The existence of a fundamental link between nutrition and reproduction is well established. It is known for decades that a critical amount of stored energy is required for sexual maturation and maintenance of fertility. This concept is based on the idea that when survival is threatened by scarcity of food or increased energy demands, male and female of most species divert energy away from reproduction. This includes sexual maturation, the production of reproductive hormones and gametes, and the maintenance of pregnancy and lactation. If excessive leanness occurs in young women, puberty is often delayed. On the other hand, excess stored energy may advance puberty in girls. In the mid-`90s, an epidemiological study reported that 6.7% of American girls had clinical evidence of puberty at age 7 years, and 14.7% at age 8 years. Later, another study showed that this phenomenon has been aggravated in the last decade. An increment of 5-10% in the number of girls with clinical evidence of puberty at age 7 and 8 years was documented. Among several potential causative factors, a high correlation between early puberty onset and childhood obesity was identified. These observations suggested the existence of a previously unrecognized deleterious effect of the increasing rates of childhood obesity: the advance in puberty, which will bring profound social and health implications for the next generations. Earlier menarche in girls is associated with increased risk of adult obesity, type 2 Diabetes and breast cancer. Thus, changing levels of key metabolic cues is an essential signal for the onset of puberty and women's health in adult life. The adipocyte-derived hormone leptin plays a fundamental role as permissive factor for the onset of puberty and maintenance of normal reproductive function in rodents and humans. Our laboratory has identified the ventral premammillary nucleus (PMV) as a key site of leptin action in pubertal development. However, the mechanisms associated with this physiological regulation are unknown. In this application, we will assess the molecular basis of leptin action on puberty by assessing the effects of leptin in the transcriptome changes of PMV neurons associated with the activation of the neuroendocrine reproductive axis. In preliminary studies, we have generated a great amount of data performing RNAseq of the posterior hypothalamus, where the PMV is located. In this application, we will refine the data by comparing leptin action in the PMV and other hypothalamic sites and cell-specific transcriptome analysis using TRAP-Seq of neurons isolated from posterior hypothalamus of LepR-Cre female mice. We expect that at the end of this project we will have identified the molecular candidates associated with sexual maturation and obesity-induced advance in puberty for further investigation.

Public Health Relevance

The link between childhood obesity and the advance in puberty in girls has been well documented. One key player in this physiological outcome is the adipocyte-derived hormone leptin which has a fundamental role as permissive factor for the onset of puberty. In this application, we will perform a systematic assessment of hypothalamic transcriptome changes associated with leptin-induced pubertal maturation to identify candidate genes involved with the activation of the neuroendocrine reproductive axis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Winer, Karen
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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