 Â 50 (pmol/g)day) during the suckling period resulted in lower body fat from day 7 of life onwards. Differences between both studies can be attributed to the different ways of leptin administration and also to the different doses of leptin used, much higher in the study of Schmidt et al Of interest, we found here that increased chronic intake of leptin during lactation has long-term effects on body weight control: rats seem to be more resistant to age-related body weight increase and to diet-induced overweight in adulthood.…”

A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat

“…The hyperleptinaemia exhibited by the obese SL rats suggested that a state of leptin resistance might exist at the hypothalamic level [15][16][17][18], explaining the hyperphagia observed in this model [22,45,49]. In order to study this issue further, mRNA levels encoding the different leptin receptor isoforms were determined in the hypothalamus of NL, SL and LL rats.…”

“…Several studies suggest the existence of alterations in the hypothalamic feeding-regulation systems in the postnatal overfeeding model. It has already been shown that these rats are hyperleptinaemic with central leptin resistance [15][16][17][18] and hyperinsulinaemic with central insulin resistance [19,20]. However, there are no data about the mechanisms underlying this programmed leptin resistance and the possible changes induced by early nutrition on the expression of hypothalamic neuropeptides.…”

Epigenetic changes in early life and future risk of obesity

“…Studies of rats in cross-fostering experiments show that high-fat feeding in the suckling period leads to an increase in adiposity, hyperleptinaemia and hypertension in the adult offspring fed with a normal diet after weaning. [63][64][65] Schmidt et al 66 have also shown that overfeeding rats during the suckling period by rearing them in small litters produces hyperphagia and obesity in adults. In addition, maternal gestational diabetes has also been shown to produce obesity in the adult offspring 67 and even transient neonatal hyperinsulinaemia can induce obesity in early adulthood.…”