S. C. Hodgkinson

The Endocrine Role of Insulin-Like Growth Factor I

The insulin-like growth factors (IGFs) were first defined as endocrine mediators of the action of growth hormone (GH). It was postulated that GH acted on the liver to release IGF-I, which then promoted growth by causing cell replication in musculoskeletal tissues. This hypothesis was the primary model for GH action for over 20 years. In the past decade, however, it has been extensively revised and its basic validity questioned (1-3). A number of observations led to the theory that the primary actions of IGF-I occurred via paracrine or autocrine mechanisms close to its site of production, and that systemically circulating IGF-I had little or no biological significance. Various lines of evidence emerged in favour of a primary paracrine action for IGF-I. 0 Immunoreactive IGF-I and polyadenylated mRNA coding for IGF-I could be extracted from many tissues, suggesting local production (4, 5). 0 It was recognized that GH had direct actions on tissues other than the liver and that GH receptors were widely distributed. Following the classical study by Isaksson el al. (6), showing direct actions of GH on the gcowth plate, GH receptors were demonstrated in the epiphyseal growth plate (7), where GH was shown to stimulate local IGF-I production (9). It was postulated that GH acted on the growth plate by causing proliferation of prechondrocytes, which then underwent clonal expansion in response to autocrine IGF-I production ( 2 ) . 0 Data from a wide variety of studies supported the general impression that GH was more effective than IGF-I in promoting longitudinal bone growth in GH-deficient animals, when both were given systemically, thus suggesting that the local action of GH on the growth plate was more important than any systemic action of IGF-I (9, 10). Similarly, experiments were presented in which GH caused growth without correlated plasma IGF-I responses (11). 0 The elucidation of the IGF-I binding proteins (BPs) led to the suggestion that their main function was to prevent systemic IGF-I from leaving the circulation. Perhaps by analogy to the accepted model of steroid hormone action, it was suggested that the low or undetectable amounts of unbound IGF-I present in the circulation constituted evidence against any endocrine role, and it was postulated that circulating IGF-I was an elimination form. As shall be discussed, none of these arguments exclude a classic endocrine role for IGF-I. Nevertheless, research in recent years has focused on the autocrine/paracrine role of IGF-I, rather than on its possible endocrine role. This paper will review recent evidence to suggest that IGF-I does have a biological function in the circulation, in addition to having local paracrine actions. This is important, as most of the potential therapeutic uses of IGF-I will depend primarily on such endocrine actions.

Supplementation with a mixture of complex lipids derived from milk to growing rats results in improvements in parameters related to growth and cognition

Alterations in nutritional factors during early development can exert long-term effects on growth, neural function, and associated behaviors. The lipid component of milk provides a critical nutritional source for generating both energy and essential nutrients for the growth of the newborn. The present study, therefore, investigated the hypothesis that nutritional supplementation with a complex milk lipid (CML) preparation, derived from the milk fat globule membrane rich in phospholipids and gangliosides from young rats, has beneficial effects on learning behavior and postnatal growth and development. Male Wistar rat offspring from normal pregnancies were treated from neonatal day 10 until postnatal day 80 with either vehicle or CML at a dose of 0.2% (low) and 1.0% (high) based on total food intake (n = 16 per group). Neonatal dosing was via daily oral gavage, while postweaning dosing was via gel supplementation to a standard chow diet. Animals underwent behavioral tasks related to spatial memory, learning, and cognitive function. Complex milk lipid supplementation significantly increased linear growth rate (P < .05), and the improved growth trajectory was not related to changes in body composition as quantified by dual-energy x-ray absorptiometry scanning or altered plasma lipid profiles. Moreover, this effect was not dose dependent and not attributable to the contribution to total energy intake of the CML composition. Supplementation of the CML to growing rats resulted in statistically significant improvements in parameters related to novelty recognition (P < .02) and spatial memory (P < .05) using standard behavioral techniques, but operant testing showed no significant differences between treatment groups. Supplementation with a CML containing gangliosides had positive growth and learning behavioral effects in young normal growing rats.

Maternal supplementation with a complex milk lipid mixture during pregnancy and lactation alters neonatal brain lipid composition but lacks effect on cognitive function in rats.

Complex milk lipids (CMLs) provide a critical nutritional source for generating both energy and essential nutrients for the growth of the newborn. The present study investigated nutritional supplementation with a CML containing gangliosides and phospholipids in pregnant and lactating rats on learning behavior and postnatal growth in male offspring. Wistar female rats were supplemented during pregnancy and lactation with either control or CML to provide gangliosides at a dose of 0.01% (low) and 0.05% (high) based on total food intake. The CML-supplemented dams showed no differences in comparison to controls regarding growth, food intake, and litter characteristics. There were significant differences in brain composition in male offspring at postnatal day 2 (P2) with higher concentrations of gangliosides (high dose, P < .05) and lower concentrations of phospholipids (low and high dose, P < .05) in the CML-supplemented groups. The distribution of individual ganglioside species was not significantly different between treatment groups. Brain weight at P2 was also significantly higher in the CML groups. Differences in the brain composition and weight were not significant by weaning (P21). As adults (P80), adiposity was reduced in the low CML-supplemented group compared to controls. No significant differences were detected between any of the treatment groups in any of the behavioral tasks (water maze, object recognition, and operant learning). These data suggest that maternal supplementation with a CML during pregnancy and lactation is safe and has a significant early impact on brain weight and ganglioside and phospholipid content in offspring but did not alter long-term behavioral function using standard behavioral techniques.

NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat

In rats, cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a diketopiperazine, is neuroprotective after ischemic brain injury and also improves motor function in a rat model of Parkinsons disease. Given nootropic actions of diketopiperazines, we investigated the effects of and potential role for acetylcholine neurotransmission in NNZ-2591 on spatial memory after scopolamine-induced amnesia in rats. Adult male Wistar rats were assigned to four groups: saline/water; saline/NNZ-2591; scopolamine/water and scopolamine/NNZ-2591. Morris Water Maze (MWM) tasks were used to determine spatial learning and memory. Thirty minutes prior to each of four daily acquisition trials, rats were intraperitoneally injected with either scopolamine (0.5 mg/kg) or saline. Either NNZ-2591 (30 mg/kg) or water was administered orally (gavages) 10 min after the injection. Immediately after completion of the day 4 acquisition trial a spatial probe trial was performed. The brains were then collected for immunohistochemical analysis. Scopolamine impaired spatial learning and memory compared to saline treated group, particularly in the day 1 acquisition trial. NNZ-2591 did not reverse this deficit, however it significantly improved memory retention by showing more time spent in the correct quadrant. NNZ-2591 also counteracted the scopolamine-induced up-regulation of choline-acetyltransferase positive neurons in the striatum and similarly counteracted the increased synaptophysin density in the hippocampus. Furthermore, a scopolamine-independent antagonistic effect on muscarinic M2 acetylcholine receptors was found after NNZ-2591 treatment, supporting its modulation of acetylcholine neurotransmission. The data suggest that NNZ-2591 prevents scopolamine-induced acute impairment in memory and modulation of acetylcholine neurotransmission may be the mode of action underlying the memory improvement.

Effects of bovine somatotrophin on insulin-like growth factor-I, insulin, growth and carcass composition of lambs

The effect of different doses (0.0, 0.05, 0.15, 0.25 and 0.55 mg/kg/day) of recombinant bovine somatotrophin (BST) on plasma concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-I), insulin, plasma metabolites, growth and body composition were studied by treating five groups (n=8/group) of pasture-fed wether lambs (6–7 months of age) with daily subcutaneous injections of saline or BST for 62 days. Lambs (n=4/group) were bled from 09.00 to 06.00 h on day 59–60. Plasma GH concentrations rose to a maximum (914 ± 184 ng/ml) by 2 h following administration of an injection of BST (0.55 mg/kg/day) and after 24 h had decreased to 30–40 ng/ml GH in 0.25 and 0.55 mg/kg/day BST groups or to control concentrations in 0.05 and 0.15 mg/kg/day BST groups. Long-term BST treatment increased (P<0.001) plasma concentrations of IGF-I, insulin, non-esterified fatty acids and glucose. Body and carcass weights were also increased (P<0.05) by BST and there was a major (P<0.01) effect on body and carcass components, particularly fat depot weights. The results from this study suggest that the growth/compositional responses to BST treatment are related to increases in plasma IGF-I and insulin concentrations.

Comparison of the effects of recombinant ovine, bovine and porcine growth hormones on growth, efficiency and carcass characteristics in lambs

The effects of daily administration of recombinantly derived ovine growth hormone (oGH) on live weight gain, food conversion and carcass composition were studied in young lambs and the effects compared with those obtained by administration of porcine (p) or bovine (b) growth hormone (GH). Forty-eight female Coopworth lambs were reared on a complete pelleted diet and, at 16 weeks of age, were allocated to one of four treatment groups. Each lamb received a daily s.c. injection of either oGH, bGH, pGH (0.1 mg/kg bodyweight) or vehicle. Food intake was measured daily and liveweights were measured weekly for 4 weeks after which the lambs were slaughtered for measurement of carcass characteristics and organ weights. Both the oGH-and bGH-treated lambs grew faster than controls (P<0.01) and had heavier carcasses at slaughter. No significant difference from control animals could be found for any treatment group with respect to food intake or relative appetite, but the oGH- and bGH-treated lambs had a better food conversion efficiency (P<0.001). With the exception of reduced carcass fatness (P<0.01) for bGH-treated lambs, no major effect of GH treatment could be detected on wool growth or carcass characteristics. Both oGH and bGH treatment resulted in increased plasma concentrations of IGF-1 (P<0.01) compared with controls and pGH-treated lambs. All GH-treated lambs produced antibodies against the GH with which they were injected.