The insulin-like growth factors-I and -II (IGFs) are involved in a wide array of cellular processes such as proliferation, prevention of apoptosis, and differentiation. Most of these effects are mediated by the IGF-I receptor, although at higher IGF concentrations the insulin receptor can also be activated. As the expression of both the IGFs and their receptors is widespread, IGFs are thought to have autocrine/paracrine modes of actions also, particularly during foetal life. The endocrine component of the IGF system is recognised to be important after birth, with IGF-I mediating many of the effects of growth hormone (GH), and linking anabolic processes to nutrient availability. Consideration of ligands and receptors, however, is insufficient to provide a complete understanding of the biology of IGF. This is because IGFs are found in binary complexes of 40-50 kDa with members of a family of IGF-binding proteins (IGFBPs-1 to -6) in all biological fluids. In addition, in postnatal serum, most IGFs are sequestered into ternary complexes of 150 kDa consisting of one molecule each of IGF, IGFBP-3 or IGFBP-5, and acid-labile subunit (ALS). Despite evidence that ALS plays an important role in the biology of circulating IGFs, it has received only limited attention relative to the other components of the IGF system. This review provides an overview on the current knowledge of ALS protein and gene structure, organisation and regulation by hormones, and insights from novel animal models such as the ALS knockout mice.
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YR Boisclair, RP Rhoads, I Ueki, J Wang, and GT Ooi
RA Ehrhardt, RM Slepetis, J Siegal-Willott, ME Van Amburgh, AW Bell, and YR Boisclair
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.
SS Block, WR Butler, RA Ehrhardt, AW Bell, ME Van Amburgh, and YR Boisclair
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 approximately 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.
J Wook Kim, RP Rhoads, SS Block, TR Overton, SJ Frank, and YR Boisclair
At parturition, dairy cows experience a 70% reduction in plasma IGF-I. This reduction coincides with decreased abundance of GHR1A, the liver-specific transcript of the growth hormone receptor (GHR) gene, suggesting impaired growth hormone-dependent synthesis of IGF-I. It is not immediately obvious that the periparturient reduction in GHR1A is sufficient to reduce hepatic GHR abundance. This is because approximately 50% of total GHR mRNA abundance in prepartum liver is accounted for by ubiquitously expressed transcripts which remain collectively unchanged at parturition. In addition, the possibility that parturition alters GHR expression in other growth hormone target tissue has not been examined. To address these questions, we measured GHR gene expression and GHR protein in liver and skeletal muscle of four dairy cows on days -35,+3 and+56 (relative to parturition on day 0). Hepatic GHR abundance and GHR1A transcripts were lower on day+3 than on day -35 and returned to late pregnancy value by day+56. Additional studies in two other groups of cows indicated that the hepatic levels of the GHR protein recovered substantially within 10 days after parturition. These changes occurred without variation in the abundance of HNF4, a liver-enriched transcription factor activating the promoter responsible for GHR1A synthesis. In contrast to liver, levels of GHR gene expression and GHR protein were identical on days -35,+3 and+56 in skeletal muscle. These data suggest a role for the GHR in regulating tissue-specific changes in growth hormone responsiveness in periparturient dairy cows.