Stanley M Hileman, PhD
PO Box 9229
108 Biomedical Road
Morgantown, WV 26506
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.
- 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) 158(6): 1827-1837. PMCID: PMC5460938 [available on 2018-06-01]
- Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, Hausman GJ, Rohrer GA, 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. Biol Reprod (2017) 96(3): 617-634
- Lopez JA, Bedenbaugh MN, McCosh RB, Weems PW, Meadows LJ, Wisman B, Coolen LM, Goodman RL, Hileman SM. Does Dynorphin Play a Role in the Onset of Puberty in Female Sheep? J Neuroendocrinol (2016) 28(12). PMCID: OMC5412962 [available on 2017-12-01]
- Grachev P, Porter KL, Coolen LM, McCosh RB, Connors JM, Hileman SM, Lehman MN, Goodman RL. Surge-like Luteinising Hormone secretion induced by retrochiasmatic area NK3R activation is mediated primarily by ARC kisspeptin neurones in the ewe. J Neuroendocrinol (2016) 28(6).
- 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 (2015) 9(11): 1852-8.
- Porter KL, Hileman SM, Hardy SL, Nestor CC, Lehman MN, Goodman RL.Neurokinin-3 receptor activation in the retrochiasmatic area is essential for the full pre-ovulatory luteinising hormone surge in ewes. J Neuroendocrinol (2014) 26(11): 776-84.
- Goodman RL, Hileman SM, Nestor CC, Porter KL, Connors JM, Hardy SL, Millar RP, Cernea M, Coolen LM, Lehman MN. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology (2013 Nov) 154(11): 4259-69.
- Nestor CC, Coolen LM, Nesselrod GL, Valent M, Connors JM, Hileman SM, Cheng G, Lehman MN, Goodman RL. Evidence that orphanin FQ mediates progesterone negative feedback in the ewe. Endocrinology (2013 Nov) 154(11): 4249-58.
- Lehman MN, Hileman SM, Goodman RL. Neuroanatomy of the kisspeptin signaling system in mammals: comparative and developmental aspects. Adv Exp Med Biol (2013) 784:27-62. doi: 10.1007/978-1-4614-6199-9_3.
- Goodman RL, Maltby MJ, Millar RP, Hileman SM, Nestor CC, Whited B, Tseng AS, Coolen LM, Lehman MN. Evidence that dopamine acts via kisspeptin to hold GnRH pulse frequency in check in anestrous ewes. Endocrinology (2012 Dec) 153(12): 5918-27. doi: 10.1210/en.2012-1611.
- Merkley CM, Porter KL, Coolen LM, Hileman SM, Billings HJ, Drews S, Goodman RL, Lehman MN. KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe.Endocrinology (2012 Nov) 153(11): 5406-14. doi: 10.1210/en.2012-1357.
- Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM.Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep.Endocrinology, (2012 Jun) 153(6):2756-65.
- Reicher S, Ramos-Nieves JM, Hileman SM, Boisclair YR, Gootwine E, Gertler A. Nonsynonymous natural genetic polymorphisms in the bovine leptin gene affect biochemical and biological characteristics of the mature hormone. J Anim Sci, (2012 Feb) 90(2):410-8.
- Hileman SM, McManus CJ, Goodman RL, Jansen HT. Neurons of thelateral preoptic area/rostral anterior hypothalamic area are required for photoperiodic inhibition of estrous cyclicity in sheep. Biol Reprod, (2011 Nov) 85(5):1057-65.
- Goodman RL, Holaskova I, Nestor CC, Connors JM, Billings HJ, Valent M, Lehman MN, Hileman SM. Evidence that the arcuate nucleus is an important site of progesterone negative feedback in the ewe. Endocrinology, (2011 Sep) 152(9):3451-60.
- Morley JE, Farr SA, Sell RL, Hileman SM, Banks WA. Nitric oxide is a central component in neuropeptide regulation of appetite. Peptides, (2011 Apr) 32(4):776-80.
- Billings HJ, Connors JM, Altman SN, Hileman SM, Holaskova I, Lehman MN, McManus CJ, Nestor CC, Jacobs BH, Goodman RL. Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology (2010), 151(8):3836-46.
- Lehman MN, Ladha Z, Coolen LM, Hileman SM, Connors JM, Goodman RL.Neuronal plasticity and seasonal reproduction in sheep. Eur J Neurosci (2010) 32(12): 2152-64.
- Singh SR, Hileman SM, Connors JM, McManus CJ, Coolen LM, Lehman MN, Goodman RL. Estradiol negative feedback regulation by glutamatergic afferents to A15 dopaminergic neurons: variation with season. Endocrinology (2009), 150(10):4663-71.