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Increased maternal nutrition alters development of the appetite-regulating network in the brain

B. S. Muhlhausler^*, C. L. Adam, P. A. Findlay, J. A. Duffield^* and I. C. McMillen^*,1

^* Research Centre for the Early Origins of Adult Health, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; and

Obesity and Metabolic Division, Rowett Research Institute, Bucksburn, Aberdeen, Scotland, UK

¹Correspondence: Sansom Research Institute, University of South Australia, SA 5005, Australia. E-mail: caroline.mcmillen{at}unisa.edu.au

SPECIFIC AIM

Individuals exposed to an increased nutrient supply before birth have a high risk of becoming obese as children and adults. It has been proposed that exposure of the fetus to high maternal nutrient intake may result in permanent changes within the central appetite regulatory network, which predisposes these individuals to an increased deposition of adipose tissue in later life. There have been no studies, however, on the impact of an increase in prenatal nutrient supply on the development of the hypothalamic appetite regulatory system in a species, such as the sheep, in which this system develops before birth, as in the human. The aim of the present study was to test whether an increase in maternal nutrition during late gestation results in changes in the relationship between the expression of the orexigenic and anorexigenic hypothalamic neuropeptides and signals of current nutritional status in early postnatal life.

PRINCIPAL FINDINGS

1. Maternal overnutrition in late pregnancy increases lamb milk intake and subcutaneous (s.c.) fat mass
Increasing maternal nutrition by 40% in late gestation significantly increased lamb milk intake during the first 3 wk of postnatal life. Plasma concentrations of glucose (Glc) were also higher in lambs of well-fed ewes during the first 4 postnatal weeks (6.3±0.01 mmol/l vs. 5.8±0.02 mmol/l, P<0.05). The relative mass of s.c. adipose tissue at 30 days was greater in lambs of well-fed ewes when compared to controls (40.0±3.9 g/kg vs. 22.1±3.5 g/kg, P<0.05), and this increase was directly related to the higher circulating Glc concentrations present in these lambs in early life (fat mass=18.4 Glc – 79.8, r²=0.50, P<0.01). These results are consistent with human clinical data, which show that adiposity is increased in infants of diabetic or Glc-intolerant mothers and suggest that the effects of increased maternal nutrition during pregnancy on fat deposition in the offspring may be mediated through an increase in plasma Glc concentrations during the early postnatal period.

2. Maternal overnutrition and expression of the anorexigenic precursor, propiomelanocortin (POMC), and orexigenic neuropeptides, NPY, and AGRP in the lamb hypothalamus
The expression of POMC mRNA in the arcuate nucleus of the hypothalamus was significantly higher in lambs from well-fed ewes when compared to controls (Fig. 1 ). Recent studies in the mouse have shown that there are subpopulations of POMC-containing neurons in the hypothalamus, which are directly Glc-responsive, and it is, therefore, possible that the effect of increased maternal nutrition on POMC expression may have been a direct consequence of the higher circulating Glc concentrations in the lambs of the well-fed ewes. There was no difference in the hypothalamic expression of either NPY or AGRP mRNA between the control and well-fed groups; however, we found that NPY and AGRP mRNA expressions were each inversely related to lamb adiposity (total fat: NPY=–0.005 total fat+0.89; r²=0.28, P<0.05, n=16; AGRP=–0.007 total fat+0.95; r²=0.39, P<0.01, n=17). These findings suggest that signals of current fat stores, rather than nutrition during the prenatal period, may be the more important determinants of NPY and AGRP expression in early postnatal life.

View larger version (34K): [in this window] [in a new window]   Figure 1. The distribution of POMC mRNA in the hypothalamus at 30 days in Control (A) and Well-Fed (B) lambs. POMC gene expression was significantly higher (P<0.05) in the well-fed group compared to controls (C). There was no difference in hypothalamic NPY expression between the control and well-fed groups (D). *Significant effect of maternal nutritional treatment on POMC gene expression. Scale bar = 5 µM.

3. Maternal overnutrition and expression of the anorexigenic neuropeptide, cocaine amphetamine-related transcript (CART) and the leptin receptor (OBRb) in the lamb hypothalamus
We have found that CART mRNA expression in the arcuate nucleus of the lamb hypothalamus was positively correlated with both relative adiposity and plasma leptin concentrations in control lambs and that these relationships were not present in the lambs of well-fed ewes (Figure 2 B). Furthermore, in lambs of well-fed ewes, but not their control counterparts, there was a significant inverse relationship between the hypothalamic expression of OBRb mRNA in the arcuate nucleus and total relative fat mass at 30 days (Figure 2A ). Thus, in lambs of well-fed ewes, the expression of OBRb was down-regulated as fat mass increased, which suggests that the sensitivity of these lambs to circulating leptin decreases with increasing adiposity. A reduced sensitivity of neurons, which express OBRb to signals of body fat mass, such as circulating leptin, may subsequently lead to central leptin resistance and therefore contribute to the continued increase in relative fat mass in lambs of well-fed ewes.

View larger version (9K): [in this window] [in a new window]   Figure 2. There was a significant positive relationship between CART mRNA expression and total relative fat mass in the Control group but not Well-Fed group (CART=0.01 total fat+0.10; r2=0.69, P<0.01, n=9) (A). There was an inverse relationship between OBRb mRNA expression in the arcuate nucleus (ARC) and total relative fat mass in the Well-Fed group (OBRbARC=–0.005 total fat+0.71, r2=0.50, P=0.05, n=8) (B).

CONCLUSIONS AND SIGNIFICANCE

This study is the first to investigate the impact of an increase in prenatal nutrient supply on the development of the hypothalamic appetite regulatory system in a species whose appetite regulatory system develops before birth, as in the human. An increase in maternal nutrition in late pregnancy increased food intake, Glc concentrations, and the relative mass of s.c. adipose tissue in the lamb in the first month of postnatal life. This is consistent with human clinical data, which have shown that fat mass is increased in offspring of pregnancies complicated by maternal diabetes or Glc intolerance. The increase in s.c. adiposity in lambs of well-fed ewes was directly related to the higher Glc concentrations present in lambs of overnourished ewes, which provides evidence that the effects of increased maternal nutrition during pregnancy on fat deposition in the offspring may be mediated through an increase in plasma Glc concentrations in early postnatal life.

Importantly, we have shown that after an increase in maternal nutrient intake in late gestation, expression of the leptin receptor in the hypothalamic arcuate nucleus decreased as fat mass increased, and the direct relationship between the expression of the central appetite inhibitor, CART, and fat mass was lost. Recent studies have shown that the density of neuronal connections between hypothalamic nuclei, and therefore the subsequent function of the neural network regulating appetite, is strongly influenced by leptin exposure during hypothalamic development. It is therefore possible that the differential regulation of CART in the well fed and control groups is a consequence of programmed changes to the hypothalamic architecture. We speculate that the failure of lambs of well-fed mothers to up-regulate hypothalamic anorexigenic pathways in response to increases in adiposity may be a consequence of a central resistance to the actions of leptin. Such changes in the hypothalamic appetite regulatory network represent a potential mechanism (Fig. 3 ), whereby exposure to an increased nutrient supply before birth may lead to a subsequent increase in childhood and adult obesity.

View larger version (23K): [in this window] [in a new window]   Figure 3. Schematic diagram representing a summary of the effects of increased maternal nutrition on food intake, plasma Glc concentrations, and regulation of expression of the appetite-regulating neuropeptides in the lamb in early postnatal life. We speculate that increased maternal nutrition results in increased milk intake in lambs in the early postnatal period, which results in an increase in circulating Glc concentrations, which leads to an increase in adipose tissue deposition. The increase in fat mass leads to down-regulation of OBRb mRNA in the arcuate nucleus and therefore results in a resistance of CART-expressing neurons to the central actions of leptin. Consequently, the central anorexigenic neuropeptide CART is no longer up-regulated appropriately in response to increases in fat mass. The development of central leptin resistance increases the subsequent propensity of these lambs toward increased adipose tissue deposition and increases their risk of later obesity.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-5241fje

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This Article Abstract Full Text Full Text (PDF) All Versions of this Article: fj.05-5241fjev1 20/8/1257    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Muhlhausler, B. S. Articles by McMillen, I. C. Search for Related Content PubMed PubMed Citation Articles by Muhlhausler, B. S. Articles by McMillen, I. C.