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Approximately 5 million beef heifers enter the U.S. cow herd annually, and their lifetime productivity is largely dependent upon their ability to attain puberty and produce a calf by 24 mo of age. However, a considerable proportion of heifers within existing U.S. production systems fail to achieve these goals, particularly in southern regions where Bos indicusinfluenced cattle predominate. Consequently, managerial approaches are needed that employ nutritional programming of the reproductive neuroendocrine axis, while minimizing feeding costs and optimizing the consistent attainment of puberty by approximately 14 mo of age. Our previous research has clearly demonstrated that increased BW gain between 4 and 8 mo of age facilitates pubertal development by programming hypothalamic centers that regulate gonadotropin releasing-hormone (GnRH) secretion. Among the different metabolic hormones, leptin has a critical role in conveying nutritional information to the hypothalamus and controlling puberty. Two hypothalamic neuronal populations that express the orexigenic peptide neuropeptide Y (NPY) and the anorexigenic peptide alpha melanocyte-stimulating hormone (aMSH; a product of the POMC gene) are key components of afferent pathways that convey inhibitory (NPY) and excitatory (aMSH) inputs to GnRH and kisspeptin neurons. Our studies have demonstrated that short-term increases in dietary energy intake after early weaning at 4 mo of age result in epigenetic, structural, and functional modifications in these hypothalamic pathways to promote high-frequency, episodic release of GnRH and luteinizing hormone. However, integrating the foundational knowledge of metabolic imprinting of the brain for early puberty with issues related to lifetime performance is complex. One approach has been to employ a novel stair-step nutritional regimen involving alternating periods of dietary energy-restriction and re-feeding during juvenile development. This approach is designed to support early onset of puberty by imprinting functional alterations in the hypothalamus during key periods of brain development while optimizing other aspects of growth and performance. Finally, while several key processes of fetal brain development occur during late gestation, neither maternal undernutrition (BCS 3.0-3.5) nor maternal obesity (BCS 7.5-8.0) during the last two trimesters of gestation impacted the organization of hypothalamic neurocircuitries controlling GnRH/LH secretion or age at puberty in the heifer offspring. Collectively, these results indicate that the adult reproductive phenotype in Bos indicus-influenced females is resilient to significant degrees of nutritional stress imposed during prenatal development, particularly if early gestation (first trimester) is avoided. These findings are in contrast with reports in Bos taurus females in which late gestation nutritional extremes result in delayed puberty in heifer offspring, suggesting that potential genotype-specific differences may exist. Research support: USDA-NIFA-AFRI (2018-67015-27595 and 2021-67015-33676). [ABSTRACT FROM AUTHOR]

Using a previously established model for nutritional acceleration of puberty, beef heifers (n = 48; 1/2 Angus × 1/4 Hereford × 1/4 Brahman) were used in a replicated 2 × 2 factorial design to examine the effects of diet type (high forage [HF] vs. high concentrate [HC]) and rate of BW gain (low gain [LG], 0.45 kg/d, vs. high gain [HG], 0.91 kg/d) on key metabolic hormones and age at puberty. After weaning at 14 ± 1 wk of age, heifers were assigned randomly to be fed HC-HG, HC-LG, HF-HG, or HF-LG (n = 12/group) beginning at 4 mo of age for 14 wk. Heifers were then switched to a common growth diet until puberty. Average daily gain was greater (P < 0.04) during the dietary treatment phase in HG heifers (0.81 ± 0.06 kg/d) than in LG heifers (0.43 ± 0.06 kg/d), and there was no diet type × rate of gain interaction. Puberty was achieved at a younger age (54.5 ± 1.8 wk) in both HG groups than in LG groups (60.2 ± 1.9 wk; P < 0.04), but dietary energy source (HC vs. HF) did not influence this variable. Moreover, mean BW at puberty did not differ by diet type or rate of gain during the dietary treatment phase. Nonetheless, heifers fed HC-HG exhibited a striking increase (P < 0.0001) in serum leptin beginning at 26 ± 1 wk of age and remained elevated (P < 0.01) throughout the remainder of the experimental feeding phase compared to all other treatments. However, serum leptin in HC-HG dropped precipitously when heifers were switched to the common growth diet and did not differ from that of other groups thereafter. Overall mean concentrations of serum glucose were greater (P < 0.006) in HG heifers than in LG during the dietary treatment phase, with serum insulin also greater (P < 0.04) in HG than in LG only during weeks 20, 22, and 30. Mean serum IGF-1 was not affected by dietary type or rate of BW gain. We speculate that failure of the marked increase in serum leptin observed in HC-HG heifers during the dietary treatment phase to further accelerate puberty compared to HF-HG occurred because of its abrupt decline at the onset of the common growth phase, thus attenuating the temporal cue for activation of the reproductive neuroendocrine system. [ABSTRACT FROM AUTHOR]

Prenatal testosterone excess causes reproductive perturbations in sheep that recapitulate those seen in women with polycystic ovary syndrome (PCOS). Obesity has a significant role in the development and severity of the PCOS phenotype. Our objective was to investigate the effects of testosterone excess from gestational days (GD) 60-90 (unlike the GD 30-90 model, these animals are not virilized) and postnatal body weight (BW) gain on puberty in firstgeneration ewe lambs. Pregnant Suffolk ewes received testosterone propionate (T; 100 mg) or corn oil (C) i.m. twice weekly from GD 60-90 (term=147d). Ewe lambs were weaned ~3 mo of age. Control and T lambs were assigned to gain either 0.3 kg/d (C and T-maintenance) or 0.4 kg/d (T-overfed). Maintenance diet was designed to promote optimal growth without excess fat deposition. Overfed ration was designed to achieve a BW ~30% above that of maintenance. Progesterone concentrations were measured via radioimmunoassay in blood samples collected twice weekly from ewe lambs (n=15/group) during the first breeding season. Puberty was defined as when progesterone concentrations were < 0.5 ng/mL for four consecutive samples followed by three consecutive samples =0.5 ng/mL. Six animals (C, n=1; T-maintenance, n=3; T-overfed, n=2) did not attain puberty during the study and puberty was assigned as last day of sampling. Average daily gain was not different among treatments (C, 0.23±0.02kg; T-maintenance, 0.25±0.01kg; T-overfed, 0.27±0.02kg). Age at puberty did not differ between groups (C, 274.6±9.9d; T-maintenance, 270.0±11.3d; T-overfed, 266.0±10.2d). Similarly, BW at puberty did not differ across treatments (C, 50.44±2.2kg; T-maintenance, 52.5±2.4kg; T-overfed, 57.3±2.5kg). In conclusion, unlike GD 30-90 exposure which advanced puberty, GD 60-90 exposure did not affect age and BW at puberty in ewe lambs. Collectively, these studies suggest that GD 30-60 is a critical developmental window in which prenatal testosterone excess advances puberty in female sheep. Research support: NIH-NICHD (R01HD099096). [ABSTRACT FROM AUTHOR]

The timing of puberty and subsequent fertility in female mammals are dependent on the integration of metabolic signals by the hypothalamus. Pro-opiomelanocortin ( POMC) neurones in the arcuate nucleus ( ARC) comprise a critical metabolic-sensing pathway controlling the reproductive neuroendocrine axis. α-Melanocyte-stimulating hormone (αMSH), a product of the POMC gene, has excitatory effects on gonadotrophin-releasing hormone (Gn RH) neurones and fibres containing α MSH project to Gn RH and kisspeptin neurones. Because kisspeptin is a potent stimulator of Gn RH release, α MSH may also stimulate Gn RH secretion indirectly via kisspeptin neurones. In the present work, we report studies conducted in young female cattle (heifers) aiming to determine whether increased nutrient intake during the juvenile period (4-8 months of age), a strategy previously shown to advance puberty, alters POMC and KISS1 mRNA expression, as well as α MSH close contacts on Gn RH and kisspeptin neurones. In Experiment 1, POMC mRNA expression, detected by in situ hybridisation, was greater (P < 0.05) in the ARC in heifers that gained 1 kg/day of body weight (high-gain, HG; n = 6) compared to heifers that gained 0.5 kg/day (low-gain, LG; n = 5). The number of KISS1-expressing cells in the middle ARC was reduced (P < 0.05) in HG compared to LG heifers. In Experiment 2, double-immunofluorescence showed limited α MSH-positive close contacts on Gn RH neurones, and the magnitude of these inputs was not influenced by nutritional status. Conversely, a large number of kisspeptin-immunoreactive cells in the ARC were observed in close proximity to α MSH-containing varicosities. Furthermore, HG heifers (n = 5) exhibited a greater (P < 0.05) percentage of kisspeptin neurones in direct apposition to α MSH fibres and an increased (P < 0.05) number of α MSH close contacts per kisspeptin cell compared to LG heifers (n = 6). These results indicate that the POMC-kisspeptin pathway may be important in mediating the nutritional acceleration of puberty in heifers. [ABSTRACT FROM AUTHOR]

Feeding a high-concentrate diet to heifers during the juvenile period, resulting in increased body weight (BW) gain and adiposity, leads to early-onset puberty. In this study, we tested the hypothesis that the increase in GnRH/LH release during nutritional acceleration of puberty is accompanied by reciprocal changes in circulating leptin and central release of neuropeptide Y (NPY). The heifers were weaned at 3.5 months of age and fed to gain either 0.5 (Low-gain; LG) or 1.0 kg/day (High-gain; HG) for 30 weeks. A subgroup of heifers was fitted surgically with third ventricle guide cannulas and was subjected to intensive cerebrospinal fluid (CSF) and blood sampling at 8 and 9 months of age. Mean BW was greater in HG than in LG heifers at week 6 of the experiment and remained greater thereafter. Starting at 9 months of age, the percentage of pubertal HG heifers was greater than that of LG heifers, although a replicate effect was observed. During the 6-h period in which CSF and blood were collected simultaneously, all LH pulses coincided with or shortly followed a GnRH pulse. At 8 months of age, the frequency of LH pulses was greater in the HG than in the LG group. Beginning at 6 months of age, concentrations of leptin were greater in HG than in LG heifers. At 9 months of age, concentrations of NPY in the CSF were lesser in HG heifers. These observations indicate that increased BW gain during juvenile development accelerates puberty in heifers, coincident with reciprocal changes in circulating concentrations of leptin and hypothalamic NPY release. [ABSTRACT FROM AUTHOR]

Nutrition during the juvenile period has a major impact on timing reproductive maturity in heifers. Restricted growth delays puberty, whereas elevated B W gain advances the onset of puberty. The initiation of high-frequency episodic release of GnRH and, consequently, LH during the peripubertal period is crucial for maturation of the reproductive axis and establishment of normal estrous cycles. Nutritional signals are perceived by metabolic-sensing cells in the hypothalamus, which interact with estradiol-receptive neurons to regulate the secretory activity of GnRH neurons. The orexigenic peptide, neuropeptide Y (NPY), and the anorexigenic peptide derived from the proopiomelanocortin (POMC) gene, melanocyte-stimulating hormone α (αMSH), are believed to be major afferent pathways that transmit inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. The neuropeptide kisspeptin is considered a major stimulator of GnRH secretion and has been shown to mediate estradiol's effect on GnRH neuronal activity. Kisspeptin may also integrate the neuronal pathways mediating the metabolic and gonadal steroid hormone control of gonadotropin secretion. Recent studies in our laboratories indicate that functional and structural changes in the pathways involving NPY, POMC, and kisspeptin neurons occur in response to high rates of BW gain during the juvenile period in heifers. Changes include regulation of expression in NPY, POMC, and KISS I and plasticity in the neuronal projections to GnRH neurons and within the neuronal network comprising these cells. Moreover, an intricate pattern of differential gene expression in the arcuate nucleus of the hypothalamus occurs in response to feeding high concentrate diets that promote elevated BW gain. Genes involved include those controlling feeding intake and cell metabolism, neuronal growth and remodeling, and synaptic transmission. Characterizing the cellular pathways and molecular networks involved in the mechanisms that control the timing of pubertal onset will assist in improving existing strategies and facilitate the development of novel approaches to program puberty in heifers. These include the use of diets that elevate BW gain during strategic periods of prepubertal development. [ABSTRACT FROM AUTHOR]

It was hypothesized that metabolic programming of processes underlying puberty can be shifted temporally through the use of a stair-step compensatory growth model such that puberty is optimally timed to occur at 11 to 12 mo of age. Forty crossbred beef heifers were weaned at approximately 3.5 mo of age and, after a 2-wk acclimation period, were assigned randomly to 1 of 4 nutritional groups: 1) low control (LC), restricted feed intake of a forage-based diet to promote BW gain of 0.5 kg/d until 14 mo of age, 2) high control (HC), controlled feed intake of a high-concentrate diet to promote BW gain of 1 kg/d until 14 mo of age, 3) stair-step 1 (SS-1), ad libitum feed intake of a high-concentrate diet until 6.5 mo of age followed by restricted access to a high-forage diet to promote BW gain of 0.35 kg/d until 9 mo of age, ad libitum feed intake of a high-concentrate diet until 11.5 mo of age, and restricted intake of a highforage diet to promote BW gain of 0.35 kg/d until 14 mo of age, and 4) stair-step 2 (SS-2), reverse sequence of SS-1, beginning with restricted access to a high-forage diet. Body weight (every 2 wk) and circulating concentrations of leptin (monthly) were determined throughout the experiment. Concentrations of progesterone in blood samples collected twice weekly beginning at 8 mo of age were used to determine pubertal status. Body weight gain followed a pattern similar to that proposed in our experimental design. Circulating concentrations of leptin increased following distinct elevations in BW but decreased abruptly after feed intake restriction. Survival analysis indicated that the percentage of pubertal heifers in the LC group was lower (P < 0.05) than all other groups throughout the experiment. Although heifers in SS-1 were nutritionally restricted between 6.5 and 9 mo of age, the proportion pubertal by 12 mo of age did not differ (P = 0.36) from that of the HC group, with 80% and 70% pubertal in SS-1 and HC, respectively. In contrast, the proportion of heifers pubertal by 12 mo of age in the SS-2 group (40%) was lower (P < 0.05) than both HC and SS-1. However, by 14 mo of age, 90% of heifers in the SS-2 group had also attained puberty compared to only 40% of the LC group. In summary, these data provide evidence that changes in the nutritional and metabolic status during the early juvenile period can program the onset of puberty that occurs months later, allowing optimal timing of sexual maturation in replacement beef heifers. [ABSTRACT FROM AUTHOR]

• The GABAergic system exerts a predominantly inhibitory effect over reproduction in an adult cow. • During sexual maturation, the endocrine nervous system goes through changes. • In the prepubertal heifer, however, there is a period the GABAergic system somehow stimulates LH secretion. • The purpose of this stimulation needs to be investigated. This study was conducted to evaluate the luteinizing hormone (LH) secretion pattern after gamma-aminobutyric acid (GABA A) antagonist to determine the effects of the GABAergic system on LH secretion during reproductive maturation in pre-pubertal Nellore heifers. Nellore heifers (n = 10) were administered a picrotoxin injection of 0.18 mg/kg, i.v. Blood samples were collected every 15 min for 3 h at different developmental stages (8, 10, 14 and 17 mo of age). Plasma concentrations of LH were quantified using an RIA (sensitivity of 0.04 ng/mL and CV of 15 %). There was an interaction between treatment and age (P = 0.034). Picrotoxin-treated heifers had lesser (P ≤ 0.05) LH mean concentrations during a 3 h period at 10 and 17 mo of age compared to control heifers (P ≤ 0.05). Comparing the period before and after Picrotoxin injection in the same animals, there was a 33 % decrease in LH concentration at 8 mo of age (P = 0.0165). These results indicate the GABAergic system has a stimulatory function in inducing LH secretion in pre-pubertal Nellore heifers. These findings corroborate previous results that GABA increases GnRH/LH secretion in other species during the pre-pubertal period. [ABSTRACT FROM AUTHOR]

Approximately 5 million beef heifers enter the U.S. cow herd annually, and their lifetime productivity is heavily-dependent upon their ability to attain puberty and produce a calf by 24 mo of age. However, a significant proportion of heifers within existing U.S. production systems fail to achieve these objectives. Therefore, approaches are needed that facilitate nutritional programming of the reproductive neuroendocrine axis, while minimizing feeding costs and optimizing the consistent establishment of puberty by 14–15 mo of age. Accelerated rates of BW gain during early calfhood, particularly between 4 and 9 mo of age, facilitate pubertal development by programming hypothalamic centers that regulate GnRH secretion. Among the different metabolic hormones, leptin plays a critical role in conveying nutritional information to the brain and controlling pubertal progression. Two hypothalamic neuronal populations 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. Our studies have demonstrated that short-term increases in dietary energy intake during juvenile development result in epigenetic, structural, and functional modifications in these hypothalamic pathways to promote high-frequency, episodic release of GnRH/LH. However, integrating the foundational knowledge of metabolic imprinting of the brain for early puberty with issues related to lifetime performance is complex. One approach has been to employ a novel stair-step nutritional regimen involving alternating periods of dietary energy-restriction and re-feeding during juvenile development. This approach is designed to support early onset of puberty by imprinting genomic, biochemical and morphologic alterations in the hypothalamus during key periods of brain development while optimizing other aspects of growth and performance. Finally, our recent findings suggest that maternal nutrition during gestation can also induce neuroendocrine changes that are likely to persist long after puberty and influence reproductive performance throughout adulthood in cattle. [ABSTRACT FROM AUTHOR]

Links between nutrition and reproductive success in heifers have been demonstrated; however, achieving a high plane of nutrition is costly, and reproductive success remains uncertain, making heifer development expensive and risky. Development could be optimized by using nutritionally efficient strategies to manage plane of nutrition without negatively impacting reproduction. At an average age of 340 d, 85 heifers (209 kg) were randomly assigned to 1 of 3 treatments: high (H, n = 29), programmed to gain 0.92 kg/d, medium (M, n = 28), 0.45 kg/d and low (L, n = 28), 0 kg/d from d 0 to d 49 (P1). Heifers were then programmed to gain 1.36 kg/d from d 50 to d 90 (P2). Heifers were individually fed a common diet (42% cracked corn, 26% DDG, 26% alfalfa hay, and 6% molasses; 15% CP, 1.2 Mcal NEg/kg), using a calan-gate system, at varying levels to achieve programmed gain. Weekly BW and blood samples were collected. Digestibility was measured beginning d 41 (P1) and d 83 (P2). All heifers were synchronized beginning d 90 using the Bee Synch protocol for fixed-time AI on d 98, followed by 56 d exposure to bulls. Pregnancy rates were determined on d 154. Gain differed between treatments in P1 (P < 0.01); M- and L-fed heifers exceeded programmed gain by 0.16 and 0.37 kg/d respectively (H = 0.83, M = 0.61, L = 0.37 kg/d). No treatment effect on gain (P = 0.07) was observed in P2 (H = 1.31, M = 1.41, L = 1.37 kg/d). Digestion in P1 differed (P = 0.01) between heifers fed H (86.2% DM) and L (88.7% DM); no differences (P = 0.23) were observed in P2. Total ADG and input costs were different among treatments (P < 0.01). The cost of development on the M or L treatments was $10 or $23 less per heifer, respectively, than H ($95.35). Body weight and number pubertal on d 90 were not different (P ≥ 0.10). Pregnancy rates on d 154 were 79, 96, and 82% for H, M, and L respectively, but were not different (P = 0.21). Developing heifers on a lower plane of nutrition decreased cost per pregnancy without apparent negative effects on reproductive success. The M strategy was the optimal development program based on cost per pregnancy; however, additional research is needed to confirm the effects on reproductive outcomes. [ABSTRACT FROM AUTHOR]

According to the USDA National Agricultural Statistics Service, approximately 5.1 million beef heifers enter the U.S. cow herd annually (2013 -2017). With inventory averaging 30.5 million cows, this annual rate of entry represents nearly 17% of the total beef cow population. Lifetime productivity of these replacements is heavily- dependent upon their ability to reach sexual maturity, to conceive early during their first breeding season as yearlings, and to calve the first time by approximately 24 mo of age. Yet, a relatively small percentage of cattlemen nutritionally pre-program their heifers as herd replacements. Therefore, approaches are needed that facilitate nutritional imprinting of the reproductive neuroendocrine system during early calfhood, while minimizing feeding costs, promoting effective mammary gland development, optimizing the consistent establishment of estrous cycles by 12 to 14 mo of age, but avoiding a high incidence of precocious puberty. It is now clear that the interval between 4 and 9 mo of age (juvenile period) represents a critical period for metabolically programming the neuroendocrine axis to achieve early and targeted reproductive maturation. By focusing on nutritionally-mediated changes during this time, we have been able to characterize a number of structural and functional modifications in hypothalamic pathways that respond to high-concentrate/high gain diets. Alterations include modifications in morphological development of neuronal pathways that regulate the gonadotropin- releasing hormone (GnRH) pulse generator, changes in factors that facilitate the ability of leptin to cross the blood-brain barrier, alterations in gene expression in specific hypothalamic nuclei, and modifications in DNA methylation patterns. However, integrating the interdependent issues of metabolic imprinting of the brain for pre-programmed puberty with issues related to lifetime performance is complex. One approach has been to employ a modified version of a novel stair-step nutritional regimen involving alternating periods of dietary energy-restriction and re-feeding phases. This approach is designed to support early onset of puberty by imprinting genomic, biochemical and morphologic alterations in the hypothalamus while avoiding morphometric changes that can impair long-term productivity. To this end, we are also learning that nutritional epigenetic effects programmed during the postnatal period interact with those occurring prenatally. These interactions may induce structural and functional changes in hypothalamic neuronal pathways that persist long after pubertal maturation, are imprinted in the genome, and are apt to influence physiological performance and fertility throughout adulthood. [ABSTRACT FROM AUTHOR]