Stanley M Hileman , PhD

Professor

Organization:

West Virginia University School of Medicine

Department:

Physiology, Pharmacology & Toxicology

Classification:

Faculty

Professor

Organization:

West Virginia University School of Medicine

Department:

Department of Neuroscience

Classification:

Faculty

Professor

Organization:

West Virginia University School of Medicine

Department:

Rockefeller Neuroscience Institute (SOM)

Classification:

Faculty

• PhD, University of Kentucky

2015

·      Huang J, Lin YC, Hileman S, Martin KH, Hull R, Yu HG.  PP2 prevents isoproterenol stimulation of cardiac pacemaker activity.  J Cardiovasc Pharmacol 65:193-202, 2015.  PMID: 25658311

·      Foskolos A, Ehrhardt RA, Hileman SM, Gertler A, Boisclair YR.  Insensitivity of well-conditioned mature sheep to central administration of a leptin receptor antagonist.  Animal 29:1-7, 2015. PMID: 26220331

·      Lin Y-C, Huang J, Hileman S, Martin K, Hull R, Davis M, Yu H-G.  Leptin decreased heart rate associated with increased ventricular repolarization via its receptor. American Journal of Physiology – Heart and Circulatory Physiology 309:H1731-H1739, 2015. PMID: 26408544

·      Foster DL, Hileman SM.  Puberty in sheep.  Knobil and Neill’s Physiology of Reproduction.  Tony Plant and Tony Zeleznik, eds. 2015.

 

2016

·      Grachev P*, Porter KL*, McCosh RB, Connors JM, Hileman SM, Lehman MN, Goodman RL.  Surge-like LH secretion induced by retrochiasmatic area NK3R activation is mediated primarily by ARC kisspeptin neurons in the ewe. Journal of Neuroendocrinology Vol 28 DOI: 10.1111/jne.12393, 2016. * Indicates shared first authorship. PMID: 27059932

·      Lopez JA. Bedenbaugh MN, McCosh RB, Meadows LJ, Wisman B, Goodman RL, Hileman SM.  Evidence that dynorphin plays an important role in puberty of female sheep. 2016, Journal of Neuroendocrinology, Vol 28, Issue 12 (December) DOI: 10.1111/jne.12445. PMID:28328155.

 

2017

·      Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman D, Barb CR, Hausman GJ, Prezotto LD, McCosh RB, Wright EC, White BR, Freking BA, Oliver WT, Hileman SM, Lents CA.  Relationship of Neuropeptide FF receptors with pubertal maturation of gilts. Biology of Reproduction, 96:717-634, 2017.  PMID:28339619

·      McCosh RB, Szeligo BM, Bedenbaugh MN, Lopez JA, Hardy SL, Hileman SM, Lehman MN, Goodman RL.  Evidence that endogenous somatostatin inhibits episodic, but not surge, secretion of LH in female sheep.  Endocrinology. 2017 Apr 3. doi: 10.1210/en.2017-00075. [Epub ahead of print]. PMID:28379327.

·      Bedenbaugh MNB, O’Connell R, Lopez JA, McCosh RB, Goodman RL, Hileman SM.  Kisspeptin, GnRH and ERα colocalise with nNOS neurones in prepubertal female sheep. Journal of Neuroendocrinology NOV 25 doi: 10.1111/jne.12560. PMID:29178496

·      Bedenbaugh MN, D’Oliveira M, Cardoso RC, Hileman SM, Williams GL, Amstalden M.  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, 2018. PMID:29145598

 

2018

·      Brooks SD, Hileman SM, Chantler P, Milde S, Lemaster K, Frisbee SJ, Shoemaker K, Jackson D, Frisbee J.  Protection from chronic stress- and depressive symptom-induced vascular endothelial dysfunction in female rats is abolished by preexisting metabolic disease.  Am J Physiol Heart Circ Physiol. 314:H1085-H1097, 2018. PMID 29451819

·      Brooks SD, Hileman SM, Chantler P, Milde S, Lemaster K, Frisbee SJ, Shoemaker K, Jackson D, Frisbee J.  Brooks SD, Hileman SM, Chantler P, Milde S, Lemaster K, Frisbee SJ, Shoemaker K, Jackson D, Frisbee J.  Protection from vascular dysfunction in female rats with chronic stress and depressive symptoms. Am J Physiol Heart Circ Physiol. 314:H1070-H1084, 2018. PMID:29451821

·      Prezotto LD, Thorson JF, Borowicz PP, Bejertness JL, Bedendbaugh MN, Hileman SM, Lents CA, Caton JS, Swanson KC.  Influences of maternal nutrition on offspring visceral metabolism and hypothalamic circuitry. Dom Anim Endocrinology 65:71-79, 2018. PMID:30007131

·      Bedenbaugh MN, McCosh RB, Lopez JA, Connors JM, Goodman RL, Hileman SM. A Neuroanatomical relationship of neuronal nitric oxide synthase to gonadotrophin-releasing hormone and kisspeptin neurons in adult female sheep and primates. Neuroendocrinology Jun 21. doi: 10.1159/000491393, 2018. PMID:29929191

·      Weems PW, Coolen LM, Hileman SM, Hardy S, McCosh RB, Goodman RL, Lehman MN.  Evidence that dynorphin acts upon KNDy and GnRH neurons during GnRH pulse termination in the ewe. Endocrinology 159:3187-3199, 2018. PMID:30016419

·      Nestor CC, Bedenbaugh MN, Hileman SM, Coolen LM, Lehman MN, Goodman RL. Regulation of GnRH pulsatility in ewes.  Reproduction 156:R83-R99, 2018. PMID 29880718

 

 

2019

·      Goodman RL, He W, Lopez JA, Bedenbaugh MN, McCosh RB, Bowdridge EC, Coolen LM, Lehman MN, Hileman SM.  Evidence that the LH surge in ewes involves both neurokinin B-dependent and –independent actions of kisspeptin.  Endocrinology 2019 Oct 10. pii: en.2019-00597. doi: 10.1210/en.2019-00597. PMID:31599937

 

2020

·      McCosh RB, Lopez JA, Szeligo BM, Bedenbaugh MN, Hileman SM, Coolen LM, Lehman MN, Goodman RL.  Evidence that nitric oxide is critical for LH surge generation in female sheep.  Endocrinology. 2020 Mar 1;161(3):bqaa010. doi: 10.1210/endocr/bqaa010. PMID:32067028

·      Bedenbaugh MN, Bowdridge EC, Hileman SM.  Role of Neurokinin B in ovine puberty.  Domest Anim Endocrinol. 2020 Jan 28:106442. doi: 10.1016/j.domaniend.2020.106442. PMID: 32209283

·      Lents CA, Lindo AN, Hileman SM, Nonneman DJ.  Physiological and Genomic Insight into neuroendocrine regulation of puberty in gilts.  Domest Anim Endocrinol. 2020 Feb 11:106446. doi: 10.1016/j.domaniend.2020.106446. PMID: 32199704

 

2021

·      Lopez JA, Bowdridge EC, McCosh RB, Bedenbaugh MN, Lindo AN, Metzger M, Haller M, Lehman MN, Hileman SM, Goodman RL. Morphological and functional evidence for sexual dimorphism in neurokinin B signaling in the retrochiasmatic area of sheep. Accepted for publication in the Journal of Neuroendocrinology

·      Porter DT, Goodman RL, Hileman SM, Lehman MN.  Evidence that synaptic plasticity of glutamatergic inputs onto KNDy neurons during the ovine follicular phase is dependent on increasing levels of estradiol.  Accepted for publication in the Journal of Neuroendocrinology.

·      Hileman SM, Lehman MN, Coolen LM, Goodman RL.  The choreography of puberty: evidence from sheep and other agriculturally important species.  Accepted for Current Opinions in Endocrine and Metabolic Research.

 

 

U.S. Obesity statistics

Obesity in WV

Society for the Study of Reproduction

Society for Women's Health Research

Dept. of Physiology and Pharmacology

Atlas of the sheep brain

Transgenic Mouse Database

The goal of my research is to define the neurobiological pathways controlling food intake in the female and how those pathways are integrated into a system whereby nutrition can influence fertility. To accomplish this goal, several surgical, endocrine and molecular biology techniques are employed, including radioimmunoassay, in situ hybridization histochemistry, immunocytochemistry, neuroanatomical tract tracing and RT-PCR, with both rodents and sheep being used as models. The work is focused on the neural mechanisms whereby certain circulating metabolic signals, such as leptin, insulin and IGF-1 may mediate nutrition-induced changes in reproduction as well as examining potential sex-dependent differences in these systems.

Impact of Nutrition on Reproduction

Nutrition is the major factor impacting reproduction in mammalian species. Nonetheless, little is known about the neural pathways through which inadequate nutrition reduces fertility. Our work focuses on identifying hypothalamic pathways through which endocrine signals such as leptin, insulin, or IGF-1 may influence secretion of gonadotropin releasing-hormone, a hypothalamic decapeptide essential for reproduction. Work is also underway to examine the mechanisms whereby the ability of estradiol to inhibit gonadotropin releasing-hormone is enhanced during negative energy balance. Our hope is to define the neural pathways involved in regulating reproduction during undernutrition with the aim of enhancing reproductive efficiency in domestic animals and fertility in humans.

Obesity in Females

The incidence of obesity has reached epidemic proportions in the United States, and in particular, West Virginia. According to recent NIH statistics, the cost of obesity in the U.S. rose above 100 billion dollars last year. Not surprisingly, in recent years there has been an increased interest in defining the neural mechanisms whereby the brain controls food intake. However, the vast majority of these studies have examined body weight regulation in males, despite the fact that obesity in human females is at least as prevalent as in males. One focus of our laboratory is to define the neural pathways through which body weight is regulated in females. This includes the identification of pathways in the hypothalamus regulating food intake or energy expenditure that may differ between males and females and examining the mechanisms that make them different. This involves the use of several experimental paradigms, such as food restriction, high-fat feeding, and administration of leptin, an adipose-derived hormone critical in controlling body weight. We have also recently begun studies to examine adiponectin, another fat-derived hormone that may be involved in regulating body weight through actions in the brain. Previous work suggests that males and females regulate body weight differently. Thus, this work may be important for defining sex-dependent treatments for obesity in the future.

 

Background

My graduate training is in the field of neuroendocrinology and during my Ph.D. at the University of Kentucky with Dr. Keith Schillo, I studied how nutrition affects hypothalamic regulation of reproduction and puberty.  After receiving my Ph.D. I did postdoctoral work at the University of Illinois with Dr.Gary Jackson examining the influence of photoperiod on the hypothalamic regulation of gonadotrophin-releasing hormone secretion. These periods of training used male and female sheep as the animal model. I then took a postdoctoral training position at Harvard Medical School/Beth Israel Deaconess Hospital and worked in the laboratory of Dr. Jeffrey Flier to study the neural control of body weight using rodent and cell-culture models.  I subsequently took a position as an Assistant Professor here at WVU in what was then the Department of Physiology and am now a Professor in the Department of Physiology and Pharmacology.  During my training, I developed extensive expertise in the measurement of circulating hormones by radioimmunoassay and ELISA and examination of various hypothalamic neuropeptides by in situ hybridization and immunohistochemistry. I also am proficient in several in vivo and in vitro techniques, including RT-PCR.  My current work focuses on the role of various hypothalamic neuropeptides within the hypothalamus in the process of puberty.  

Puberty is a process wherein an individual gains the ability to reproduce.  It requires the integration of a complex milieu of internal and external cues, resulting in changes within the hypothalamic-pituitary-gonadal (HPG) axis that ultimately impart the capacity for reproductive success. While species have various timelines for pubertal development, a common thread amongst mammalian species is an elevation of gonadotropin-releasing hormone (GnRH) release from the hypothalamus, and subsequently luteinizing hormone (LH) secretion from the anterior pituitary. While the endocrinology of puberty is relatively well-characterized, the neural mechanisms responsible for the pubertal increase in GnRH/LH secretion remain largely unknown. The appropriate timing of puberty is important. In humans, both precocious and delayed puberty can have negative health outcomes, which include increased risk of eating disorders, obesity, osteoporosis, cardiovascular disease, breast cancer, depression, substance abuse, and suicide. In domestic livestock, delayed puberty can reduce the lifetime productivity of an individual and thereby reduce profitability.

Our work uses female sheep as the animal model and incorporates neurosurgical approaches to injecting tract-tracing agents or saporin conjugates within specific nuclear hypothalamic areas to examine the role of KNDy peptides within the arcuate nucleus, so called because kisspeptin (K), neurokinin B (N), and dynorphin (Dy) are co-expressed within the same neurons. Kisspeptin and neurokinin B are critical for human puberty and stimulate the release of gonadotrophin-releasing hormone while dynorphin inhibits it. Our work has been funded by the USDA for the past several years. I currently direct our graduate program in Cellular and Integrative Physiology and have been a member of the Neuroscience and Reproductive Physiology programs here at WVU and place the highest emphasis on training students.  I have supervised graduate students, summer research students from our NIH-funded INBRE program (for which I am the Program Coordinator), and undergraduates. I contribute heavily to the teaching mission of our university and have served on >40 Ph.D. and Master’s committees. 

 

Current Research

The neural mechanisms underlying puberty are not well understood.  Based on naturally occurring gene deletion studies in humans and transgenic mouse studies, neurons in the arcuate nucleus of the hypothalamus co-expressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) are critical for puberty onset.  During my time at WVU, we have begun studies to look at the involvement of these three peptides in mediating estradiol negative feedback, a key component of puberty onset, in sheep.  We have found that kisspeptin expression is mediated by estradiol in a way that is consistent with an important role for this peptide in puberty onset.  We have also demonstrated that dynorphin is part of the prepubertal brake that keeps GnRH and LH secretion suppressed during that time period.  More recently, we have examined the neuroanatomy of nNOS-containing neurons and their relationship to KNDy neurons. Our most recent work examines the developmental relationship during puberty amongst the KNDy peptides and the role of the receptor for NKB, NK3R, within the arcuate nucleus in puberty onset.  We have found that kisspeptin and NKB expression are readily evident well before puberty onset and do not change in association with puberty-related increases in LH secretion.  We have also observed that deletion of neurons expressing NK3R within the arcuate nucleus blocks puberty onset in female lambs.  Future work will focus on the role of NK3R in the preoptic area on puberty onset and the role of arcuate nucleus neurons expressing the receptor for kisspeptin in puberty. We also collaborate closely with Dr. Casey Nestor at North Carolina State University to study mechanisms whereby nutrition impacts reproduction.

 

Relevant Publications

a. Nestor CC, Goodman RL, Seebaugh A, Hoffman S, Valent M, Hileman SM. Evidence of a role for kisspeptin and neurokinin-B in puberty of female sheep.  Endocrinology 153:2756-2765, 2012. PMID:22434087

b. Foster DL, Hileman SM.  Puberty in sheep.  Knobil and Neill’s Physiology of Reproduction.  Tony Plant and Tony Zeleznik, eds. 2015.

c. Lopez JA. Bedenbaugh MN, McCosh RB, Meadows LJ, Wisman B, Goodman RL, Hileman SM.  Evidence that dynorphin plays an important role in puberty of female sheep. 2016, Journal of Neuroendocrinology, Vol 28, Issue 12 (December) DOI: 10.1111/jne.12445. PMID:28328155. 

d. Bedenbaugh MNB, O’Connell R, Lopez JA, McCosh RB, Goodman RL, Hileman SM.  Kisspeptin, GnRH and ERα colocalise with nNOS neurones in prepubertal female sheep. Journal of Neuroendocrinology NOV 25 doi: 10.1111/jne.12560, 2018. PMID:29178496

e. Bedenbaugh MN, McCosh RB, Lopez JA, Connors JM, Goodman RL, Hileman SM. Neuroanatomical relationship of neuronal nitric oxide synthase to gonadotrophin-releasing hormone and kisspeptin neurons in adult female sheep and primates. Neuroendocrinology Jun 21. doi: 10.1159/000491393, 2018. PMID:29929191

f. Goodman RL, He W, Lopez JA, Bedenbaugh MN, McCosh RB, Bowdridge EC, Coolen LM, Lehman MN, Hileman SM.  Evidence that the LH surge in ewes involves both neurokinin B-dependent and –independent actions of kisspeptin.  Endocrinology 2019 Oct 10. pii: en.2019-00597. doi: 10.1210/en, 2019. PMID:315999371

g. Bedenbaugh MN, Bowdridge EC, Hileman SM.  Role of Neurokinin B in ovine puberty.  Domest Anim Endocrinol. 2020 Jan 28:106442. doi: 10.1016/j.domaniend.2020.106442. PMID: 32209283

h. Aerts EG, Harlow K, Griesgraber MJ, Bowdridge EC, Hardy SL, Nestor CC, Hileman SM. Kisspeptin, neurokinin B, and dynorphin expression during pubertal development in female sheep.  Accepted in Biology, an open access journal from MDPI.