Neuroendocrine regulation of the hypothalamus-pituitary-gonad (HPG) axis
PI: Maricedes Acosta-Martinez
Dept. of Physiology & Biophysics
Research in this laboratory investigates the interplay between metabolism and reproductive physiology. Poor nutrition and obesity are linked to multiple hormonal and reproductive disorders. For example, in girls, obesity is associated with earlier pubertal onset, which is in turn associated with increased risk of breast cancer, cardiovascular disease, asthma, and type 2 diabetes. Obesity also exacerbates the reproductive and metabolic abnormalities accompanying polycystic ovarian syndrome (PCOS), the most common reproductive disorder among women of reproductive age. Thus, to alleviate the health burden accompanying obesity, it is imperative to achieve a better understanding of the mechanisms underlying the metabolic control of HPG axis function. Only then can we potentially devise therapies that reduce the risk of metabolic-related disorders such as early puberty and PCOS. The goal of our studies is to understand how hypothalamic neurons integrate hormonal and metabolic signals to maximize reproductive and metabolic fitness. Specifically, we seek to elucidate the molecular mechanisms by which sex steroid hormones and metabolic signals relay information about nutritional status to the gonadotropin releasing hormone (GnRH) network. Our research centers on the hypothesis that PI3K is a key integrator of metabolic and neural signals regulating GnRH / luteinizing hormone (LH) release (Fig. 1). For example, GnRH and kisspeptin-expressing neurons are pivotal for the onset and maintenance of fertility, and their activity is influenced by gonadal hormones and by metabolic cues. Using a combination of transgenic animal models, neuroimaging and molecular biology techniques, our laboratory has demonstrated that PI3K signaling in GnRH and kisspeptin neurons participates in the control of gonadotropin release and neuropeptide gene expression in a sexually dimorphic fashion. Ongoing studies in my lab include: 1) Investigating the impact of metabolic stress on gonadotropin release in mice with impaired PI3K signaling in kisspeptin neurons, 2) Testing the hypothesis that PI3K mediates estradiol effects on metabolism and reproduction, and 3) Investigating whether estradiol regulation of autophagy, a PI3K-regulated cellular process, participates in the control of metabolism and reproduction.
Clinical/Translational Research: Profiling of circulating exosome-miRNAs during pregnancy: potential biomarkers to monitor and predict pregnancy-associated disorders like gestational diabetes.
The lack of reliable diagnostic tests for early detection of pregnancy-specific disorders such as gestational diabetes and preeclampsia remains an unmet challenge in maternal/fetal medicine. The diagnosis of these pregnancy complications occurs during or after the second trimester, when the pathology is well established and the options to reverse or limit adverse outcomes are limited. Exosomes are bi-lipid membrane-bound-nanovesicles released via exocytosis from virtually every tissue, including the placenta. They are excellent candidates for translational biomarkers because their surface signals as well as cargo are dependent on their cell of origin as well as on the physiological or pathophysiological state. Obesity before and during pregnancy is a major risk factor for two of the most common medical risks in pregnancy: diabetes and hypertension. While pregnancy is associated with a significant increase in plasma exosomes, to date no study has investigated the differential expression of circulating pregnancy-associated exosomes and their content in healthy pregnancies vs. those in high-risk pregnancies such as obese pregnant women. In collaboration with the Dept. of Obstetrics, Gynecology and Reproductive Medicine, my laboratory is characterizing the expression profile of circulating exosome-derived miRNAs from pregnant women with a normal BMI and obese pregnant women with BMI > 30 kg/m2. By investigating circulating miRNA expression during pregnancy, our study focuses on a specific molecular mechanism underlying differential gene expression during the evolution of pregnancy-associated diseases. Therefore, our studies have the potential to provide a new clinical strategy to identify women at risk of developing diseases associated with maternal obesity.
Fig. 1. Kisspeptin expressing neurons are intermediaries for peripherally produced signals to communicate changes in energy status to the GnRH network. In this model, PI3K serves as an integrator of E2, leptin, insulin, and IGF-1 effects on GnRH neuronal function. Alterations in the levels and sensitivity to peripheral hormones and metabolic signals play a major role in HPG axis dysfunction during chronic metabolic stress. We propose that altered PI3K signaling in specific neuronal populations mediates the negative effects of metabolic imbalance on pubertal development and fertility. Our research: 1) Targets specific PI3K signaling components such as PTEN in kisspeptin neurons to investigate if hyperactivation of mTOR signaling changes the sensitivity of the HPG axis to metabolic stressors in females, 2) Investigates the role of PI3K-dependent, membrane-initiated ERα pathway in the estrogen regulation of gonadotropin release and energy homeostasis, and 3) Investigates whether autophagy, a catabolic cellular process control by PI3K, is utilized by estrogen to regulate metabolism and reproduction.
Negrón, A.L, Beymer, M., Warren, K.A., Yu G., AcostaMartínez, M., (2015) Prolonged hyperglycemia and hyperinsulinemia increase BDNF mRNA expression in the posterior ventromedial hypothalamus and the dorsomedial hypothalamus of fed female rats. Neuroscience, 30 (10): 422432
Dubois, S.L., AcostaMartínez, M., DeJoseph, M.R., Wolfe, A., Radovick, S., Boehm, U., Urban, J.H., and Levine, J.E., (2015) Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor a in kisspeptin neurons. Endocrinology, 156(3): 1111–1120
Beymer, M., Negrón, A.L., Yu, G., Wu,S., Mayer, C., Lin, R.Z., Boehm, U.,Acosta-Martínez, M., (2014) Kisspeptin cellspecific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility. American Journal of Physiology Endocrinology and Metabolism 307 (11): E969E982.
Aziz, R*. Beymer, M*. Negrón, A.L. Newshan, A., Yu, G. Rosati, B. McKinnon, D.Fukuda, M., Lin, R.Z., Mayer, C. Boehm, U., Acosta-Martínez M., (2014) Galanin-like peptide (GALP) neuron-specific PI3K signaling regulates GALP mRNA levels in the hypothalamus of males and LH levels in both sexes. J. Neuroendocrinology, 26(7): 426-38.
Acosta-Martinez, M., (2012) PI3K: An attractive candidate for the central integration of metabolism and reproduction. Front. Endocrinology, 2(110): 1-15
Mayer, C*, Acosta-Martinez, M.*, Dubois, S., Wolfe, A., Radovick, S., Boehm U., andLevine, J.E. (2010) Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons. Proceedings of the National Academy of Sciences, 107(52): 22693-8.