Nutritional Programming of Neuroendocrine Pathways Controlling the Onset of Puberty in Heifers

Accelerated body weight gain during the juvenile period leads to early maturation of the reproductive neuroendocrine system and puberty by advancing the onset of high-frequency release of gonadotropin-releasing hormone (GnRH). In a series of studies conducted as part of this dissertation, it was hypothesized that nutritional regimens that accelerate pubertal development alter the function of kisspeptin and neuropeptide Y (NPY) neurons, known modulators of the release of GnRH. In addition, alterations in the pattern of methylation of target genome sequences were investigated in DNA collected from the arcuate nucleus, a hypothalamic region well-characterized for its role in mediating the metabolic control of reproductive function. Early-weaned crossbred heifers were fed diets to promote an average daily gain of 0.5 Kg (Low Gain; n=12) or 1.0 Kg (High Gain; n=12) from approximately 4 to 8 mo of age. This nutritional regimen has been demonstrated to facilitate early onset of puberty in heifers. At eight mo of age, heifers were slaughtered and a block of tissue containing the preoptic area and hypothalamus was collected and processed for examining the expression of NPY and KISS1, investigating the innervation of GnRH and kisspeptin neurons by NPY fibers, and characterizing the methylation profile of target genomic DNA sequences isolated from the arcuate nucleus. Mean body weight and circulating concentrations of leptin were greater in High-gain than in Low-gain heifers. Elevated rate of body weight gain was associated with reduced expression of NPY in the arcuate nucleus, reduced proportion of GnRH neurons in apposition to NPY-containing varicosities, particularly in GnRH neurons located in the mediobasal hypothalamus, and a reduced number of KISS1-expressing cells in the mid portion of the arcuate nucleus. The rate of body weight gain during the juvenile period did not affect NPY innervation of kisspeptin neurons. Differential methylation of target genomic DNA sequences isolated from the arcuate nucleus was observed in association with rate of body weight gain in juvenile heifers, and genes affected included GHR, IGF2, IGF1R, LEPR, PEG3, LIN28B and HMGA2. Overall, results from these studies support the hypothesis that accelerated body weight gain during the juvenile period promotes alterations in cellular functions within the hypothalamus that facilitate early onset of puberty in heifers.