Dairy cows suffer from an intense energy deficit at parturition due to the onset of copious milk synthesis and depressed appetite. Despite this deficit, maternal metabolism is almost completely devoted to the support of mammary metabolism. Evidence from rodents suggests that, during periods of nutritional insufficiency, a reduction in plasma leptin serves to co-ordinate energy metabolism. As an initial step to determine if leptin plays this role in periparturient dairy cows, changes in the plasma concentration of leptin were measured during the period from 35 days before to 56 days after parturition. The plasma concentration of leptin was reduced by 50% after parturition and remained depressed during lactation despite a gradual improvement in energy balance; corresponding changes occurred in the abundance of leptin mRNA in white adipose tissue. To determine whether negative energy balance caused this reduction in circulating leptin, cows were either milked or not milked after parturition. Absence of milk removal eliminated the energy deficit of early lactation, and doubled the plasma concentration of leptin. The plasma concentration of leptin was positively correlated with plasma concentrations of insulin and glucose, and negatively correlated with plasma concentrations of growth hormone and non-esterified fatty acids. In conclusion, the energy deficit of periparturient cows causes a sustained reduction in plasma leptin. This reduction could benefit early lactating dairy cows by promoting a faster increase in feed intake and by diverting energy from non-vital functions such as reproduction.
Studies of leptin in large domestic ruminants have been limited to measurements of gene expression because methods to measure circulating levels are not available. To develop a bovine leptin radioimmunoassay, we produced recombinant bovine leptin and used it to immunize rabbits, and to prepare bovine leptin tracer and standards. A single antiserum with sufficient affinity and titer was identified. Using this antiserum, logit-transformed binding of 125 I-labeled bovine leptin was linearly related (R 2 = 0·99) to the log of added bovine or ovine leptin between 0·1 to 2·0 ng. Serial dilution of bovine and ovine plasma, chicken serum and bovine milk gave displacement curves that were parallel to those of bovine or ovine leptin. Recoveries of external addition of bovine leptin in ewe and cow plasma ranged between 94 and 104%. Plasma leptin concentration measured by this assay was directly related to the plane of nutrition in growing calves and lambs. At 11-14 weeks of age, ewe lambs had a higher circulating leptin concentration than ram lambs. Finally, plasma leptin concentration was linearly related to the fat content of the empty carcass in growing cattle and to body condition score in lactating dairy cows. We conclude that circulating leptin in sheep and cattle is increased by fatness and plane of nutrition, consistent with results in humans and rodents. This assay provides an important tool to investigate mechanisms that regulate plasma leptin in cattle and sheep.
Prior to puberty, elevated nutrient intake has been shown to negatively affect prepubertal mammary development in the heifer. The objective of this study was to evaluate the effects of increased nutrient intake on mammary development in Holstein heifers at multiple body weights from birth through puberty. Specifically, this study evaluated the effects of nutrient intake and body weight at harvest on 1) total weight and DNA content of the parenchyma (PAR) and mammary fat pad (MFP) and 2) PAR and MFP composition. Starting at 45 kg of body weight, heifers (n = 78) were assigned to either a restricted (R) or elevated (E) level of nutrient intake supporting 650 (R) or 950 (E) g/d of body weight gain. Heifers were harvested at 50-kg increments from 100 to 350 kg of body weight. Mammary fat pad weight and DNA content were greater in E- than in R-heifers. Additionally, E-heifers had a greater fraction of lipids and a smaller fraction of protein in their MFP than did R-heifers. Parenchyma weight and DNA were lower in E- than in R-heifers; however, when analyzed with age as a covariate term, treatment was no longer a significant term in the model. Level of nutrient intake had no effect on the lipid, protein, or hydroxyproline composition of the PAR. Collectively, these data demonstrate that PAR is refractory to the level of nutrient intake whereas MFP is not. Furthermore, the covariate analysis demonstrated that age at harvest, not the level of nutrient intake, was the single greatest determinant of total PAR DNA content.
It is well documented that elevated nutrient intake prior to puberty reduces prepubertal mammary development in the bovine. The companion paper demonstrated that age at harvest is a primary determinant of parenchymal (PAR) mass and that any effects of elevated energy intake on mechanisms regulating mammary development are dwarfed by this effect of time. Therefore, it is hypothesized that while causing a decrease in prepubertal PAR mass, elevated nutrient intake will have no effect on growth characteristics of the mammary gland. The objectives of this experiment were to evaluate the effects of increased nutrient intake from early in life on 1) mammary epithelial cell proliferation, 2) mammary PAR DNA accretion rates, and 3) the dynamics of prepubertal allometric PAR growth. Holstein heifers (n = 78) were fed from 45 kg of body weight either elevated (E) or restricted (R) levels of nutrients to support 950 (E) or 650 (R) g/d of body weight gain. Six heifers per treatment were harvested at 50-kg increments from 100 to 350 kg of body weight. Heifers on the E plane of nutrition had higher plasma leptin and less PAR DNA than their body weight-matched R-intake cohorts. Despite this reduction in PAR DNA, treatment did not negatively influence mammary epithelial cell proliferation or the PAR DNA accretion rate. Dynamics of allometric and isometric mammary growth were also unaffected by the level of nutrient intake, as was exit from allometric growth. This work represents the first demonstrating that the level of nutrient intake and the concomitant increase in plasma leptin have no measurable influence on 1) the rate of PAR DNA accretion, 2) mammary epithelial cell proliferation, or 3) total PAR mass and, by default, the local or systemic controls that coordinate these processes.
It is well established that estrogen is required for mammary epithelial cell proliferation and ductal development in the growing animal, and that lobuloalveolar development during gestation is dependent on progesterone. The effects of these steroid hormones on gene expression in the mammary gland are mediated primarily by their respective nuclear hormone receptors, which function as hormone-bound transcription factors. To gain insight into how estrogen and progesterone regulate mammary gland growth and function in cattle, we and others have characterized the expression patterns of their cognate nuclear hormone receptors in the bovine mammary gland throughout development, pregnancy, and lactation. This work has identified a lack of expression of estrogen receptor beta and a greater abundance of progesterone receptor during lactation in the bovine mammary gland, compared with the rodent gland. We speculate that interactions among the estrogen receptor isoforms that regulate progesterone receptor expression may contribute to these species differences. Further, demonstrated expression of substantial quantities of estrogen receptor within the prepubertal bovine mammary fat pad, along with coordinated insulin-like growth factor-I expression, suggests that this tissue may stimulate parenchymal growth via an estrogen-responsive paracrine mechanism. In addition, the recent availability of bovine genomic sequence information and microarray technologies has permitted the study of global gene expression in the mammary gland in response to the steroid environment. We have identified more than 100 estrogen-responsive genes, of which the majority are novel estrogen gene targets. Estrogen-induced changes in gene expression were consistent with increased mammary epithelial cell proliferation, increased extracellular matrix turnover in parenchyma, and increased extracellular matrix deposition in the fat pad. A comparison of estrogen-responsive genes in the mammary glands of humans, mice, and cattle suggests considerable variation among species, as well as potential differences in regulatory elements in common estrogen receptor gene targets. Continuing studies using advanced molecular techniques should assist in elucidating the complex regulation of mammary function at the transcript level.
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