Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [a control diet or a hypercaloric (30% fat) diet]. Food intake in offspring from UN mothers was significantly elevated at an early postnatal age. It increased further with advancing age and was amplified by hypercaloric nutrition. UN offspring also showed elevated systolic blood pressure and markedly increased fasting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is now increasing evidence that alterations in the fetal environment have long-term consequences on metabolic and endocrine pathophysiology in adult life. This process has been termed "fetal programming," and we have shown that undernutrition of the mother during gestation leads to obesity, hypertension, hyperphagia, hyperinsulinemia, and hyperleptinemia in offspring. Using this model of maternal undernutrition throughout pregnancy, we investigated whether prenatal influences may lead to alterations in postnatal locomotor behavior, independent of postnatal nutrition. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (ad libitum group) or at 30% of ad libitum intake (undernourished group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [control or hypercaloric (30% fat)]. At ages of 35 days, 145 days, and 420 days, voluntary locomotor activity was assessed. At all ages studied, offspring from undernourished mothers were significantly less active than offspring born of normal birth weight for all parameters measured, independent of postnatal nutrition. Sedentary behavior in programmed offspring was exacerbated by postnatal hypercaloric nutrition. This work is the first to clearly separate prenatal from postnatal effects and shows that lifestyle choices themselves may have a prenatal origin. We have shown that predispositions to obesity, altered eating behavior, and sedentary activity are linked and occur independently of postnatal hypercaloric nutrition. Moreover, the prenatal influence may be permanent as offspring of undernourished mothers were still significantly less active compared with normal offspring at an advanced adult age, even in the presence of a healthy diet throughout postnatal life.

To study whether colostrum-borne growth factors are responsible for the rapid GI tissue growth in naturally suckled newborn animals, newborn unsuckled piglets were bottle-fed for 24 h with infant milk formula with or without addition of 2 μg/ml of recombinant human insulin-like growth factor-I (IGF-I) or insulin-like growth factor-II (IGF-II), a level which approximated that of porcine colostrum. The animals were then sacrificed for measurements of their digestive organ weights and contents of protein, RNA and DNA in the organs. The treatment with IGF-I or IGF-II failed to show any significant effect on the weight of the esophagus, stomach, small intestine, large intestine, mandibular glands, kidneys and the spleen, and had no effects on the contents of protein, RNA and DNA in the small intestinal mucosa, the liver and the spleen. However, piglets fed with infant formula containing IGF-I (n = 7) or IGF-II (n = 7) had a heavier pancreas (p < 0.05) compared to formula-fed controls (n = 7). The DNA content in the stomach and the pancreas were greater in animals treated with IGF-I or IGF-II than in controls. Using a cell labelling technique it was shown that both IGF-I and IGF-II stimulated cell proliferation in the small intestinal crypts. The results indicate that the substantial GI tissue growth reported in newborn animals is unlikely due to colostrum-borne IGF-I or IGF-II alone. On the other hand the study does suggest that oral IGF-I and IGF-II are capable of stimulating cell proliferation in the GI tract.

Fetal growth is normally constrained by maternal factors. This constraint is demonstrated by the usual inverse linear relationship between litter size and mean fetal weight. Cross-breeding experiments between mice of lines selected for high or low plasma insulin-like growth factor (IGF-I) levels suggested that elevations in maternal IGF-I abolish (P less than 0.01) this constraining effect and reverse the usual positive relationship between fetal and placental size in late gestation. This was confirmed by treating mice and rats throughout pregnancy with IGF-I. In normal mice and in low IGF-I line mice treatment with IGF-I (10 micrograms 8-hourly s.c. from day 1 to 19 of pregnancy) abolished maternal constraint whereas 0.9% (w/v) NaCl treatment did not. In Wistar rats osmotic pumps were implanted to deliver IGF-I (1 microgram/g body weight per day), bovine GH (bGH; 0.6 microgram/g body weight per day) or saline from day 1 to 19 of pregnancy. IGF-I therapy but not bGH or saline abolished (P less than 0.01) maternal constraint and altered (P less than 0.01) the relationship between placental and fetal weight. When high or low IGF-I line mice embroys were transplanted into a normal line of mice, the expected negative relationship (P less than 0.05) between mean fetal weight and litter size was maintained. However, the embryos of the high line were heavier (P less than 0.05) than those from the low line irrespective of fetal number, suggesting a direct role for IGF-I in the regulation of fetal growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Well-fed castrated male sheep (N= 3) and 125 days gestation pregnant ewes (N = 6) with chronically catheterized fetuses were fasted for 72 h. Insulin-like growth factor-binding protein (IGFBP) levels in fed and starved fetal, maternal and castrated male sheep plasma were measured using ligand blot analysis. IGFBPs in adult and fetal sheep differed in distribution both before and after 72 h starvation. IGFBP-3 was the major postnatal binding protein, while in the fetus IGFBP-2, IGFBP-3 and the circulating IGF type 2 receptor fragment each contributed 2 5–30% of total IGF binding capacity. After starvation, total IGF binding capacity and IGFBP-3 fell in plasma of maternal and castrated male sheep (p<0.05). Total IGF binding capacity rose with starvation in fetal plasma (p <0.05) as a result of an increase in IGFBP-1 (p< 0.01) and IGFBP-2 (p<0.05). The different nutritional control of the IGFBPs in the fetus and the adult may reflect ontogenic differences in the regulation and function of circulating IGFs and their binding proteins.

This chapter discusses the endocrine regulation of growth and metabolism in ruminants with special emphasis on hormonal control of somatotropic axis (growth hormone, growth hormone receptors, insulin-like growth factor I, insulin-like growth factor binding proteins, insulin-like growth factor receptors and somatomedin).

Objective: To assess associations between physical activity (PA), body composition, and biomarkers of metabolic health in Pacific and New Zealand European (NZE) women who are known to have different metabolic disease risks.Methods: Pacific (n = 142) or NZE (n = 162) women aged 18–45 years with a self-reported body mass index (BMI) of either 18.5–25.0 kg⋅m–2 or ≥30.0 kg⋅m–2 were recruited and subsequently stratified as either low (&lt;35%) or high (≥35%) BF%, with approximately half of each group in either category. Seven-day accelerometery was used to assess PA levels. Fasting blood was analysed for biomarkers of metabolic health, and whole body dual-energy X-ray absorptiometry (DXA) was used to estimate body composition.Results: Mean moderate-to-vigorous physical activity (MVPA; min⋅day–1) levels differed between BF% (p &lt; 0.05) and ethnic (p &lt; 0.05) groups: Pacific high- 19.1 (SD 15.2) and low-BF% 26.3 (SD 15.6) and NZE high- 30.5 (SD 19.1) and low-BF% 39.1 (SD 18.4). On average Pacific women in the low-BF% group engaged in significantly less total PA when compared to NZE women in the low-BF% group (133 cpm); no ethnic difference in mean total PA (cpm) between high-BF% groups were observed: Pacific high- 607 (SD 185) and low-BF% 598 (SD 168) and NZE high- 674 (SD 210) and low-BF% 731 (SD 179). Multiple linear regression analysis controlling for age and deprivation showed a significant inverse association between increasing total PA and fasting plasma insulin among Pacific women; every 100 cpm increase in total PA was associated with a 6% lower fasting plasma insulin; no significant association was observed in NZE women. For both Pacific and NZE women, there was an 8% reduction in fasting plasma insulin for every 10-min increase in MVPA (p ≤ 0.05).Conclusion: Increases in total PA and MVPA are associated with lower fasting plasma insulin, thus indicating a reduction in metabolic disease risk. Importantly, compared to NZE, the impact of increased total PA on fasting insulin may be greater in Pacific women. Considering Pacific women are a high metabolic disease risk population, these pre-clinical responses to PA may be important in this population; indicating promotion of PA in Pacific women should remain a priority.

Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women. Acta Endocrinol 1993:129:427-35. ISSN 0001-5598 We performed a double-blind randomized placebo-controlled trial of recombinant human growth hormone (hGH) in normally lactating women (N = 8 per group) to investgate the endocrine mode of action of the galactopoietic effect of this hormone. Insulin-like growth factors I (IGF-I) and II (IGF-II) and their binding proteins (IGFBP-1, IGFBP-2 and IGFBP-3) were measured by radioimmunoassay in plasma and milk samples collected throughout the study. All assays were validated for human plasma and milk. Human GH treatment (0.1 IU\m=.\kg\m=-\1body wt\m=.\day\m=-\1 for 7 days) increased plasma concentrations of IGF-I from 22.1 \m=+-\1.3nmol/l (mean\m=+-\sem) to 59.7\m=+-\2.5nmol/l (p<0.01). At the end of the study the increase in plasma IGF-I correlated significantly with the increase in milk volume (r=0.67, p<0.005, N=16). The IGF-I levels were considerably lower in milk, with 0.14\m=+-\0.03 nmol/l before and 0.31 \m=+-\0.04nmol/l after hGH treatment. The increase in milk IGF-I levels (134.0\m=+-\14.5%)with hGH treatment was significant (p<0.01) and plasma and milk IGF-I concentrations correlated significantly when considering all samples of the study (r=0.45, p<0.001, N= 56). The concentrations of IGF-II were not changed significantly with hGH treatment in plasma (52.5 \m=+-\2.5 nmol/l before and 42.6 \m=+-\3.9nmol/l after treatment) or milk (2.1 \m=+-\0.29 nmol/l before and 2.3\m=+-\0.49nmol/l after hGH treatment). The IGFBP-1 levels were not changed with hGH treatment in plasma (approximately 1.3 nmol/l) or milk (approximately 0.2 nmol/l). Although IGFBP-2 concentrations in plasma were reduced significantly (p<0.05) after hGH treatment (11.1\m=+-\1.5 before and 8.4\m=+-\0.9nmol/l after hGH treatment), milk IGFBP-2 levels did not respond to hGH treatment. Milk levels were markedly higher (sevenfold) in comparison to plasma levels. Plasma IGFBP-3 showed a delayed and smaller rise with hGH treatment in comparison to the rise observed in IGF-I. However, at the end of the study the response (38.6\m=+-\4.9%) to hGH was significant (p<0.01) and a significant correlation was observed also between the increase in IGFBP-3 and the increase in milk volume (r=0.55, p =0.03, N=16). Plasma IGF-I and IGFBP-3 concentrations correlated significantly when considering all samples of the study (r=0.61, p<0.001, N=63). Milk IGFBP-3 levels were approximately 100-fold lower in comparison to plasma levels and did not correlate with any other measurements. Our data show that hGH-stimulated galactopoiesis in normally lactating women is mediated by significant elevations of plasma and milk IGF-I and plasma IGFBP-3. While IGF-I may be a principal mediator of the galactopoietic effect of hGH, we cannot simply attribute the action of hGH solely to a systemic rise in IGF-I. The increase in plasma IGFBP-3 with hGH treatment suggests that IGFBP-3 could facilit...