Increased prevalence of obesity in girls has been associated with reductions in average age at pubertal onset, suggesting that excessive energy during the juvenile period accelerates puberty. Establishment of reproductive cycles is preceded by increased frequency of episodic release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone, which are highly dependent upon adequate nutrition. Nutritional and metabolic cues act upon metabolic-sensing pathways in the hypothalamus and support elevated GnRH neuronal activity. Excessive weight gain during early adolescence promotes a state of nutrient sufficiency, which stimulates earlier maturation of the reproductive neuroendocrine system. Our long-term goal is to identify the neuroendocrine mechanisms and pathways that mediate the permissive effects of nutrient sufficiency on the pubertal onset of high-frequency episodic release of GnRH. Herein, we propose that kisspeptin, a peptide synthesized by neurons in the preoptic area and hypothalamus, plays a critical role in mediating the influence of growth and metabolism on age at puberty.
The specific aims are to assess the effects of accelerated weight gain and increased adiposity on: 1) the release of kisspeptin in the cerebrospinal fluid (CSF) collected from the third ventricle, and 2) the hypothalamic expression of Kiss1, the gene encoding kisspeptin. In these studies, we will use the sheep as the animal model because the peripubertal activation of the reproductive neuroendocrine axis in the ewe lamb is similar to that in humans. In addition, serial collections of CSF from the third ventricle can be performed in the sheep without noticeable disruption of GnRH release. The outcomes of this research will advance our understanding of kisspeptin biology, and are expected to implicate the kisspeptin system on the ontogeny of accelerated onset of puberty induced by elevated weight gain. Therefore, these studies may lay the foundation to better treat alterations of puberty associated with an excess (overnutrition and obesity) or deficiency (undernutrition and excessive energy expenditure) of nutrients in girls.
In the US, more than 3 million girls between ages 6 and 11 are at greater risk for developing severe health complications associated with excessive body weight, including diabetes and cardiovascular disease. Obesity in girls is also associated with early breast development and menarche, which increase the risk for development of polycystic ovarian syndrome, reproductive cancers and psychosocial distress. The goal of this research is to examine the influence of adiposity on the activation of kisspeptin neurons and early onset of puberty. Understanding of the mechanisms by which kisspeptin neurons are regulated by overnutrition will lay the foundation for designing better treatments for alterations in pubertal development associated with excess or deficiency of nutrients.
| Bedenbaugh, Michelle N; D'Oliveira, Marcella; Cardoso, Rodolfo C et al. (2018) Pubertal Escape From Estradiol Negative Feedback in Ewe Lambs Is Not Accounted for by Decreased ESR1 mRNA or Protein in Kisspeptin Neurons. Endocrinology 159:426-438 |
