P. C. Owens

Placental control of fetal growth

The placenta exerts its effects on the growth of the fetus from the beginning of pregnancy via metabolic and endocrine mechanisms. To achieve this, the placenta exchanges a wide array of nutrients, endocrine signals, cytokines and growth factors with the mother and the fetus. These exchanges modulate or programme fetal growth and development. This review concentrates on the function and structure of the placenta in humans and in animals, and the effects of experimental perturbation of placental size and function on fetal growth. The consequences for fetal growth of varying the abundance of peptides or, by deleting genes, insulin-like growth factors or cytokines, are also described. Maternal nutritional and hormonal state from as early as the first few days after fertilization, can influence the growth rate of the placenta and the fetus and also the length of gestation. Influences on placental development and their consequences will clearly have an impact on the placental control of fetal growth. Variations in the maternal environment and consequent perturbation of the metabolic and endocrine environment of the placenta and fetus are implicated as being responsible for the associations between prenatal growth of the placenta and its fetus and the subsequent risk of adult disease. The next challenge will be to determine the dominant influences at each stage of fetal and placental growth.

Leptin alters the structural and functional characteristics of adipose tissue before birth

This study aimed to determine for the first time whether leptin can act to alter the structural and functional characteristics of adipose tissue before birth. Leptin (0.48 mg/kg/day) or saline was infused intravenously into fetal sheep for 4 days from either 136 or 137 days of gestation (term=147±3 days). Circulating leptin concentrations were increased approximately four‐ to fivefold by leptin infusion. Leptin infusion resulted in a significant increase in the proportion of smaller lipid locules present within fetal perirenal adipose tissue (PAT), and this was associated with a significant increase in the proportion of multilocular tissue and a significant decrease in the proportion and relative mass of unilocular tissue in fetal PAT. The relative abundance of leptin mRNA in fetal PAT was significantly lower in the leptin‐infused group, and there was a positive correlation between the relative abundance of leptin mRNA and the proportion of unilocular adipose tissue in fetal PAT. The amount of uncoupling protein 1 tended to be higher (P=0.06) in leptin‐infused compared with saline‐infused fetuses. This is the first demonstration that leptin can act to regulate the lipid storage characteristics, leptin synthetic capacity, and potential thermogenic functions of fat before birth.

Circulating leptin concentrations are positively related to leptin messenger RNA expression in the adipose tissue of fetal sheep in the pregnant ewe fed at or below maintenance energy requirements during late gestation

Abstract We have investigated the effects of maternal undernutrition during late gestation on maternal and fetal plasma concentrations of leptin and on leptin gene expression in fetal perirenal adipose tissue. Pregnant ewes were randomly assigned at 115 days of gestation (term = 147 ± 3 days [mean ± SEM]) to either a control group (n = 13) or an undernourished group (n = 16) that received ∼50% of the control diet until 144–147 days of gestation. Maternal plasma glucose, but not leptin, concentrations were lower in the undernourished ewes. A significant correlation was found, however, between mean maternal plasma leptin (y) and glucose (x) concentrations (y = 2.9x − 2.4; r = 0.51, P < 0.02) when the control and undernourished groups were combined. Fetal plasma glucose and insulin, but not fetal leptin, concentrations were lower in the undernourished ewes, and no correlation was found between mean fetal leptin concentrations and either mean fetal glucose or insulin concentrations. A positive relationship, however, was found between mean fetal (y) and maternal (x) plasma leptin concentrations (y = 0.18x + 0.45; r = 0.66, P < 0.003). No significant difference was found in the relative abundance of leptin mRNA in fetal perirenal fat between the undernourished (0.60 ± 0.09, n = 10) and control (0.70 ± 0.08, n = 10) groups. Fetal plasma concentrations of leptin (y) and leptin mRNA levels (x) in perirenal adipose tissue were significantly correlated (y = 1.5x ± 0.3; r = 0.69, P < 0.05). In summary, the capacity of leptin to act as a signal of moderate maternal undernutrition may be limited before birth in the sheep.

Food restriction alters pregnancy-associated changes in IGF and IGFBP in the guinea pig

The effect of moderate food restriction on pregnancy-associated changes in weight gain, body composition, and circulating insulin-like growth factors (IGF) I and II and IGF-binding proteins (IGFBP)-1 through-4 and their relationship was determined in the guinea pig. Pregnancy did not stimulate weight gain but reduced fat deposition in ad libitum-fed animals and increased weight gain and fat deposition in food-restricted animals relative to their respective virginal group. Pregnancy increased the abundance of circulating IGF-I regardless of food intake and increased that of IGF-II in food-restricted animals only. Pregnancy also increased circulating IGFBP-1 and -2 in ad libitum-fed and food-restricted animals and IGFBP-4 in ad libitum-fed animals. Multiple regression analysis showed that maternal weight gain was negatively associated with circulating IGF-II and IGFBP-2. Fetal weight was positively associated with maternal circulating IGF-II and negatively associated with maternal circulating IGFBP-1 and -2. Significant interactions indicate, however, that the role of IGF-II and IGFBP-1 on fetal growth is dependent on the nutritional status of the mother.The effect of moderate food restriction on pregnancy-associated changes in weight gain, body composition, and circulating insulin-like growth factors (IGF) I and II and IGF-binding proteins (IGFBP)-1 through -4 and their relationship was determined in the guinea pig. Pregnancy did not stimulate weight gain but reduced fat deposition in ad libitum-fed animals and increased weight gain and fat deposition in food-restricted animals relative to their respective virginal group. Pregnancy increased the abundance of circulating IGF-I regardless of food intake and increased that of IGF-II in food-restricted animals only. Pregnancy also increased circulating IGFBP-1 and -2 in ad libitum-fed and food-restricted animals and IGFBP-4 in ad libitum-fed animals. Multiple regression analysis showed that maternal weight gain was negatively associated with circulating IGF-II and IGFBP-2. Fetal weight was positively associated with maternal circulating IGF-II and negatively associated with maternal circulating IGFBP-1 and -2. Significant interactions indicate, however, that the role of IGF-II and IGFBP-1 on fetal growth is dependent on the nutritional status of the mother.

Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system

OBJECTIVES Leptin, an important hormonal regulator of body weight, has been shown to stimulate the sympathetic nervous system (SNS) in vitro although the physiological relevance remains unclear. Increased SNS activity has been implicated in the pathogenesis of insulin resistance and an increased cardiovascular risk. We have therefore investigated the relationship between leptin, insulin resistance and cardiac autonomic activity in healthy young adults. 130 healthy men and women age 20.9 years were studied. Insulin sensitivity was assessed using the IVGTT and minimal model with simultaneous measures of leptin. Cardiac autonomic activity was assessed using spectral analysis of heart rate variability. RESULTS Women showed significantly higher fasting leptin, heart rate and cardiac sympathetic activity, and lower insulin sensitivity. Men showed inverse correlations between insulin resistance and heart rate, and between insulin resistance and cardiac sympatho-vagal ratio. Women, in contrast, showed no SNS relationship with insulin resistance, but rather an inverse correlation between leptin and the sympatho-vagal ratio, suggesting that leptin in women is associated with SNS activity. The correlation remained significant after adjustment for BMI and waist-to-hip ratio (beta=-0.33 and p=0.008). CONCLUSION Insulin resistance and SNS activity appear to be linked, although the relationship showed marked gender differences, and the direction of causality was unclear from this cross-sectional study. Leptin appears to exert a greater effect on the SNS in women, possibly because of their greater fat mass.

Variable maternal nutrition and growth hormone treatment in the second quarter of pregnancy in pigs alter semitendinosus muscle in adolescent progeny

Maternal nutrition and growth hormone (GH) treatment during early- to mid-pregnancy can each alter the subsequent growth and differentiation of muscle in progeny. We have investigated the effects of varying maternal nutrition and maternal treatment with porcine (p) GH during the second quarter of pregnancy in gilts on semitendinosus muscle cross-sectional area and fibre composition of progeny, and relationships between maternal and progeny measures and progeny muscularity. Fifty-three Large White x Landrace gilts, pregnant to Large White x Duroc boars, were fed either 2.2 kg (about 35 % ad libitum intake) or 3.0 kg commercial ration (13.5 MJ digestible energy, 150 g crude protein (N x 6.25)/kg DM)/d and injected with 0, 4 or 8 mg pGH/d from day 25 to 50 of pregnancy, then all were fed 2.2 kg/d for the remainder of pregnancy. The higher maternal feed allowance from day 25 to 50 of pregnancy increased the densities of total and secondary fibres and the secondary:primary fibre ratio in semitendinosus muscles of their female progeny at 61 d of age postnatally. The densities of secondary and total muscle fibres in semitendinosus muscles of progeny were predicted by maternal weight before treatment and maternal plasma insulin-like growth factor-II during treatment. Maternal pGH treatment from day 25 to day 50 of pregnancy did not alter fibre densities, but increased the cross-sectional area of the semitendinosus muscle; this may be partially explained by increased maternal plasma glucose. Thus, maternal nutrition and pGH treatment during the second quarter of pregnancy in pigs independently alter muscle characteristics in progeny.

Effects of Leptin on Fetal Plasma Adrenocorticotropic Hormone and Cortisol Concentrations and the Timing of Parturition in the Sheep

Abstract We investigated whether leptin can suppress the prepartum activation of the fetal hypothalamus-pituitary-adrenal (HPA) axis and delay the timing of parturition in the sheep. First, we investigated the effects of a 4-day intravascular infusion of recombinant ovine leptin (n = 7) or saline (n = 6) on fetal plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations, starting from 136 days gestation (i.e., at the onset of the prepartum activation of the fetal HPA axis. The effects of a continuous intrafetal infusion of leptin (n = 7) or saline (n = 5) from 144 days gestation on fetal plasma ACTH and cortisol concentrations and the timing of delivery were also determined in a separate study. There was an increase in fetal plasma ACTH (P < 0.01) and cortisol (P < 0.001) concentrations when saline was infused between 136–137 and 140–141 days gestation. Plasma ACTH and cortisol concentrations did not rise, however, when leptin was infused during this period of gestation. When leptin was infused after 144 days gestation, there was no effect of a 4- to 5-fold increase in circulating leptin on fetal ACTH concentrations. In contrast, leptin infusion from 144 days gestation suppressed (P < 0.05) fetal plasma cortisol concentrations by around 40% between 90 and 42 h before delivery. There was no difference, however, in the length of gestation between the saline- and leptin-infused groups (saline infused, 150.2 ± 0.5 days; leptin infused, 149.8 ± 1.0 days). In saline-infused fetuses, there was a significant negative relationship between the plasma concentrations of cortisol (y) and leptin (x) between 138 and 146 days gestation (y = 81.4 − 7.7x, r = 0.38, P < 0.005). This study provides evidence for an endocrine negative feedback loop between leptin and the HPA axis in fetal life.

Gender differences in the insulin-like growth factor axis response to a glucose load.

Aims:  The insulin‐like growth factors (IGFs) are thought to contribute to glucose homeostasis. The aim of our study was to examine the response of the IGFs and their binding proteins to an intravenous load of glucose in a cohort of young men and women with normal glucose tolerance.

Insulin‐like growth factor I alters renal function and stimulates renin secretion in late gestation fetal sheep

1 While it is known that treatment with insulin‐like growth factor I (IGF‐I) stimulates growth of the fetal kidney, nothing is known about the short term or long term effects of IGF‐I on fetal renal function. To investigate the acute effects of IGF‐I on fetal renal function and on the activity of the fetal renin‐angiotensin system, studies were carried out in 12 chronically catheterized fetal sheep aged 120 ± 1 days, before and during a 4 h I.V. infusion of IGF‐I at 80 μg h−1. Seven control fetuses were infused over the same period with vehicle (0.1% bovine serum albumin in 0.15 M saline). 2 IGF‐I infusion increased plasma IGF‐I concentrations by about 80%. There was a small fall in arterial PO2 (P < 0.01), arterial PCO2 increased (P < 0.05), plasma lactate levels increased (P < 0.01) and arterial pH fell (P < 0.05). Fractional bicarbonate reabsorption increased and bicarbonate excretion decreased (P < 0.05). 3 Infusions of IGF‐I had no sustained effect on fetal arterial pressure. Glomerular filtration rate (GFR) did not change significantly during IGF‐I infusion, but renal blood flow (RBF) fell (P < 0.05). Therefore filtration fraction relative to control values increased (P < 0.05), suggesting that efferent arteriolar vasoconstriction had occurred. 4 IGF‐I infusion led to an antidiuresis (P < 0.01), a rise in urinary osmolality (P < 0.05) and a fall in free water clearance (P < 0.01). Since fetal PO2 fell, it is probable that these effects were mediated by arginine vasopressin. 5 The excretion rates of sodium, chloride and phosphate were all reduced by 4 h of infusion (P < 0.05), because their fractional reabsorption rates were all increased (sodium, P < 0.01; chloride, P < 0.01; and phosphate, P < 0.05). 6 Plasma renin concentration increased by 275 ± 52% during infusion of IGF‐I (P < 0.005). Plasma renin activity also increased (P < 0.005), while circulating angiotensinogen concentrations fell (P < 0.05). 7 In the adult, IGF‐I increases both RBF and GFR, enhances tubular reabsorption and stimulates the renin‐angiotensin system. In the fetus, however, it decreased RBF and had no effect on GFR, but was associated with enhanced tubular function and intense stimulation of renin secretion. Some of these effects of IGF‐I on fetal renal function may be involved in maturation of the kidney in preparation for life after birth.