Early Metabolic Programming of Puberty Onset: Impact of Changes in Postnatal Feeding and Rearing Conditions on the Timing of Puberty and Development of the Hypothalamic Kisspeptin System

Abstract

Kiss1 neurons have recently emerged as a putative conduit for the metabolic gating of reproduction, with leptin being a regulator of hypothalamic Kiss1 expression. Early perturbations of the nutritional status are known to predispose to different metabolic disorders later in life and to alter the timing of puberty; however, the potential underlying mechanisms remain poorly defined. Here we report how changes in the pattern of postnatal feeding affect the onset of puberty and evaluate key hormonal and neuropeptide [Kiss1/kisspeptin (Kp)] alterations linked to these early nutritional manipulations. Female rats were raised in litters of different sizes: small (four pups per dam: overfeeding), normal (12 pups per dam), and large litters (20 pups per litter: underfeeding). Postnatal overfeeding resulted in persistently increased body weight and earlier age of vaginal opening, as an external sign of puberty, together with higher levels of leptin and hypothalamic Kiss1 mRNA. Conversely, postnatal underfeeding caused a persistent reduction in body weight, lower ovarian and uterus weights, and delayed vaginal opening, changes that were paralleled by a decrease in leptin and Kiss1 mRNA levels. Kisspeptin-52 immunoreactivity (Kp-IR) in the hypothalamus displayed similar patterns, with lower numbers of Kp-IR neurons in the arcuate nucleus of postnatally underfed animals, and a trend for increased Kp-positive fibers in the periventricular area of early overfed rats. Yet, gonadotropin responses to Kp at puberty were similar in all groups, except for enhanced responsiveness to low doses of Kp-10 in postnatally underfed rats. In conclusion, our data document that the timing of puberty is sensitive to both overfeeding and subnutrition during early (postnatal) periods and suggest that alterations in hypothalamic expression of Kiss1/kisspeptin may underlie at least part of such programming phenomenon.

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…In this context, our studies in models of postnatal underand over-nutrition in female rats have documented that rats with restricted feeding during lactation are leaner during the pubertal transition and displayed delayed vaginal opening at the time of puberty, despite they were allowed to eat ad libitum from weaning onward. In contrast, overfed female rats during lactation because of breeding in small litters showed earlier entry into puberty (69). In both extremes, there was a tight correlation between body weight, circulating leptin, and hypothalamic Kiss1/kisspeptin levels, so that leaner animals had low serum levels of leptin and reduced Kiss1 expression and numbers of kisspeptin-positive neurons at the hypothalamus, while heavier rats had higher leptin concentrations and increased Kiss1 mRNA levels and kisspeptin-positive fibers in the RP3V immediately before puberty (69).…”

“…In contrast, overfed female rats during lactation because of breeding in small litters showed earlier entry into puberty (69). In both extremes, there was a tight correlation between body weight, circulating leptin, and hypothalamic Kiss1/kisspeptin levels, so that leaner animals had low serum levels of leptin and reduced Kiss1 expression and numbers of kisspeptin-positive neurons at the hypothalamus, while heavier rats had higher leptin concentrations and increased Kiss1 mRNA levels and kisspeptin-positive fibers in the RP3V immediately before puberty (69). Recent data have confirmed our previous (rat) observations in female mice submitted to postnatal under-nutrition (70).…”

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…To assess whether the delayed pubertal maturation detected in LR Δα mice is secondary to the reduced body weight, we performed an early postnatal overnutrition paradigm to increase their body weight (28,30,31). At weaning day (at 3 weeks of age), LR Δα females from small litters (LR Δα -SL mice) had body weight similar to controls from normal litters (α fl -NL mice; Figure 3C).…”

Treadmill walking differently affects body composition and metabolic parameters of female rats from normal or small litters

“…The nutritional experiences at early life lead to the changes of growth and metabolism in later stages. The research demonstrates that the development of adipose cellularity at this early stage can determine the body composition of the adult and thus the appearance and aggravation of obesity-related diseases (6,14,23,35,37,38,42,45).…”