Abstract
Proper nutrition is important for growth and development. Maturation of the reproductive axis and the timing of pubertal onset can be delayed when insufficient nutrition is available, or possibly advanced with nutritional abundance. The childhood obesity epidemic has been linked to a secular trend in advanced puberty in some populations. The increase in circulating leptin that occurs in association with obesity has been suggested to act as a signal that an adequate nutritional status exists for puberty to occur, allowing activation of central mechanisms. However, obesity-associated hyperleptinemia is linked to decreased leptin sensitivity, at least in adults. Here, we analyzed whether neonatal overnutrition modifies the response to an increase in leptin in peripubertal male rats, as previously demonstrated in females. Wistar rats were raised in litters of 4 (neonatal overnutrition) or 12 pups (controls) per dam. Leptin was administered sc (3 µg/g body weight) at postnatal day 35 and the rats killed 45 min or 2 h later. Postnatal overfeeding resulted in increased body weight and circulating leptin levels; however, we found no overweight-related changes in the mRNA levels of neuropeptides involved in metabolism or reproduction. In contrast, pituitary expression of luteinizing hormone (LH) beta-subunit was increased in overweight rats, as was testicular weight. There were no basal differences between L4 and L12 males or in their response to leptin administration in pSTAT3 levels in the hypothalamus at either 45 min or 2 h. In contrast, pJAK2 was found to be higher at 45 min in L4 compared to L12 males regardless of leptin treatment, while at 2 h it was higher in L4 leptin-treated males compared to L12 leptin-treated males, as well as L4 vehicle-treated rats. There were no changes in response to leptin administration in the expression of the neuropeptides analyzed. However, serum LH levels rose only in L4 males in response to leptin, but with no change in testosterone levels. In conclusion, the advancement in pubertal onset in males with neonatal overnutrition does not appear to be related to overt modifications in the central response to exogenous leptin during the peripubertal period.
Highlights
Pubertal onset is the culmination of maturational processes that result in an increase in the activation of gonadotropin-releasing hormone (GnRH) neurons, which activate the gonadotropin axis to induce maturation of the gonads and reproductive function [1,2,3,4]
Circulating leptin levels are increased as early as 10 days of life in both males and females with neonatal overnutrition [30] and here we found that they continued to be higher at PND35 in males with neonatal overnutrition, as previously reported for peripubertal (PND30) females [31]
As leptin is an important permissive signal involved in the timing of pubertal onset [19, 23, 24, 37], the increase in this hormone during prepubertal life could be involved in the advancement of puberty in these animals
Summary
Pubertal onset is the culmination of maturational processes that result in an increase in the activation of gonadotropin-releasing hormone (GnRH) neurons, which activate the gonadotropin axis to induce maturation of the gonads and reproductive function [1,2,3,4]. Studies suggest that the mean age of pubertal onset is advanced in the growing population of obese/ overweight children in developed countries compared to their lean peers, with both boys and girls being affected [1, 2, 8,9,10,11]. This trend in overall earlier pubertal development should not be confused with pathological precocious puberty, it could result in an increased risk for these individuals to develop hypertension or metabolic diseases in later life [12], emphasizing the importance in understanding the mechanisms underlying this phenomenon
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