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J. Biol. Chem., Vol. 277, Issue 3, 1629-1632, January 18, 2002
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From the Department of Biochemistry, School of Medicine and
Biomedical Sciences, State University of New York,
Buffalo, New York 14214
The normal programmed development of a
multicellular organism from the germ cell is a synchronized series of
events driven by genetic instructions acquired during conception.
During the early critical periods in life the organism also has the
ability to respond to environmental situations that are alien to normal development by adaptations at the cellular, molecular, and biochemical levels. Such early adaptations to a nutritional stress/stimulus permanently change the physiology and metabolism of the organism and
continue to be expressed even in the absence of the stimulus/stress that initiated them, a process termed "metabolic programming" (1).
A brief summary of the findings from human epidemiological and animal
studies is presented below in support of the concept of metabolic
programming induced by nutritional experiences during critical periods
in development with consequences later in adulthood. For detailed
accounts the reader is referred to excellent reviews on this subject
(2-5). This minireview will focus on metabolic programming with
reference to a novel rat model developed in our laboratory.
Extensive epidemiological findings indicate that metabolic
programming occurs in humans. Barker (6) was the first to suggest from
epidemiological studies that the disproportionate size of the newborn
resulting from maternal malnutrition correlated with an increased risk
for adverse health outcomes (type II diabetes, hypertension, and
cardiovascular diseases) later in adult life. These primary
observations resulted in the now widely recognized "fetal origins"
hypothesis emphasizing the importance of adequate maternal nutrition
during pregnancy (4).
Nutritional programming has been demonstrated in animal studies.
In pioneering studies with rodents, McCance (7) demonstrated by
adjusting litter size that the quantity of food consumed during early
periods of postnatal life has long term consequences on growth. The
consequences of maternal malnutrition induced by either a low protein
diet or caloric restriction during gestation and lactation cause major
changes in the structure and function of several organs in the
offspring. Pregnant rats fed a low protein diet produced pups with
alterations in pancreatic islets (8, 9). These include reduced islet
vascularization, Most of the above cited animal studies deal with maternal
malnutrition during pregnancy leading to intrauterine growth
retardation and accompanying adaptations in the fetus for survival
under adverse conditions. Except for the effect of overnourishment
caused by reducing litter size, the effect of an altered nutrition
during the suckling period has not been investigated extensively in the rat. This is because of experimental difficulties in successfully rearing rat pups on a modified milk formula away from nursing mothers.
The artificial rearing technique as described by Hall (13) provides a
means to study the effects of altered nutrition during the suckling
period in the rat. We have adapted this technique to evaluate the
consequences of a switch in the "quality" of nutrition (from
fat-rich rat milk to high carbohydrate
(HC)1 milk formula) during
the suckling period in the rat. The result is the "pup in a cup"
rat model (also referred to as the HC rat) where the newborn rats are
reared in Styrofoam cups floating in a temperature-controlled water
bath. Four-day-old rats are fed via intragastric cannulas, introduced
nonsurgically, raised on a HC milk formula (56% of the calories
derived from carbohydrate compared with 8% in rat milk) up to day 24, and then weaned onto laboratory chow. Four-day-old rats artificially
reared on a high fat milk formula (macronutrient composition similar to
rat milk to show that the artificial rearing technique per
se has no metabolic programming effects) and pups nursed by their
own mothers served as controls. The detailed protocol followed by our
laboratory for the experiments performed using the "pup in a cup"
rat model is described elsewhere (14, 15). Fig.
1A depicts metabolic adaptations in the first generation HC rats.
An immediate outcome of the HC dietary intervention is the onset
of hyperinsulinemia within 24 h; this persists throughout the
suckling period and into adulthood even after the withdrawal of the HC
milk formula at the time of weaning (15, 16) (Figs. 1A
and 2A). During the suckling
period there are no differences in body weights and in plasma glucose
levels between the HC and age-matched control groups (17). The overlap
of the critical window for postnatal pancreatic development with the
high carbohydrate nutritional intervention in the HC rat suggests that
the endocrine pancreas is a target organ for significant adaptations.
We have observed significant alterations at the cellular, molecular,
and biochemical levels in islets isolated from neonatal HC rats and have also observed the programming of these adaptations into
adulthood.
Cellular adaptations induced by dietary intervention during the
suckling period include an increased number of smaller sized islets in
the HC pancreas compared with controls (18). Such HC islets have a
larger immunopositive area for insulin resulting in a net increase in
the insulin-producing mass in HC islets (18). Additionally, the rate of
apoptosis and the expression of proliferating cell nuclear antigen are
inversely altered in islets and the ductal epithelium of the HC rat
(18). One of the factors contributing to the altered ontogeny has been
attributed to the change in the expression of insulin-like growth
factor II (18).
Several molecular adaptations are observed in neonatal islets in
response to the HC dietary intervention. Increases in insulin biosynthesis and in gene expression of preproinsulin are observed in
islets of neonatal HC rats (19) (Fig. 2B). Additionally, mRNA levels of transcription factors such as pancreatic duodenal homeobox factor-1 (PDX-1, also known as somatostatin transcription factor-1) (Fig. 2B), islet factor-1 (Isl-1), upstream
stimulatory factor-1, regenerating factor-3 (reg-3) (19, 20), and
Beta2/NeuroD and hepatocyte nuclear factor
MINIREVIEW
Metabolic Programming: Causes and Consequences*
and
INTRODUCTION
Evidence for Metabolic Programming from Human Epidemiological
Data
Evidence for Metabolic Programming in Animals
cell proliferative capacity, and islet size with
rightward shift (decreased sensitivity) in glucose-stimulated insulin
secretion and altered sensitivity to insulin in muscle (8, 9).
Furthermore, hypothalamic nuclei are malformed in these weanling rats;
this is accompanied by reduced vascularization of the cerebral cortex
in the progeny (10). Metabolic capacities of the liver, muscle, and
adipose tissue are compromised by maternal protein restriction during
gestation and lactation with adverse adult onset outcomes (11).
Elevated insulin concentrations during critical periods of development, as occurs perinatally in the offspring of gestationally diabetic mothers, lead to permanent malorganization of the ventromedial hypothalamic nuclei followed by glucose intolerance in adult
life (12). Collectively, the results from animal models indicate that
even brief periods of dietary manipulation in early life have
implications for ill health outcomes, which become evident only in adulthood.
"Pup in a Cup" Rat Model
View larger version (39K):
[in a new window]
Fig. 1.
Diet-induced metabolic programming in first
and second generation HC rats. Metabolic adaptations in first
generation (A) and second generation (B) HC rats
in response to feeding a HC milk formula to first generation
neonatal rat pups are shown. GTT, glucose tolerance
test.
Immediate Metabolic Adaptations in the Suckling Period
View larger version (36K):
[in a new window]
Fig. 2.
Biochemical adaptations in pancreatic islets
from neonatal HC rats. A represents plasma insulin levels
(pM) in neonatal HC rats. B is the relative
levels of preproinsulin and PDX-1 mRNAs in islet from 12-day-old HC
and mother-fed (MF) rats. C represents the
insulin secretory response to a glucose (Glu) stimulus by
islets from 12-day-old first generation HC rats at 60 min. Insulin
secretion is expressed as femtomoles of insulin/30 islets/60 min.
D represents the activity of the low Km
hexokinase activity in supernatant (S) and pellet
(P) fractions of islet extracts of 12-day-old HC rats and
mother-fed control rats. Activity is expressed as milliunits/mg of
protein.
-32 are significantly
increased in neonatal HC islets. mRNA levels of stress-activated
protein kinase-2 (SAPK-2), phosphatidylinositol 3-kinase
(PI3-kinase), acetyl-CoA carboxylase, glucose transporter 2, and
insulin receptor substrate-1 and -2 are also significantly higher in
these HC islets (19, 20). PDX-1 is an important transactivator of the
insulin gene and is an essential component of the mechanisms whereby
glucose modulates insulin promoter activity (21). DNA binding activity
of PDX-1 has been proposed to be modulated by glucose via a
phosphorylation cascade(s) involving SAPK-2 and PI3-kinase, which
facilitates the translocation of the 46-kDa, phosphorylated active form
to the nucleus resulting in increased insulin gene transcription (21)
(Fig. 3). The possible correlation
between the observed effects of the HC dietary intervention in neonatal
HC rats and preproinsulin gene transcription is shown in Fig. 3. In
addition PDX-1 is an important transcription factor that commits the
progression of the pluripotent ductal cell into an endocrine cell (22).
The significant increase in the gene expression, DNA binding activity,
and protein content of PDX-1 in neonatal HC islets suggests that it
plays a pivotal role in the cellular adaptations as well as in the
onset and maintenance of hyperinsulinemia in this rat model (19).
Transcription factors like Isl-1, Beta2/NeuroD, reg-3, and hepatocyte
nuclear factor -3 also contribute to pancreatic organogenesis
(22-24). The increases in the gene expression of these factors suggest
that they too contribute to the modification of the islet architecture
in the neonatal HC rats. cDNA array analysis has indicated
significant changes in global gene expression patterns in neonatal HC
islets as well as in adult HC islets suggesting that a wide range of molecular alterations is essential for the onset and persistence of the
HC phenotype in HC rats (20).
View larger version (18K):
[in a new window]
Fig. 3.
Putative pathway for the regulation of
preproinsulin gene transcription in neonatal HC islets. This
scheme indicates the various responses induced in the HC rat to the
high carbohydrate dietary intervention, the possible interactions among
them, and the consequent regulation of preproinsulin gene
transcription. USF-1, upstream stimulatory
factor-1.
TOP
INTRODUCTION
Evidence for Metabolic...Significant biochemical adaptations summarized below initiate and
sustain hyperinsulinemia in neonatal HC rats. A characteristic feature
of neonatal HC rats is about a 6-fold increase in the concentration of
circulating insulin (16, 25) (Fig. 2A). There is a distinct
leftward shift (increased sensitivity) in the glucose-stimulated insulin secretory response in HC islets (Fig. 2C), and this
is associated with increases in the low Km
hexokinase activity (Fig. 2D) and an increase in glucose
transporter 2 protein content (25). Insulin secretion by islets is
regulated by three pathways (the KATP
channel-dependent pathway, the KATP
channel-independent augmentation pathway, and the Ca2+
channel-independent augmentation pathway (26)), and these pathways are
up-regulated in HC islets (27). Circulating levels of glucagon-like peptide-1 (GLP-1) are significantly higher in HC rats suggesting that
GLP-1-mediated events contribute significantly to the hyperinsulinemia of HC rats (27). In addition to its insulinotropic effects, GLP-1
stimulates transcription of the preproinsulin gene and PDX-1 gene and
also the proliferation and neogenesis of cells from ductal
epithelium in rodents (28-30). In light of the above, the significant
increase in circulating levels of GLP-1 in 12-day-old HC rats has
important implications for the HC phenotype in suckling HC rats.
Because of chronic hyperinsulinemia the capacity for hepatic
lipogenesis is enhanced in neonatal HC rats (16). Enzymes such as
glucokinase and malic enzyme that normally appear in the liver at
weaning are precociously induced by this dietary treatment suggesting
that their appearance is not development-dependent but is
controlled by the presence of the stimulus (diet-induced hyperinsulinemia) (16). It is evident from the above that feeding rats
an HC milk formula, instead of mother's milk, during the suckling
period elicits significant alterations in islet functions as well as in
metabolic responses of peripheral tissues, which are important for the
development of adult-onset obesity (Fig. 4, Adaptive
Phase).
|
| |
Programming of Early Onset Adaptations into Adulthood |
|---|
Hyperinsulinemia persists into adulthood of HC rats despite
withdrawal of the HC nutritional intervention on day 24 (Fig. 1A). Alterations in the insulin secretory pathway observed
in the neonatal HC islets are programmed into adult islets (31, 32).
The molecular changes (increase in the preproinsulin gene transcription) observed in islets from neonatal HC rats are also observed in adult HC islets (32). There is an increase in the insulin-producing mass of the adult HC pancreas (17). Chronic hyperinsulinemia is accompanied by an increase in the body weight of
the animals from day 55 onward and full blown obesity by day 100 (15)
(Fig. 1A). Although the adult HC rats maintain
normoglycemia, an abnormal response to an oral glucose tolerance test
is observed in HC animals on approximately day 75 (17) (Fig.
1A). In addition, liver and adipose tissue show increased
lipogenic capacities in adulthood (15). An increase in the cell size in
epididymal adipose tissue reflects the adiposity observed in adulthood
(15). Glycogen content and the glycogen synthase activation cascade are
down-regulated in liver and skeletal muscle (33) and up-regulated in
epididymal adipose tissue of adult HC rats (34). Taken together these
findings indicate that early adaptations are programmed and are
accompanied by additional changes probably triggered by adult-onset
factors (Fig. 4, Persistence Phase).
| |
Nutritionally Induced Generational Effect on Metabolic Programming |
|---|
An important and unexpected consequence of the nutritionally
induced metabolic programming noted above is the transmission of the
phenotype from the HC mother to the progeny (see Fig. 1B). Female rats fed an HC milk formula during their suckling period spontaneously transmitted their metabolic characteristics to their progeny without the pups themselves having to undergo any nutritional treatment (35). The second generation HC rats display hyperinsulinemia and an altered insulin secretory pattern within 48 h after weaning them onto laboratory chow on day 24.2 Molecular adaptations
(increases in mRNA levels of preproinsulin, PDX-1, upstream
stimulatory factor-1, SAPK-2, and PI3-kinase) are also programmed in
second generation HC rats.2 The growth pattern of HC rats
in the second generation parallels that of first generation HC rats
(35) (Fig. 1B). Cross-breeding experiments have demonstrated
that only HC females transmit these traits to the progeny, suggesting
that the intrauterine experience may be essential for the transmission
(Fig. 4, Transmission Phase).
| |
Potential Mechanisms of Metabolic Programming |
|---|
Metabolic programming is an "adaptive process" that occurs in response to a nutritional stimulus/insult during a vulnerable period of susceptibility early in life. Direct evidence for mechanisms responsible for metabolic programming is not yet available. Potential mechanisms have been discussed by Lucas (1) and Waterland and Garza (5). The immediate effects of a nutritional stress on structural development with long term consequences have been demonstrated in rats (8, 10). Experimentally induced hyperinsulinemia in neonatal rats during the critical period of brain development results in alterations in body weight, blood pressure, and glucose metabolism in adult life because of disorganization of the ventromedial hypothalamic nuclei (12). The HC milk formula induces responses in pancreatic islets and the small intestine as evidenced by increases in the circulating plasma levels of insulin and GLP-1 in neonatal HC rats. In the context of reports on the effects of a nutritional modification on the brain and the effects of the HC dietary intervention on the islets and gut in neonatal HC rats, it is tempting to suggest that cross-talk may occur among the pancreas, small intestine, and brain resulting in the onset and persistence of hyperinsulinemia in HC neonates.
Epigenetic mechanisms that mediate phenomena such as genomic imprinting
may also contribute to programming (36). Epigenetic modification is
triggered by changes in environment and can occur in both somatic and
germ cell lineage during development (37). Altered DNA methylation
patterns have been shown to be caused by protein deficiency and folate
depletion (38). Nutritional alterations early in life may modify
cell-specific DNA methylation patterns leading to altered levels of
gene expression in specific tissues. In addition, because the altered
DNA methylation patterns in specific cells are transmitted to the
daughter cells by replication, the initial modifications are
immortalized (Fig. 4).
| |
Concluding Remarks |
|---|
The "pup in a cup" rat model is unique in that it permanently programs the metabolism of an adult rat by merely modifying the composition of the milk fed to the animal during its suckling period. In addition, this type of metabolic programming is transmitted to the next generation by the mother. It is evident from our studies with rats that the nature and the timing of the dietary treatment programs the onset of pathological conditions in the adult that mimic major metabolic diseases noted in humans, such as obesity and type II diabetes. Evidence points to diet-induced hyperinsulinemia as the primary event in metabolic programming in the HC rat.
In a recent report Mokdad et al. (39) have pointed out that
the epidemic of obesity is a critical public health threat in the
United States (nearly one of five Americans is obese). Because there
has not been a significant change in the gene pool in the United States
in recent decades (39), it is unlikely that genes related to obesity
are involved in the increased incidence in this disease. There has also
been a 33% increase in the incidence of diagnosed diabetes in the past
decade, and this has been highly correlated with the increase in the
incidence of obesity, suggesting that obesity is a major risk factor
for chronic diseases (39). It is becoming clear that the origins of
chronic diseases are not limited to only inherited genes and/or
sedentary life styles. The results from the HC rat model suggest that
nutritional experiences of infants during the immediate postnatal life
such as overfeeding of formula and early introduction of supplemental
weaning foods high in carbohydrates (e.g. cereals, fruits,
juices, etc.) may contribute to metabolic programming leading to
adult-onset diseases like obesity and diabetes. The newly emerging
field of metabolic programming therefore offers an additional route to
examine the etiology of adult-onset chronic diseases.
| |
ACKNOWLEDGEMENTS |
|---|
We sincerely thank Dr. Richard W. Hanson of Case Western Reserve University for fruitful discussions and for critical reading of the manuscript and Dr. Gail Willsky of this department for comments on the manuscript.
| |
FOOTNOTES |
|---|
* This minireview will be reprinted in the 2002 Minireview Compendium, which will be available in December, 2002. The work performed in the authors' laboratory and summarized in this article was supported in part by NICHD Grant HD-11089 and NIDDK Grants DK-51601 and DK-61518 from the National Institutes of Health.
To whom correspondence should be addressed: Dept. of Biochemistry,
140 Farber Hall, SUNY, 3435 Main St., Buffalo, NY 14214. Tel.:
716-829-3074; Fax: 716-829-2725; E-mail: mspatel@buffalo.edu.
Published, JBC Papers in Press, November 6, 2001, DOI 10.1074/jbc.R100017200
2 M. S. Patel, M. Srinivasan, F. Song, and R. Aalinkeel, unpublished observations.
| |
ABBREVIATIONS |
|---|
The abbreviations used are: HC, high carbohydrate; HC rat, rat raised on a high carbohydrate milk formula; PDX-1, pancreatic duodenal homeobox factor-1; SAPK-2, stress-activated protein kinase-2; PI3-kinase, phosphatidylinositol 3-kinase; GLP-1, glucagon-like peptide-1.
| |
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Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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