Neuroendocrine signaling pathways and the nutritional control of puberty in heifers
Puberty is a complex physiological process in females that requires maturation of the reproductive neuroendocrine system and subsequent initiation of high-frequency, episodic release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Genetics and nutrition are two major factors controlling the timing of puberty in heifers. While nutrient restriction during the juvenile period delays puberty, accelerated rates of body weight gain during this period have been shown to facilitate pubertal development by programming hypothalamic centers that underlie the pubertal process. Among the different metabolic factors, leptin plays a critical role in conveying nutritional information to the neuroendocrine axis and controlling pubertal progression. Because GnRH neurons are devoid of the leptin receptor, leptin’s effects on GnRH neurons must be relayed via an afferent neuronal network. Two neuronal populations located in the arcuate nucleus (ARC) that express the orexigenic peptide neuropeptide Y (NPY), and the anorexigenic peptide alpha melanocyte-stimulating hormone (αMSH), are key components of afferent pathways that convey inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. In addition, ARC neurons expressing kisspeptin, a potent stimulator of GnRH release, are also involved in the nutritional regulation of puberty. Our studies have demonstrated that increased planes of nutrition during juvenile development result in morphological and functional changes in hypothalamic pathways comprising NPY, proopiomelanocortin (POMC), and kisspeptin neurons. Changes included differential expression of NPY, POMC, and Kiss1 in the ARC, and plasticity in the axonal projections to GnRH and kisspeptin neurons. Additionally, increased rates of body weight gain also promoted changes in the pattern of DNA methylation, a key epigenetic mechanism for regulation of gene expression. Finally, our most recent findings suggest that maternal nutrition during gestation can also induce structural and functional changes in hypothalamic neurocircuitries that are likely to persist long after pubertal maturation and influence reproductive performance throughout adulthood in cattle.
Adam C, Findlay P. 2010. Decreased blood-brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance. Int J Obes, 34:980-988.
Allen C, Alves BRC, Li X, Tedeschi LO, Zhou H, Paschal JC, Riggs PK, Braga-Neto UM, Keisler DH, WilliamsGL, Amstalden M. 2012. Gene expression in the arcuate nucleus of heifers is affected by controlled intake of high-and low-concentrate diets. J Anim Sci, 90:2222-2232.
Allen C, Tedeschi LO, Keisler DH, Cardoso RC, Alves BRC, Amstalden M, Williams GL. 2017. Interaction of dietary energy source and body weight gain during the juvenile period on metabolic endocrine status and age at puberty in beef heifers. J Anim Sci, 95:2080-2088.
Alves BR, Cardoso RC, Prezotto LD, Thorson JF, Bedenbaugh M, Sharpton SM, Caraty A, Keisler DH, Tedeschi LO, Williams GL, Amstalden M. 2015. Elevated body weight gain during the juvenile period alters neuropeptide Y-gonadotropin-releasing hormone circuitry in prepubertal heifers. Biol Reprod, 92:46:1-10.
Alves BR, Cardoso RC, Doan R, Zhang Y, Dindot SV, Williams GL, Amstalden M. 2016. Nutritional programming of accelerated puberty in heifers: alterations in DNA methylation in the arcuate nucleus. Biol Reprod, 96:174-184.
Amstalden M, Alves BR, Liu S, Cardoso RC, Williams GL. 2011. Neuroendocrine pathways mediating nutritional acceleration of puberty: insights from ruminant models. Front Endocrinol, 2:3389. doi: 10.3389/fendo.2011.00109.
Backholer K, Smith J, Clarke IJ. 2009. Melanocortins may stimulate reproduction by activating orexin neurons in the dorsomedial hypothalamus and kisspeptin neurons in the preoptic area of the ewe. Endocrinology, 150:5488-5497.
Backholer K, Smith JT, Rao A, Pereira A, Iqbal J, Ogawa S, Li Q, Clarke IJ. 2010. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology, 151:2233-2243.
Banks WA. 2001. Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity. Curr Pharm Des, 7:125-133.
Barb C, Kraeling R. 2004. Role of leptin in the regulation of gonadotropin secretion in farm animals. Anim Reprod Sci, 82:155-167.
Barker DJ. 2004. The developmental origins of adult disease. J Am Coll Nutr, 23:588S-595S.
Barker DJ. 2007. The origins of the developmental origins theory. J Intern Med, 261:412-417.
Bedenbaugh MN, D'Oliveira M, Cardoso RC, Hileman SM, Williams GL, Amstalden M. 2018. 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.
Bouret SG, Draper SJ, Simerly RB. 2004. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science, 304:108-110.
Bronson F. 1981. The regulation of luteinizing hormone secretion by estrogen: relationships among negative feedback, surge potential, and male stimulation in juvenile, peripubertal, and adult female mice. Endocrinology, 108:506-516.
Burdge GC, Hoile SP, Uller T, Thomas NA, Gluckman PD, Hanson MA, Lillycrop KA. 2011. Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition. PloS One, 6:e28282. doi.org/10.1371/ journal.pone.0028282.
Cao J, Patisaul HB. 2011. Sexually dimorphic expression of hypothalamic estrogen receptors α and β and Kiss1 in neonatal male and female rats. J Comp Neurol, 519:2954-2977.
Cardoso RC, Alves BR, Prezotto LD, Thorson JF, Tedeschi LO, Keisler DH, Amstalden M, Williams GL. 2014a. Reciprocal changes in leptin and NPY during nutritional acceleration of puberty in heifers. J Endocrinol, 223:289-298.
Cardoso RC, Alves BR, Prezotto LD, Thorson JF, Tedeschi LO, Keisler DH, Park CS, Amstalden M, Williams GL. 2014b. Use of a stair-step compensatory gain nutritional regimen to program the onset of puberty in beef heifers. J Anim Sci, 92:2942-2949.
Cardoso RC, Alves BR, Sharpton SM, Williams GL, Amstalden M. 2015. Nutritional programming of accelerated puberty in heifers: involvement of pro‐opiomelanocortin neurones in the arcuate nucleus. J Neuroendocrinol, 27:647-657.
Castellano JM, Bentsen AH, Sánchez-Garrido MA, Ruiz-Pino F, Romero M, Garcia-Galiano D, Aguilar E, Pinilla L, Diéguez C, Mikkelsen JD, Tena-Sempere M. 2011. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system. Endocrinology, 152:3396-3408.
Chan YY, Clifton DK, Steiner RA. 1996. Role of NPY neurones in GH-dependent feedback signalling to the brain. Horm Res, 45:12-14.
Cheong RY, Czieselsky K, Porteous R, Herbison AE. 2015. Expression of ESR1 in glutamatergic and GABAergic neurons is essential for normal puberty onset, estrogen feedback, and fertility in female mice. J Neurosci, 35:14533-14543.
Cheung CC, Clifton DK, Steiner RA. 1997. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology, 138:4489-4492.
Cone RD. 1999. The central melanocortin system and energy homeostasis. Trends Endocrinol Metab, 10:211-216.
Day M, Imakawa K, Garcia-Winder M, Zalesky DD, Schanbacher BD, Kittok RJ, Kinder JE. 1984. Endocrine mechanisms of puberty in heifers: estradiol negative feedback regulation of luteinizing hormone secretion. Biol Reprod, 31:332-341.
Day M, Imakawa K, Garcia-Winder M, Kittok RJ, Schanbacher BD, Kinder JE. 1986. Influence of prepubertal ovariectomy and estradiol replacement therapy on secretion of luteinizing hormone before and after pubertal age in heifers. Domest Anim Endocrinol, 3:17-25.
Day M, Imakawa K, Wolfe P, Kittok R, Kinder J. 1987. Endocrine mechanisms of puberty in heifers. Role of hypothalamo-pituitary estradiol receptors in the negative feedback of estradiol on luteinizing hormone secretion. Biol Reprod, 37:1054-1065.
Donato J Jr, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S Jr, Coppari R, Zigman JM, Elmquist JK, Elias CF. 2011. Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest, 121:355-368.
Dorling AA, Todman MG, Korach KS, Herbison AE. 2003. Critical role for estrogen receptor alpha in negative feedback regulation of gonadotropin-releasing hormone mRNA expression in the female mouse. Neuroendocrinology, 78:204-209.
Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE. 2016. Estradiol restrains prepubertal gonadotropin secretion in female mice via activation of ERα in kisspeptin neurons. Endocrinology, 157:1546-1554.
Egan OK, Inglis MA, Anderson GM. 2017. Leptin signaling in AgRP neurons modulates puberty onset and adult fertility in mice. J Neurosci, 37:3875-3886.
Elmquist JK, Bjørbaek C, Ahima RS, Flier JS, Saper CB. 1998. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol, 395:535-547.
Fortes MR, Reverter A, Nagaraj SH, Zhang Y, Jonsson NN, Barris W, Lehnert S, Boe-Hansen GB, Hawken RJ. 2011. A single nucleotide polymorphism-derived regulatory gene network underlying puberty in 2 tropical breeds of beef cattle. J Anim Sci, 89:1669-1683.
Foster DL, Lemons JA, Jaffe RB, Niswender GD. 1975. Sequential patterns of circulating luteinizing hormone and follicle-stimulating hormone in female sheep from early postnatal life through the first estrous cycles. Endocrinology, 97:985-994.
Foster DL, Ryan KD. 1979. Endocrine mechanisms governing transition into adulthood: a marked decrease in inhibitory feedback action of estradiol on tonic secretion of luteinizing hormone in the lamb during puberty. Endocrinology, 105: 896-904.
Funabashi T, Daikoku S, Shinohara K, Kimura F. 2000. Pulsatile gonadotropin-releasing hormone (GnRH) secretion is an inherent function of GnRH neurons, as revealed by the culture of medial olfactory placode obtained from embryonic rats. Neuroendocrinology, 71:138-144.
Ganu RS, Harris RA, Collins K, Aagaard KM. 2012. Maternal diet: a modulator for epigenomic regulation during development in nonhuman primates and humans. Int J Obes Suppl, 2:S14-S18.
Gasser CL, Behlke EJ, Grum DE, Day ML. 2006a. Effect of timing of feeding a high-concentrate diet on growth and attainment of puberty in early-weaned heifers. J Anim Sci, 84:3118-3122.
Gasser CL, Bridges GA, Mussard ML, Grum DE, Kinder JE, Day ML. 2006b. Induction of precocious puberty in heifers III: Hastened reduction of estradiol negative feedback on secretion of luteinizing hormone. J Anim Sci, 84:2050-2056.
Gazal OS, Leshin LS, Stanko RL, Thomas MG, Keisler DH, Anderson LL, Williams GL. 1998. Gonadotropin-releasing hormone secretion into third-ventricle cerebrospinal fluid of cattle: correspondence with the tonic and surge release of luteinizing hormone and its tonic inhibition by suckling and neuropeptide Y. Biol Reprod, 59:676-683.
Gluckman PD, Hanson MA. 2004. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res, 56:311-317.
Goodman RL, Hileman SM, Nestor CC, Porter KL, Connors JM, Hardy SL, Millar RP, Cernea M, Coolen LM, Lehman MN. 2013. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology, 154:4259-4269.
Hahn TM, Breininger JF, Baskin DG, Schwartz MW. 1998. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci, 1:271-272.
Hughes H. 2013. Raised replacement heifers: Some economic considerations. Vet Clin North Am Food Anim Pract, 29:643-652.
Iwasa T, Matsuzaki T, Murakami M, Fujisawa S, Kinouchi R, Gereltsetseg G, Kuwahara A, Yasui T, Irahara M. 2010. Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats. J Physiol, 588:821-829.
Kato J, Atsumi Y, Inaba M. 1974. Estradiol receptors in female rat hypothalamus in the developmental stages and during pubescence. Endocrinology, 94:309-317.
Kinder JE, Day M, Kittok R. 1987. Endocrine regulation of puberty in cows and ewes. J Reprod Fertil Suppl, 34:167-186.
Lehman MN, Ebling FJ, Moenter SM, Karsch FJ. 1993. Distribution of estrogen receptor-immunoreactive cells in the sheep brain. Endocrinology, 133:876-886.
Lehman MN, Coolen LM, Goodman RL. 2010. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology, 151:3479-3489.
Léonhardt M, Lesage J, Croix D, Dutriez-Casteloot I, Beauvillain JC, Dupouy JP. 2003. Effects of perinatal maternal food restriction on pituitary-gonadal axis and plasma leptin level in rat pup at birth and weaning and on timing of puberty. Biol Reprod, 68:390-400.
Leranth C, MacLusky NJ, Shanabrough M, Naftolin F. 1988. Immunohistochemical evidence for synaptic connections between pro-opiomelanocortin-immunoreactive axons and LH-RH neurons in the preoptic area of the rat. Brain Res, 449:167-176.
Lesmeister J, Burfening P, Blackwell R. 1973. Date of first calving in beef cows and subsequent calf production. J Anim Sci, 36:1-6.
Li XF, Kinsey-Jones JS, Cheng Y, Knox AM, Lin Y, Petrou NA, Roseweir A, Lightman SL, Milligan SR, Millar RP, O'Byrne KT. 2009. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PloS One, 4:e8334. doi: 10.1371/journal.pone.0008334.
Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG Jr. 2011. Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology, 152:2302-2310.
Manfredi-Lozano M, Roa J, Ruiz-Pino F, Piet R, Garcia-Galiano D, Pineda R, Zamora A, Leon S, Sanchez-Garrido MA, Romero-Ruiz A, Dieguez C, Vazquez MJ, Herbison AE, Pinilla L, Tena-Sempere M. 2016. Defining a novel leptin–melanocortin–kisspeptin pathway involved in the metabolic control of puberty. Mol Metab, 5:844-857.
Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE. 2010. Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons. Proc Natl Acad Sci USA, 107:22693-22698.
McShane TM, May T, Miner JL, Keisler DH. 1992. Central actions of neuropeptide-Y may provide a neuromodulatory link between nutrition and reproduction. Biol Reprod, 46:1151-1157.
Miller DW, Harrison JL, Bennett EJ, Findlay PA, Adam CL. 2007. Nutritional influences on reproductive neuroendocrine output: insulin, leptin, and orexigenic neuropeptide signaling in the ovine hypothalamus. Endocrinology, 148:5313-5322.
Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. 2009. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci, 29:11859-11866.
Nijland MJ, Ford SP, Nathanielsz PW. 2008. Prenatal origins of adult disease. Curr Opin Obstet Gynecol, 20:132-138.
Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. 1997. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science, 278:135-138.
Pentinat T, Ramon-Krauel M, Cebria J, Diaz R, Jimenez-Chillaron JC. 2010. Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition. Endocrinology, 151:5617-5623.
Pierroz DD, Gruaz NM, d'Alièves V, Aubert ML. 1995. Chronic administration of neuropeptide Y into the lateral ventricle starting at 30 days of life delays sexual maturation in the female rat. Neuroendocrinology, 61:293-300.
Pinheiro AR, Salvucci ID, Aguila MB, Mandarim-de-Lacerda CA. 2008. Protein restriction during gestation and/or lactation causes adverse transgenerational effects on biometry and glucose metabolism in F1 and F2 progenies of rats. Clin Sci, 114:381-392.
Qiu J, Nestor CC, Zhang C, Padilla SL, Palmiter RD, Kelly MJ, Rønnekleiv OK. 2016. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. Elife,5:e16246. doi: 10.7554/eLife.16246.
Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE, Grattan DR, Anderson GM. 2009. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology, 150:2805-2812.
Ratra DV, Elias CF. 2014. Chemical identity of hypothalamic neurons engaged by leptin in reproductive control. J Chem Neuroanat, 61:233-238.
Ravelli GP, Stein ZA, Susser MW. 1976. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med, 295:349-353.
Redmond JS, Baez-Sandoval GM, Spell KM, Spencer TE, Lents CA, Williams GL, Amstalden M. 2011a. Developmental changes in hypothalamic Kiss1 expression during activation of the pulsatile release of luteinising hormone in maturing ewe lambs. J Neuroendocrinol, 23:815-822.
Redmond JS, Macedo GG, Velez IC, Caraty A, Williams GL, Amstalden M. 2011b. Kisspeptin activates the hypothalamic–adenohypophyseal–gonadal axis in prepubertal ewe lambs. Reproduction, 141:541-548.
Roa J, Herbison AE. 2012. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology, 153:5587-5599.
Ryan KD, Foster DL. 1980. Neuroendocrine mechanisms involved in onset of puberty in the female: concepts derived from the lamb. Fed Proc, 39:2372-2377.
Sánchez-Garrido MA, Castellano JM, Ruiz-Pino F, Garcia-Galiano D, Manfredi-Lozano M, Leon S, Romero-Ruiz A, Diéguez C, Pinilla L, Tena-Sempere M. 2013. Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges. Endocrinology, 154:3387-3400.
Schams D, Schallenberger E, Gombe S, Karg H. 1981. Endocrine patterns associated with puberty in male and female cattle. J Reprod Fertil Suppl, 30:103-110.
Short R, Bellows R. 1971. Relationships among weight gains, age at puberty and reproductive performance in heifers. J Anim Sci, 32:127-131.
Simpson RB, Armstrong JD, Harvey RW, Miller DC, Heimer EP, Campbell RM. 1991. Effect of active immunization against growth hormone-releasing factor on growth and onset of puberty in beef heifers. J Anim Sci, 69:4914-4924.
Sisk CL, Foster DL. 2004. The neural basis of puberty and adolescence. Nat Neurosci, 7:1040-1047.
Sizonenko PC, Aubert ML. 1986. Neuroendocrine changes characteristic of sexual maturation. J Neural Transm Suppl, 21:159-181.
Smith JT. 2009. Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects. Peptides, 30:94-102.
Staigmiller R, Short R, Bellows R. 1979. Induction of LH surges with 17β estradiol in prepuberal beef heifers: an age dependent response. Theriogenology, 11:453-459.
Swanson L, Hafs H, Morrow D. 1972. Ovarian characteristics and serum LH, prolactin, progesterone and glucocorticoid from first estrus to breeding size in Holstein heifers. J Anim Sci, 34:284-293.
Terasawa E, Guerriero KA, Plant TM. 2013. Kisspeptin and puberty in mammals. Adv Exp Med Biol, 784:253-273.
Trevino LS, Wang Q, Walker CL. 2015. Phosphorylation of epigenetic "readers, writers and erasers": Implications for developmental reprogramming and the epigenetic basis for health and disease. Prog Biophys Mol Biol, 118:8-13.
Vulliémoz NR, Xiao E, Xia-Zhang L, Wardlaw SL, Ferin M. 2005. Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology, 146:784-789.
Zhang Y, O’Neil MM, Scarpa JO, Alves BRC, Welsh Jr. TH, Cardoso RC, Williams GL. 2017. Perinatal nutrition alters NPY neuronal projections to GnRH neurons and leptin receptor expression in the choroid plexus of prepubertal heifer. In: Proceedings of the 50th Annual Meeting of the Society for the Study of Reproduction, 2017, Washington, DC.Washington, DC: SSR. pp. 283 (Abstract).
Zieba D, Amstalden M, Williams G. 2005. Regulatory roles of leptin in reproduction and metabolism: a comparative review. Domest Anim Endocrinol, 29:166-185.