Download Neonatal Programming of Body Weight Regulation and Energetic

Bioscience Reports, Vol. 25 Nos. 3/4, June/August 2005 ( 2005)
DOI: 10.1007/s10540-005-2888-3
Neonatal Programming of Body Weight Regulation
and Energetic Metabolism
Egberto Gaspar de Moura1,3 and Magna Cottini F Passos2
Programming is an epigenetic phenomena by which nutritional, hormonal, physical psychological and other stressful events acting in a critical period of life, such as gestation and
lactation, modifies in a prolonged way certain physiological functions. This process was
preserved by natural selection as an important adaptive tool for survival of organisms living
in nutritional impaired areas. So, malnutrition during gestation and lactation turns on
different genes that provide the organism with a thrifty phenotype. In the case of an
abundant supply of nutrients after this period, those organisms that were adapted to a low
metabolic waste and higher energy utilization will be in a higher risk of developing metabolic
diseases, such as obesity, hyperlipidemia, diabetes mellitus and hypertension. The kind of
malnutrition, duration and intensity are important for the type of programming obtained.
We discuss some of the hormonal and metabolic changes that occur in gestation or lactation, when malnutrition is applied to the mothers and their offspring. Some of these changes,
such as an increase of maternal triiodothyronine (T3), leptin and glucocorticoids (GC) and
decrease in prolactin are by itself potential programming factors. Most of these hormones
can be transfer through the milk that has other important macronutrients composition
changes in malnourished dams. We discuss the programming effects of some of these
hormones upon body weight and composition, leptin, thyroid and adrenal functions, and
their effects on liver, muscle and adipose tissue metabolism and the consequences on
thermogenesis.
KEY WORDS: Programming; neonatal; body weight; malnutrition; hormones; leptin;
thyroid.
INTRODUCTION
Some studies have shown that gestation and/or lactation could be a critical period
for the future nutritional and hormonal status of the progeny, a relationship that has
been termed programming. This term is defined as the basic biological phenomena
that putatively underlie relations among nutritional experiences of early life and
early diseases (Lucas et al., 1994). Among the programming factors that act in a
1
Dept. Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do
Rio de Janeiro, Rio de Janeiro, Brasil.
2
Dept. Nutrição Aplicada, Instituto de Nutrição, Universidade do Estado do Rio de Janeiro, Rio de
Janeiro, Brasil.
3
To whom should be addressed. E-mail: [email protected]
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0144-8463/05/0800-0251/0 2005 Springer Science+Business Media, Inc.
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Moura and Passos
critical period in the initial phases of life are: nutrition, hormones, physical stimuli,
like temperature, light/dark cycle, and other stressful events.
Most of the authors studied malnutrition over gestation or both gestation and
lactation periods (Coleoni et al., 1983; Anguita et al., 1993; Burns et al, 1997; Bertin
et al., 1999). However, few studies were restricted to evaluate malnutrition only
during the lactation period (Passos et al., 2000; Ramos et al, 2000; Moura et al.,
2002), that seems to be the most crucial period in mammals to the establishment of
programming.
Hormones and their receptors exert marked tissue-specific and age specific
effects on development (Dauncey et al., 2001). During fetal development, the
coordinated actions of IGF-1, IGF-2, insulin, thyroid hormones (TH) and glucocorticoids (GC) play central roles in the control of differentiation, growth and
maturation (Fowden, 1995).
The present paper reviews the programming of endocrine and intermediary
metabolism, with emphasis on the energy balance and thermogenesis.
PROGRAMMING ENDOCRINE CHANGES
Endocrine dysfunctions were shown in adult animals whose mothers were
submitted to malnutrition, stressful events and hormonal dysfunctions or treatment
during lactation and/or pregnancy. Here, we discuss the programming of glucose
metabolism regulation, with emphasis in the mechanism of insulin resistance, and the
programming of hormonal systems as TH, GC, catecholamine and leptin that have
profound effects on metabolic rate. The combination of insulin resistance and
changes in the action of lipolytic hormones can result in the higher prevalence of the
metabolic syndrome in adult animals that were malnourished or submitted to
hormonal treatment during the prenatal or neonatal periods.
PROGRAMMING BODY WEIGHT
Malnutrition and Body Weight Programming
Obesity and related metabolic disorders have become a major health issue in
modern society and it is widely accepted that obesity in humans is commonly due to
lifestyle and dietary factors. The mechanisms by which diet and environment
modulate the physiological systems that control appetite, weight regulation and the
etiology of metabolic disorders are poorly understood. Increasing evidence suggests
that the origin of some metabolic disorders, which manifest in adult life, may have
their roots before birth. Early support for the ‘‘fetal origins’’ hypothesis was based
on epidemiological studies of adverse health outcomes in humans in which size at
birth was related to the occurrence of metabolic or cardiovascular disorders at an
adult age (Osmond et al., 1993).
Many studies have shown that a small size or thinness at birth are associated
with an increased propensity to adverse health outcomes in adulthood including
obesity, type 2 diabetes, abnormal lipid and carbohydrate metabolism, coronary
heart disease and elevated blood pressure (Godfrey and Barker, 2000). Prospective
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animal studies to test the ‘‘fetal origins’’ or ‘‘programming’’ hypothesis have imposed
perturbations such as moderate to severe maternal undernutrition, feeding of lowprotein diets throughout pregnancy, or GC exposure during fetal development. The
large majority of studies confirm that perturbations of fetal growth and development
lead to obesity, reduced insulin sensitivity (Holemans et al., 1996), elevated blood
pressure (Langley-Evans et al., 1996; Tonkiss et al., 1998) and growth hormone
dysfunctions (Woodall et al., 1996).
There is increasing evidence that obesity may also be associated with impaired
fetal development since epidemiological studies suggests that children born with
intrauterine growth retardation (IUGR) has an increased risk of developing obesity
later in life (Desai and Hales, 1997). This was clearly shown in the Dutch Famine
Study where poor maternal nutrition resulted in increased rates of obesity in adult
males (Ravelli et al., 1976). However, obesity seems to develop only if the nutritional
conditions improve thereafter, since in Russia, Stanner et al. (1997) failed to observe
programming of obesity in adults, whose mothers suffered famine during gestation at
the German siege of Leningrad in World War II. The uterine milieu seems to be
more important than genetic factors to the programming of growth and it has been
estimated that 62% of the variation of human birthweight results from the intrauterine environment, compared with 20% and 18% from maternal and paternal
genes, respectively (Holt, 2002).
We have studied an animal model for programming of body weight, that concomitantly affects leptin and TH function at adult age (Passos et al., 2000; Passos
et al., 2002; Teixeira et al., 2002; Dutra et al., 2003; Passos et al., 2004). In this
model we submitted the mothers to a low-protein (8%) or energy restricted (40%)
diet throughout lactation. At weaning the pups received a normal diet and the body
weight and food intake were monitored until 180 days of age.
We demonstrated with this experimental model that the kind of mother’s
nutrition during lactation may influence the body weight of their offspring in the
adult life, and this can be mainly associated with protein and lipid milk concentration (Passos et al., 2000). Protein-restricted (PR) mothers had lower protein
concentration in milk, while energy-restricted (ER) mothers had higher lipid milk
concentration. Both malnourished offspring had lower body weight until weaning.
After weaning, though, ER offspring were heavier than the controls, while PR
presented lower body weight from birth to 180 days old (Passos et al., 2000). In
addition, those animals had several abnormalities in their leptin action and thyroid
function as will be discussed in the next section. A schematic view of body weight
programming can be seen in Fig. 1.
Numerous investigations have shown that nutrition markedly influences the
synthesis and metabolism of many hormones involved in development, growth and
metabolism (Dauncey et al., 2001). Effects are exerted both by specific nutrients and
by changes in overall food intake, as occurs during undernutrition, A further
mechanism by which nutrition modulates hormone action is by regulation of hormone receptors. Particularly important is the finding that the response to nutrition
can be tissue-specific, because this factor enables highly specific and diverse functional responses to a given circulating hormone level. Postnatal undernutrition down
regulates GH receptor gene expression in liver, whereas it is up regulated in muscle
(Dauncey et al., 1994; Weller et al., 1994). This situation will affect the GH-IGF-I
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Protein restricted dams during
lactation
Adult offspring
Body weight
Leptin resistance
Pituitary leptin receptors
Serum leptin at
weaning
Energy restricted dams during
lactation
Adult offspring
Body weight
Leptin resistance
Pituitary leptin receptors
Serum leptin at
weaning and
Fat milk
Fig. 1. Model of body weight programming and leptin secretion and action at adult age.
axis and limit growth by reducing hepatic IGF-I synthesis (Katsumata et al., 2000).
The probable mechanism by which early malnutrition may exert permanent or longterm effects on development is that the actions of hormone receptors on cellular
development persist long after subsequent optimization of nutrition has restored
hormone receptor expression to its appropriate level.
Despite some reports in IUGR born children, of changes in the GHRH-GHIGF1 axis (Albertsson-Wikland et al., 1998) and GH resistance (Cutfield et al.,
2002), those changes are transitory since in a cohort study in UK, they failed to
relate urinary GH and serum IGF-I in adults to birthweight, other measurements at
birth, or weight at 1 year (Holt et al., 2004). So it seems, that the long term changes
in body composition and intermediary metabolism may be attributed to the
programming effects on other hormones, such as leptin, epinephrine, TH and GC.
Leptin and Body Weight Programming
Leptin is a protein produced by the obesity gene (ob) and is secreted mainly by
the adipocyte and regulates food ingestion and energetic balance (Zhang et al.,
1994). This hormone regulates energy disposal in the peripheral adipose tissue by
specific hypothalamic signals, and affects many functions such as body weight, food
intake, body temperature, and metabolic rate (Friedman and Halaas, 1998).
These effects are mediated in part by leptin’s ability to modulate hypothalamic
function in the arcuate nucleus (Arc) of the hypothalamus. The signaling form of the
leptin receptor (ObRB) is coexpressed with neuropeptide Y (NPY) and agouti-related
peptide (AgRP) in a group of orexigenic neurons and with proopiomelanocortin
(POMC) that contain the anorectic peptide a-melanocyte-stimulating hormone
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(a-MSH) and cocaine- and amphetamine-regulated transcript (CART) in a group of
anorexigenic neurons (Erickson et al., 1996). Increased NPY activity and reduced
POMC activity appear to increase feeding and fat deposition, whereas reduced NPY
activity and increased POMC activity decrease feeding and body mass (Huszar et al.,
1997). Leptin increases the firing rate of POMC neurons and decreases NPY firing
rate in the Arc (Cowley et al., 2001).
Several mice strains develop abnormalities in leptin or in its receptor expression.
Obesity in ob/ob mice results from a mutation in the leptin gene that leads to
hyperphagia, excess body weight, and decreased thermogenesis; all these effects can
be reversed by exogenous leptin administration (Hwa et al., 1997). Other genetic
rodent models of obesity (db/db) result from the mutation in the functional leptin
receptor (Chua et al., 1996). Unfortunately, human studies have shown the scarcity
of such mutations as causes of obesity (Considine et al., 1996), and leptin deficiency
is a rare occurrence in human obesity. Instead, most obese humans exhibit elevated
levels of circulating leptin correlated to body mass index (Considine et al., 1996).
Leptin is transported into the brain through a saturable system of short form of
leptin receptors (ObRa and ObRc) where its actions are to modulate energy functions through the long-form of leptin receptor (ObRb) and activation of a
JAKSTAT and PI3P signaling pathway (Banks et al., 1996; Friedman and Halaas,
1998). Thus, several steps in the leptin signaling pathway can be affected, leading to
the development of obesity.
In the ob/ob hypothalamus, the amounts of NPY RNAs are increased, whereas
the RNAs for POMC are decreased and leptin treatment of these animals normalizes
the amount of these RNAs (Stephens et al., 1995). The number and activity of
excitatory or inhibitory synapses to these neurons also is regulated by the presence of
leptin (Pinto et al., 2004). Bouret et al. (2004a) showed the specificity of these leptin
morphogenetic effects, since other hypothalamic nuclei or nerval projections to the
limbic system were not affected, by the absence of leptin in the ob/ob model or the
treatment of those animals with leptin. Leptin treatment of neonatal ob-mice on days
4–12 of life reversed the reduction in nerve fibres to POMC neurons (Bouret et al.,
2004b). However, if the treatment was postponed to the adult age it did not result in
the formation of anorexigenic and orexigenic nerve fibres. This confirms that there is
a critical period for the formation of leptin-dependent neurons in mice. Although,
this neural plasticity is not completely limited to this initial phase of life (Pinto et al.,
2004). These data give a morphological support for the programming hypothesis,
since different levels of leptin during hypothalamic morphogenesis could permanently changes the distribution of excitatory or inhibitory synapses to NPY or
POMC neurons, modifying permanently the response of these neurons to orexigenic
or anorexigenic stimuli.
Some authors have suggested that the higher leptin serum concentrations could
downregulate hypothalamic leptin receptors or their blood-brain barrier carriers,
which could result in leptin resistance and start a vicious cycle of higher food
ingestion and even higher leptin serum concentration (Considine et al., 1996). Mice
made obese by feeding on a high-fat diet were shown to lose their response to
peripherally administered leptin, but not to centrally administered leptin (Van Heek
et al., 1997); these studies suggest that impairment of leptin transport might contribute to the development of obesity. However, Martin et al. (2000) also showed an
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association between leptin resistance in obese rats and leptin receptor
downregulation.
Therefore, the failure of the hypothalamus to detect leptin or leptin resistance
may occur for one of several reasons leptin may fail to cross the blood-brain barrier,
the hypothalamic receptors may be downregulated, or downstream signaling may be
inhibited.
Leptin decreases food intake 2 h after injection, in adult rats kept in a 24 h
fasting, and then allowed to eat ad libitum a standard diet (Martin et al., 2000). In
contrast animals whose mothers were submitted to PR or ER diets during lactation
showed no decrease in the feeding response to this acute dose of peripheral leptin
(Passos et al., 2004), characterizing a hypothalamic leptin resistance.
The leptin resistance, which is observed in programmed offspring, may be a
mechanism induced by the experience of a nutrient-deprived intrauterine environment to store large quantities of triglycerides when food is plentiful. Leptin resistance would therefore create a competitive advantage in preparation for a nutrientdeprived environment to store as much fat as possible when food becomes available.
Thus, leptin resistance may be a mechanism for the thrifty phenotype proposed by
Hales and Barker (1992). However, when hypercaloric nutrition persists for long
periods of time, leptin resistance may lead to adipogenic diabetes mellitus (Breier
et al., 2001).
Both PR and ER offspring presented at weaning higher serum leptin concentrations (Teixeira et al., 2002). As leptin is present in milk it is possible that this
hormone is transfer to the pups through the milk (Casabiell et al., 1997;
Houseknecht et al., 1997). The higher fat milk concentration could increase leptin
production in the pups. This relation was evidenced in humans (Mantzoros et al.,
1997) and animals (Rousseau et al., 1997; Trottier et al., 1998).
So, we hypothesized that this higher serum leptin at weaning could be one of the
factors that programs the endocrine disorders observed at adult age. Based on these
findings we developed another experimental model where the pups were injected with
murine leptin (8 lg/100 g BW, sc) during the first 10 or last 10 days of lactation
(Cravo et al., 2002). In this study we observed that hiperleptineamia in both the first
and the last 10 days of lactation was associated with higher serum leptin concentration at 150 days of age and , paradoxically, with higher food intake and body
weight, suggesting also a leptin resistance.
PROGRAMMING THYROID FUNCTION
Neonatal TH Dysfunctions and Thyroid Function Programming
The widespread actions of hormones during development are exemplified by the
striking effects of TH on differentiation, growth and metabolism of many tissues and
cell types (Fisher et al., 1977). Particularly well recognized are the effects of TH on
myelination and development of the central nervous system (Barradas et al., 2000),
and TH deficiency during the perinatal period results in severe mental and physical
retardation (Oppenheimer and Schwartz, 1997; Chan and Kilby, 2000).
There are a considerable bulk of data about the effects of maternal hyperthyroidism and programming of the thyroid function in the offspring. Neonatal
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hyperthyroidism is associated to secondary hypothyroidism in the adulthood
(Varma and Crawford, 1979; Dussault e cols., 1982). Walker and Courtain (1985)
showed that this TSH insensitivity to the lower T4 and T3 concentration in adult rats
that were T4 treated in the neonatal period, were in part due to a higher pituitary
deiodinase activity. The effects of maternal or neonatal hypothyroidism in
programming thyroid function were less marked than those observed for hyperthyroidism (Pracyk et al., 1992), consisting mainly in TSH changes.
Neonatal Malnutrition and Thyroid Function Programming
Several changes in thyroid economy are detected in food-restricted animals. TH
secretion (Moura et al., 1987) and metabolism (Harris et al., 1978), as well as thyroid
regulation by hypothalamic and pituitary hormones (Jolin and Lamas, 1984) are
impaired in this situation. Similar changes were reported for PR adult humans
(Rastogi et al., 1974) and animals (Rostom de Mello et al., 1989). However, few
studies could correlate thyroid dysfunction in adulthood with malnutrition in the
first days of life.
During gestation, protein malnutrition causes a delay in thyroid follicle formation and a reduction in gland area, follicle number, colloid space and cell size in
the thyroid tissue of fetal and neonatal pups from PR dams (Shrader et al., 1977), A
decrease in T3 level with normal serum T4 and thyroid stimulating hormone (TSH)
levels was shown in the fetuses or newborns from PR lactating dams (Friedman and
Zeman, 1979). Oberkotter and Rasmussen (1992) reported that the offspring of
chronically ER dams showed lower serum T3 and higher serum reverse T3 (rT3, an
inactive metabolite of T4) during lactation.
We showed that protein malnutrition only during lactation was associated with
thyroid dysfunction in 60-days-old (Ramos et al., 1997) or 180 days old offspring
(Passos et al., 2002). Those changes may be related to maternal thyroid dysfunction,
like the higher T3 serum concentration in PR dams (Ramos et al., 2000). Those
mothers, probably, had an increase in T3 thyroidal production, plus an increase in T4
to T3 conversion, due to higher thyroid, brown adipose tissue (BAT) and skeletal
muscle deiodinase activities (Lisboa et al., 2003). Only in the mammary gland, the
D1 activity was lower in the 4th day of lactation. Considering that this enzyme also
converts T3 to T2, that is inactive, it is possible that this effect contributes to a higher
transfer of T3 from the maternal serum to the milk. In fact, protein malnourished
mothers transfer more T3 to their offspring (Passos et al., 2001 a). A schematic view
of thyroid hormone metabolism in malnourished mothers can be seen in Fig. 2.
We also showed that protein malnutrition during lactation programs a higher
T4 and T3 serum concentration in the adult offspring (Passos et al., 2002), in part due
to a higher liver deiodinase activity in those animals (Dutra et al., 2003). The
hyperthyroidism in animals from protein-restricted mothers could explain the low
body weight observed in these animals. Similar results were found by Coleoni et al.
(1983), who showed that adult rats whose mothers had been fed a low protein diet
during gestation and lactation and the offspring were kept up to 50 days after
weaning on this diet presented higher T3 serum concentrations and higher
T3-inducible enzymes, as hepatic glycerophosphate dehydrogenase and malic
enzyme, even after a long period of nutritional recovery. In that study, malnutrition
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Protein restricted dams during lactation
malnourished pups
malnourished dams
T3
T4
D1
mammary
gland
Serum T3
Milk T3
Serum T3
T3
T4
Thyroid
D1
Skelectal
muscle
Brown adipose
tissue
Fig. 2. Transfer to T3 through the milk in protein restricted lactating rats. D1-deiodinase type 1.
was imposed during perinatal period until puberty. In contrast, deprivation in our
experimental model was applied only during the lactation period, and we already
observed the same permanent changes at the thyroid function. So, the critical phase
for the metabolic imprinting seems coincide with the lactation period.
Leptin and Thyroid Function Programming
Although leptin secretion was initially reported exclusively from adipose tissue,
other studies have identified leptin production in a few others tissues including the
brain and pituitary (Morash et al., 1999), skeletal muscle. (Wang et al., 1998),
placenta (Senaris et al., 1997), stomach (Bado et al., 1998), and epithelial cells of the
mammary gland (Smith-Kirwin et al., 1998).
Jin et al. (2000) have reported leptin in the rat anterior pituitary cells that
produces the b subunit for thyroid–stimulating hormone (TSH) and follicle-stimulating hormone (FSH)/luteinizing hormone (LH). It becomes subsequently clear that
leptin functions not only in the regulation of food intake and energy metabolism, but
Neonatal Programming of Body Weight Regulation
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also in different areas, i.e., secretory regulation of pituitary hormones (Ahima et al.,
2000).
Studies in normal rodents have demonstrated the expression of leptin receptor
in the pituitary by reverse transcriptase polymerase chain reaction (Jin et al., 2000)
and also by immunoblotting and immunohistochemical analysis (Sone et al., 2001;
Vicente et al., 2004). It has been shown that leptin regulates the function of GH cells
(Sone et al., 2001) and also has acute stimulatory effect on TSH release, in vivo,
acting probably at the hypothalamus (Legradi, 1997; Seoane et al., 2000).
In a recent study (Vicente et al., 2004), we demonstrated that the protein or
energy restriction during lactation is associated with a higher expression of leptin
receptor in the pituitary glands of adult offspring (Fig. 3). These animals had higher
T4 and T3 serum concentrations and lower TSH. The lower serum TSH is in
agreement with thyroid hormones negative feedback on the hypothalamic-pituitary
axis. However, the higher expression of leptin receptor in the pituitary gland could
also indicate an inhibitory effect of leptin on TSH secretion, since it has been
demonstrated that the in vitro effect of leptin on TSH release is inhibitory (OrtigaCarvalho et al., 2002). These animals showed hypothalamic leptin resistance, as
discussed above (Passos et al., 2004), and the increase in SOCS-3 expression was
associated with both leptin resistance and higher ObRb expression (Bjorbaek et al.,
1998). Conversely, if this higher expression of pituitary leptin receptor is associated
with a resistance to leptin action, it could also contribute to the lower TSH.
These data provide new insights regarding the physiological importance of
nutritional status and consequent changes in leptin levels during neonatal period,
Fig. 3. Immunohistochemical staining for leptin receptor in pituitary of adult rats
whose mothers were fed a control (2A), protein-restricted (2B), and energy-restricted
(2C) diet during.
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and suggest that leptin may play an important role on the thyroid-pituitary axis
regulation in the adult.
Nutrition has a major influence both on the hypothalamic-pituitary-thyroid axis
and on nuclear TH binding in peripheral tissues. A low energy intake reduces thyroid
gland activity, plasma TH levels and total TR numbers, and the decrease in nuclear
TH binding is even greater when metabolic demand is increased by lowering the
environmental temperature (Swoap et al., 1994). IUGR also down regulates TR
(Dauncey et al., 2001). Thus, when energy is restricted, because of either a low intake
or a high expenditure, the reduction in TR will limit responsiveness to TH and result
in reduced growth and metabolism.
Besides programming, another factor by which environmental changes may
interfere with fetal and neonatal thyroid function, even before conception, is the
genome imprinting. This phenomenon is characterized by the fact that some genes
are grouped and can express in a different way if the allele is paternal or maternal
(Fergunson-Smith and Surani, 2001). So, genomic imprinting is a form of nonmendelian epigenetic process in which the two parental alleles of a gene are differentially expressed according to parental origin and depending on environmental
factors express only one parental allele. Around 50 genes are known to be genomic
imprinted, including the DIO3 gene that express deiodinase III in placenta, affecting
the transfer of thyroid hormones from the mother to the foetus (Tsai et al., 2002).
PROGRAMMING DIABETES MELLITUS (DM)
There are strong inverse relationships between birthweight and the risk of
developing type 2 DM, evidenced by epidemiological studies (Ozanne and Hales,
2002). In a 64-year-old men population of UK, Hales et al. (1991) showed an
association between low birthweight and glucose intolerance. It was confirmed later
by Phillips et al. (1994) that carried out insulin tolerance tests on 103 men and
women in Preston and found that in people with similar current body weight, the
insulin resistance was greater in those who had a lower birthweight. Conversely, at
each birthweight, the insulin resistance was greater in those with heavier body
weights at adulthood, more pronounced in those who had developed obesity as
adults (Hales et al., 1991). Short pre pubertal IUGR children also have impaired
insulin sensitivity compared to their normal birthweight peers (Hofman et al., 1997).
In a regional cohort study, in France, Leger et al. (1997), showed that IUGR was
associated to reduce final height, raised insulin and proinsulin concentrations in
young adults born small for gestational age. In Sweden, another study of 1333 men
aged 50–60 confirmed that reduced fetal growth is associated with insulin resistance
and non-insulin dependent diabetes mellitus (Lithell et al., 1996). The molecular
basis for these programming are under intense investigation, but the complete
understanding of this process is still elusive.
Fetal and neonatal life is a crucial period for pancreatic b-cell development
(Rahier et al., 1981). In rats, the mother’s protein malnutrition during the first days
of lactation was associated with a decrease of insulin secretion in the 60- and 90-dayold progeny (Moura et al., 1997). This deficiency can be accelerated by a high-fat
diet (Holness, 1996). The adult offspring, whose mothers were PR during pregnancy,
exhibited an increase in gluconeogenesis metabolism (Burns et al., 1997) and a
Neonatal Programming of Body Weight Regulation
261
significant decrease in pancreatic insulin content and beta-cell mass (Bertin et al.,
1999). It seems that an amino acid specific deficiency can be responsible for this
programming effect, since the mother’s diet supplementation with taurine prevents
the impairment of insulin secretion in the offspring of PR mothers (Cherif et al.,
1998).
In the other side, the ‘‘insulin resistance syndrome’’ is composed of a wide range
of metabolic disorders including glucose intolerance, hyperinsulinemia, increased
very-low-density lipoprotein (VLDL), decreased high-density lipoprotein (HDL),
and hypertension (Howard, 1999). Insulin resistance is thought to contribute towards the development of hypertension, hyperinsulinism, dyslipidemia, obesity, and
cardiovascular disease, known as syndrome X or metabolic syndrome (Reaven,
1993). This syndrome was also related to low birthweight (Barker et al., 1993).
Hales and Barker (1992) proposed the ‘‘thrifty phenotype’’ hypothesis which
suggests that intrauterine malnutrition leads to adaptive responses that changes the
nutrient disposal to the organs, affecting their normal growth. The brain is spared in
detrimental of other organs, such as liver, pancreas and muscle. One adaptation of
this hypothesis, is the ’fetal salvage’ hypothesis (Hofman et al., 1997) that adds to
the ‘‘thrifty phenotype’’ hypothesis the permanent reduction in the skeletal muscle
glucose transporter number or function, and in the antilipolytic action of insulin
(Ozanne et al., 2001), that leads a stimulation of b-cell to produce larger amount of
insulin to achieve glycaemic control that eventually leads to b-cell exhaustion.
More importance is given to the insulin resistance rather than through b cell
dysfunction (Lithell et al., 1996), Other alternative hypothesis for the association of
low birthweight and type2 DM in adulthood were proposed, including a genetic link,
but it fail to be confirmed, because these mutations affecting both fetal growth and
insulin secretion or action are very rare (Ozanne and Hales, 2002). Reinforcing the
hypothesis of programming in detrimental of a genetic link are the studies with twins
that were discordant for type 2 DM (Poulsen et al., 1997; Bo et al., 2000). In both
studies, the twin that was born with the lower birthweight was the one that presented
the higher risk of developing type 2 DM.
Other forms of programming can be associated to insulin resistance as the
higher serum cortisol in adults that had low birthweight (Phillips et al., 1998) and
GC treatment during gestation, that will be discussed in the next section.
PROGRAMMING OF THE HYPOTHALAMUS–PITUITARY–ADRENAL
(HPA) AXIS
Malnutrition and hormonal treatment during gestation or lactation are stressful
events that can activate the HPA axis. Despite the use of appropriated controls,
models of HPA disruption during this critical period of life can be useful to
individualize the programming effects of malnutrition and isolated hormonal
treatments from those caused by pure stress.
Several different manipulations in early development can program HPA function in adult primates, guinea pigs, sheep and rats. Examples of prenatal manipulation are maternal stress (Welberg and Seckl, 2001; Weinstock, 2001), exposure to
synthetic GC (Matthews, 2000; Liu et al., 2001) and nutrient restriction (Lingas and
Matthews, 2001; Lesage et al., 2002). Postnatal manipulations include neonatal
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handling (Meaney et al., 2000), modified maternal behavior (Meaney, 2001) and
exposure to GC (Bakker et al., 2001).
Maternal treatment with synthetic GC (e.g. dexamethasone) has provided a
useful tool to investigate the impact of GC on the development and subsequent
function of the HPA axis. In the rat, daily treatment with synthetic GC in the final
week of gestation results in elevated basal plasma corticosterone levels in the adult
offspring (Welberg et al., 2001]. This was associated with increased blood pressure
(Levitt et a1., 1996) and obesity in adulthood (Bjorntorp and Rosmond, 2000).
In another study, maternal synthetic GC treatment on gestational days 17 to 19
resulted in adult offspring that mounted a greater corticosterone response to stress
(Muneoka et al., 1997).
Prenatal dexamethasone (dex) exposure in the rat lowers birthweight and
programs for lower adult body weight, smaller fat pads, and relatively preserved
muscle mass, fasting and postprandial hyperglycemia, associated with increased
hepatic gluconeogenesis driven by elevated liver and adipose tissue GC receptor
(GR) expression (Cleasby et al., 2003). Increased hepatic gluconeogenesis is probably explained by permanent elevation in expression of hepatic phosphoenolpyruvate carboxykinase in dex-treated offspring (Nyirenda et al., 1998). Paradoxically,
plasma leptin was increased in 1-yr-old rats given dex continuously during their third
week of gestation (Sugden et al., 2001).
Permanent GR up-regulation has been reported in the offspring of PR mothers,
which also exhibit insulin resistance and hypertension (Bertram et al., 2001).
However, in the model of dex prenatal exposure, GR is not widespread up-regulated,
because its expression is lower at the hippocampus (Welberg et al., 2001). So,
programming can affect hormonal regulation in a tissue-specific way. Regardless the
causing factors, time and duration of the stimulus, that can cause differences on
HPA programming, prenatal or neonatal GC increase programs for a higher
vigilance status in adulthood, increasing the ability to survive to a menacing
environment.
PROGRAMMING OF SYMPATHOADRENAL FUNCTION
Environmental exposures at critical period of development permanently alter
sympathoadrenal function in mammals. The sympathetic innervations of peripheral
tissues and the responsiveness of sympathetic nerves and adrenal medulla to standard stimuli are susceptible to modification by exposures in early life, such as
environmental temperature, nutrition and stress. Effects of temperature exposure in
early life on thermoregulation appear to be qualitatively different from those of cold
and heat acclimatization in adult animals (Ferguson et al., 1981).
Although less extensively studied than the effects of environmental temperature,
both maternal and neonatal nutrition contribute to development of SNS anatomy
and function. It was shown, recently, that young adult humans that were born with
low birthweight showed increase in their sympathetic activity, that could contribute
to hypertension (Boguszewski et al., 2004).
One model often employed to manipulate neonatal nutrition is variation in litter
size (Young, 2002). Animals reared in small litters are considered to be ‘‘overnourished’’, whereas those reared in large litters are ‘‘undernourished’’ The
Neonatal Programming of Body Weight Regulation
263
stimulatory effect of dietary sucrose on cardiac SNS activity was completely absent
in rats reared from one day of age in small litters (Young, 2002). These findings are
potentially important, because the impairment in activation of cardiac sympathetic
nerves by dietary sucrose seen in rats reared in small litters is similar to reported
effects of the neurotoxin, gold thioglucose, in adult mice (Young, 1980). Gold
thioglucose destroys neurons within the ventromedial hypothalamus (among other
sites), a lesion that is dependent upon the presence of insulin (Debons et al., 1968).
Because circulating insulin levels are increased in neonatal rats reared in small litters
(Plagemann et al., 1992) and because administration of insulin to neonatal rats alters
hypothalamic morphology (Plagemann et al., 1992; Plagemann et al., 1999),
neonatal hyperinsulinemia might induce permanent changes in insulin-dependent
SNS responses, such as those related to dietary carbohydrate. These findings are
analogous to the impairments observed in ventilatory regulation in adult rats
exposed to hyperoxia during the first month of life (Ling et al., 1996), and suggest
that regulatory pathways governing vegetative function could be susceptible to
desensitization and/or damage by excessive stimulation at an early age.
SUMMARY AND CONCLUSIONS
Programming is based on the observation that environmental changes can reset
the developmental path during a critical period of life, when the tissues still have
some plasticity and are in a higher proliferating and differentiating phase. Leptin
seems to be a hormone that reunites all the predicates to be a signaling factor of
nutritional environmental conditioning the animal to different levels of nutrient
supply during life. The prenatal or neonatal level of leptin can modify the neuronal
and adipocyte plasticity adapting the animal to resist to a lower nutrient
supply.However, if those conditions changes to a higher nutrient supply the
organism can develop the metabolic syndrome. Other factors, such as glucocorticoids and thyroid hormones also can play some programming effects in concern with
the nutritional status of the animal. The sympathetic activation may contribute to
the lower body weight and hypertension observed in the programming by neonatal
protein restriction. The interactions of these programming factors predispose the
animal to increment their body weight rate, food behavior and metabolic rate,
during life.
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