A minimum amount of stored energy is required for normal pubertal development and for reproductive health in adult life. On the other hand, excess energy negatively impacts the reproductive physiology. Elevated adiposity in women aggravates polycystic ovary syndrome, ovulatory dysfunction and decreases the reproductive capacity. In obese men, fertility is diminished due to altered activity of the hypothalamo- pituitary-gonadal (HPG) axis and defective steroidogenesis in the testis. The increasing rates of childhood obesity have been correlated with early puberty and its deleterious consequences. Earlier menarche in girls is associated with increased risk of adult obesity, type 2 Diabetes and breast cancer. Thus, metabolic cues are essential signals for the onset of puberty and the adequate functioning of the reproductive system in adult life. The adipocyte hormone leptin informs the amount of energy stored to the HPG axis. Humans and mice with leptin signaling deficiency are obese and infertile, remaining in a pre-pubertal state. Although important for proof-of-principle, these mutations are rare. Human obesity is associated with hyperleptinemia, not leptin deficiency. Obese individuals exhibit low or absent response to leptin administration suggesting a functional leptin resistance, what contributes to the fertility deficits induced by excess energy stores. The recent development of molecular techniques for brain mapping and the use of genetically-modified murine models have enhanced our understanding of the brain sites involved in metabolic control. However, the neural basis for the primary reproductive actions of metabolic cues remains unclear. Our laboratory has identified the hypothalamic ventral premammillary nucleus (PMV) as an essential relay of leptin action in reproductive physiology. Guided by strong preliminary data, we hypothesize that the PMV has three distinct neuronal components (i.e., excitatory, inhibitory, and synchronizer) and that the balance among them determines the response of the HPG axis to metabolic cues. This hypothesis will be tested in three independent but complementary aims.
In aims 1 and 2, we will use viro- and chemo-genetic in mouse models to determine the roles of glutamate neurotransmission (excitatory component) and dopamine transporter-expressing neurons (inhibitory component) in reproductive control.
In Aim 3, we will assess the action of nitric oxide (synchronizer component) in the activity of the PMV neuronal network using mouse genetics and calcium imaging. Results from these experiments will open new opportunities for the understanding of the neural basis of the metabolic control of puberty initiation and reproductive function. Our findings will allow site-specific investigation of the causes and mechanisms underlying the reproductive deficits induced by metabolic disorders (e.g., obesity, diabetes, anorexia), including early puberty, ovulatory dysfunction, hypothalamic amenorrhea and infertility.

Public Health Relevance

Extreme metabolic conditions (from anorexia to morbid obesity) have deleterious effects in the reproductive health. The experiments proposed in this application were designed to determine the neuronal network associated with the metabolic control of the reproductive function. Our studies will contribute to the understanding of the mechanisms associated with infertility caused by obesity, diabetes and other metabolic dysfunctions whose prevalence have dramatically increased worldwide.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Ravindranath, Neelakanta
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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