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* Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA; and
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
2Correspondence: Novartis Institute of Biomedical Research, 130-2265, 556 Morris Ave., Summit, NJ 07901, USA. E-mail: mathew.toth{at}pharma.novartis.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: intestine • gene targeting • mouse • I-FABP
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
. In this
family, nine types have been identified and are named for the tissue in
which they were first identified. The gene structure of this family is
highly conserved while the amino acid sequences of these proteins are
more similar among the species than among the different types. The
function of these proteins is not well understood. Their ability to
bind lipid ligands suggests a role in lipid metabolism, but direct
evidence for this idea is still lacking.
Detailed studies of I-FABP and its gene (Fabpi) have been
performed (4
5
6
7
8
9
10
11)
. The Kd for various
fatty acids has been measured in the 0.01–1 µM region. In addition,
the crystal structure (in the absence and presence of substrate) as
well as a nuclear magnetic resonance structure have been solved. A
collisional model involving I-FABP has been proposed to explain the
transfer of lipids within the cell, and biophysical experiments have
shown the importance of the alpha helical region of I-FABP to this
mechanism. An interesting variant of human Fabpi (FABP2) was
first identified in the Pima Indians of the American Southwest, a
native population with an extraordinary high rate of type II diabetes
(12)
. Because of its tissue localization, I-FABP is
thought to be involved in the transport of dietary fatty acids in the
small intestine (4
, 5
, 12
, 13)
. To test directly the
importance of I-FABP in this process, we disrupted Fabpi in
the mouse and studied its effect on weight and plasma parameters.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Creation of I-FABP-deficient mice
P1 clones containing the mouse Fabpi gene were
isolated from a Strain 129/ola mouse embryonic stem (ES) cell genomic
library (Genome Systems Inc., St. Louis, Mo.). The library was screened
by polymerase chain reaction (PCR) using primers (sense primer 1:
5'-CACACAGCTGAGATCATGGC-3'; antisense primer:
5'-AGCAGGAGGTGCAAGTATGG-3') based on the mouse I-FABP cDNA sequence
(14)
. The primers were designed to generate a 208 bp
amplification product. Clones isolated from the library were further
characterized by Southern blotting using the 208 bp PCR fragment
labeled with [32P]dCTP (3000 Ci/mmol; Amersham
Pharmacia Biotech, Piscataway, N.J.) by random priming using the
Megaprime DNA Labeling System (Amersham Pharmacia Biotech, Arlington
Heights, Ill.). Hybridizing DNA fragments from these P1 clones were
subcloned into pBluescript (Stratagene, La Jolla, Calif.) and
characterized by restriction enzyme mapping and sequencing. The Strain
129 ES cell line CJ7 (provided by T. Gridley) was cultured on mitomycin
C-treated mouse primary embryonic fibroblast feeder layers in DMEM
medium, as described previously (15)
. ES cells
(3.5x107) suspended in phosphate-buffered saline
(0.8 ml) were mixed with the ClaI-linearized targeting
vector DNA (30 µg), electrophorated at 230 V and 500 µF using a
Bio-Rad GenePulser apparatus (Bio-Rad, Hercules, Calif.), and then
plated on four 60 mm feeder plates. The growth medium was replaced the
following day with medium containing 350 µg/ml Geneticin (Life
Technologies, Rockville, Md.) and 2 µg/ml
1(1–2-deoxy-2-fluoro-ß-darabinofuransyl)-5-iodouracil (FIAU, a gift
from Eli Lilly). Selection was continued for 7 days. The surviving ES
cell clones were picked and expanded into 48-well feeder plates. ES
cell clones were screened for homologous recombination by Southern blot
analysis. ES cell clones bearing the correctly disrupted
Fabpi allele were injected into C57BL/6J blastocysts to
obtain chimeric founders (16)
. PCR was used to screen the
genotypes of the progeny from the chimeric mice. DNA from tail biopsies
was isolated using standard procedures (17)
. The primers
used to identify the wild-type Fabpi allele were sense
primer 1 and 5'-TGTACACCACCATGGTTTGC-3'. The primers used to identify
the disrupted Fabpi allele were sense primer 1 and
5'-TGTGGAATGTGTGTGCGAGG-3'. The cycle profile was touchdown PCR: 94°C
for 1 min, 20 cycles of [94°C for 10 s, 70°C for 90 s,
decrease 0.5°C per cycle], 20 cycles of [94°C for 10 s,
60°C for 90 s], 15°C overnight. Heterozygous mice were mated to
obtain mice that were homozygous for the disrupted Fabpi
gene. The genotype of the mice was confirmed by Southern blot analysis
of HindIII-digested tail DNA using the DNA sequence shown as
the probe in Fig. 1A
.
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RNA blot, RT-PCR, and immunoblot analyses
Poly-A RNA was prepared using the Oligotex Direct mRNA kit
(Qiagen, Valencia, Calif.) and was blotted using the NorthernMax-Plus
kit (Ambion, Austin, Tex.). Probes for the RNA blot were made using the
Lig’nScribe and the Strip-EZ kits from Ambion, and the DNA fragments
were amplified from total RNA prepared from wild-type mouse ileum using
the TRI Reagent (Molecular Research Center, Cincinnati, Ohio). These
probes corresponded to the cDNAs for nucleotides 19–475 of intestinal
FABP, for nucleotides 58–264 of liver FABP, and for nucleotides
95–357 of ileal lipid binding protein (Genbank accession #s M65034,
Y14660, and U00938, respectively). Total RNA for the
reverse-transcriptase (RT) -PCR analysis was prepared from the
enterocytes of the small intestine using the TRI Reagent. First strand
cDNA was prepared using Superscript Reverse Transcriptase (Life
Technologies). The PCR reaction used the oligonucleotides sense primer
1 and 5'-GCTTAGCTCTTCAGCGTTGC-3' under the following cycling
conditions: 94°C for 3 min, 30 cycles of [94°C for 20 s,
60°C for 10 s, 72°C for 1 min], 4°C overnight. Crude
protein extracts from tissues were prepared using a Polytron
homogenizer (Brinkman, Westbury, N.Y.), separated on a 15%
polyacrylamide gel, blotted to PVDF paper, and reacted with rabbit
antisera made against rat I-FABP (Molecular Probes, Eugene, Oreg.). The
immunoblot was visualized with the ECL system (Amersham Pharmacia
Biotech).
Plasma and organ composition analyses
Between age 25 and 30 wk, mice were fasted overnight and briefly
anesthetized with CO2. Blood samples (
0.5 ml)
were collected from the retro-orbital sinus into a tube containing 50
µl of 5% EDTA (pH 7.3) as an anticoagulant. After mixing, the blood
was separated by centrifugation and the plasma fraction was stored at
-80°C until analysis. In Table 1
, plasma was assayed for cholesterol, triacylglycerols, glucose, and
insulin using commercially available diagnostic kits (kits #352, #339,
#315 from Sigma-Aldrich (St. Louis, Mo.) and kit RPA547 from Amersham
Pharmacia Biotech, respectively).
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Six nonfasted mice 32–36 wk old from each group were killed and their
organs dissected out and weighed. To determine lipid composition
analysis, samples of liver and epididymal fat pads were homogenized,
extracted with chloroform/methanol (2:1), and the chloroform layer was
dried down under a stream of N2. The dried
material was dissolved in 0.5 ml of acetone and assayed for cholesterol
and triacylglycerol content using the same assays described above. The
values were normalized to grams of organ weight and presented in
Table 2
. The killed mice also had their blood collected by cardiac puncture,
processed to plasma as described above, and assayed for mouse leptin
using the ML-82K mouse leptin RIA kit (Linco Research Inc., St.
Charles, Mo.).
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Statistical analyses
Quantitative variables were analyzed using the SigmaStat,
version 2.0 software (SPSS Inc., Chicago, Ill.) and significant
differences were determined using Student’s t test. Where
indicated, those data groups that did not pass tests for normality
(Kolmogorov-Smirnov) or for variance (Levene median) were compared
using the Mann-Whitney Rank Sum test. Discrete variables were analyzed
using the 
2 test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, B
). Linearized targeting vector
was used to transform an 129/Sv ES cell line, and clones with the
correctly disrupted I-FABP gene were injected into blastocysts to
produce chimeric mice. Several germline chimeric males were obtained,
and mice homozygous for the targeted Fabpi allele were
identified in subsequent F2 generations. Analysis of the small
intestine from Fabpi-/- mice showed the
absence of the Fabpi mRNA as determined by RNA blotting and
by RT-PCR (Fig. 1C
, D
), as well as the absence of
I-FABP as determined by immunoblotting (Fig. 1E
). Mice with
the disrupted Fabpi allele were viable, fertile, and
displayed no obvious morphological abnormalities.
Other members of the FABP family are expressed in the proximal and
distal portions of the small intestine; therefore, RNA from this organ
was analyzed by RNA blotting to determine whether the loss of I-FABP
altered the expression of these genes. No obvious changes in the
abundance of the mRNAs encoding the liver FABP or the ileal lipid
binding protein were apparent (Fig. 1C
). In addition, mRNAs
for the adipocyte FABP and the heart FABP remained undetectable (data
not shown) although these proteins are not normally found in the small
intestine.
To minimize genetic variability, the disrupted Fabpi allele was backcrossed to the C57BL/6J background for five generations and then intercrossed to produce Fabpi-/- and Fabpi+/+ lines. The fecundity and the sex ratio of the litters from the backcrossed Fabpi-/- and Fabpi+/+ lines were similar. Median litter sizes of eight for Fabpi+/+ and six for Fabpi-/- were not significantly different using a Mann-Whitney Rank Sum test (P=0.15, n=13–14). There was no significant deviation from the expected male/female ratio of 1:1 for either the Fabpi-/- (P=0.6) or the Fabpi+/+ litters (P=0.4).
Weight and weight gain were used as indicators of dietary fat
assimilation. We expected that if I-FABP was necessary for the uptake
of dietary fatty acids, then mice deficient in I-FABP would not gain as
much weight as their normal counterparts. Surprisingly, on the low-fat
(LF) diet the male Fabpi-/- mice were
consistently heavier (110% of Fabpi+/+) than
their normal counterparts, whereas the female
Fabpi-/- and Fabpi+/+
mice were indistinguishable in weight (Fig. 2A
). When switched from a low-fat to a high-fat (HF) diet at
age 15 wk, male Fabpi-/- mice gained more
weight (130% of Fabpi+/+) by 25 wk age whereas
the Fabpi-/- female mice actually gained less
weight (70% of Fabpi+/+) over the same time
interval (Fig. 2B
). Consistent with the weight increase in
males, plasma leptin levels were significantly elevated in the male
Fabpi-/- mice after 32–36 wk on the chow diet
(11±1.6 vs. 3.9±0.9 ng/ml, Fabpi-/- vs.
Fabpi+/+, respectively, n=5–6,
P=0.002). Female mice after 32–36 wk on a chow diet showed
no significant difference in plasma leptin levels (6.1±1.1 vs.
6.2±1.0 ng/ml, Fabpi-/- vs.
Fabpi+/+, respectively, n=5–6,
P=0.9).
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We hypothesized that these aberrations in weight gain observed for the
Fabpi-/- mice should also be accompanied by
other changes, particularly in the plasma concentrations of energy-rich
compounds and metabolic hormones (Table 1)
. Plasma triacylglycerol
concentrations in male Fabpi-/- mice were
higher (130–150% of Fabpi+/+) on both the LF
and HF diets, which correlates with their increased body weight. Female
Fabpi-/- mice were not significantly different
in plasma triacylglycerol levels on either diet compared to female
Fabpi+/+ mice, but they did show a significant
lowering (93% of Fabpi+/+) in plasma
cholesterol on the HF diet. The lipoprotein particles in the plasma of
Fabpi-/- and Fabpi+/+
mice were analyzed for cholesterol and triacylglycerols by
high-performance liquid chromatography gel filtration, and the
distribution was similar between these two strains (data not shown). In
addition, I-FABP deficiency caused a significant elevation (1.4- to
4-fold of Fabpi+/+) in plasma insulin
concentration, which was independent of gender and dietary fat status.
This hyperinsulinemic effect of I-FABP deficiency was not accompanied
by a significant change in plasma glucose concentration compared to
their Fabpi+/+ counterparts.
In Fig. 3
the weights of several organs were compared. On the LF diet, the organ
weights of the female Fabpi-/- mice were
similar to their Fabpi+/+ counterparts, which
was expected given that their total body weights were also similar
(Fig. 3A
). On the HF diet, female
Fabpi-/- mice had significantly lower weights
for uterine fat pads (65%) and livers (93%) compared to
Fabpi+/+ females (Fig. 3B
). On the LF
diet, the male Fabpi-/- mice had significantly
greater masses for epididymal fat pads (200%) and kidneys (120%), but
not for livers, when compared to Fabpi+/+ males
(Fig. 3C
). On the HF diet, the male
Fabpi-/- mice had significantly greater
weights for livers (200%) and kidneys (120%), but not for epididymal
fat pads, when compared to Fabpi+/+ males (Fig. 3D
). In Table 2
we compared the concentration of cholesterol
and triacylglycerols in the liver and the epididymal fat pads and found
no significant differences between the
Fabpi-/- and the
Fabpi+/+ male mice on either the LF or HF diets.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 5
, 12
, 13)
. Surprisingly, we
have found that inactivation of the Fabpi gene in mice is
not lethal. The Fabpi-/- mice appeared
morphologically normal and produced litters with sizes and sex
distributions that were comparable to
Fabpi+/+mice. There was no apparent
up-regulation of mRNAs for the other FABPs in the small intestine of
Fabpi-/- mice (Fig. 1C
) to
compensate for the loss of I-FABP. It is possible that the existence of
multiple types of FABPs in the small intestine represents a mechanism
that ensures functional redundancy. Nevertheless, it is clearly evident
that the complete absence of I-FABP does not have a detrimental effect
of dietary fat absorption.
The deficiency of Fabpi did produce small but highly
reproducible alterations in body weight and weight gain in the
Fabpi-/- mice that depended on the sex of the
mouse (Fig. 2)
. Male Fabpi-/- mice were
slightly heavier (10%) than male Fabpi+/+
mice on either a LF or HF diet, whereas female
Fabpi+/+ or Fabpi-/-
mice were indistinguishable on the LF diet (Fig. 2A
). When
challenged with a HF diet the female Fabpi-/-
mice did not gain weight as quickly as Fabpi+/+
females (Fig. 2B
). This opposing effect on weight gain
between the male and female mice indicates that the loss of I-FABP does
not result in a consistent effect on body weight, and it further calls
into question the idea that I-FABP functions primarily in the uptake
and intracellular transport of dietary fatty acids. Consistent with the
weight differences of Fig. 2A
, at 32–36 wk plasma leptin
levels were elevated in male but not in female
Fabpi-/- mice.
As expected, the differences in body weight for the
Fabpi-/- mice reflected differences in the
weight of organs (Fig. 3)
that are known to store energy (fat depots
and liver). Because the concentrations of triacylglycerols and
cholesterol in the liver and fat pads were not different between the
Fabpi-/- and the
Fabpi+/+ male mice on either the LF or HF diets
(Table 2)
, we assume that the increases in organ weights in Fig. 3C
, D
reflect a quantitative rather than a
qualitative difference. The reason why the fat content of the diet
altered the weight of either the livers or the epididymal fat pads of
the Fabpi-/- male mice is unclear. We suggest
that on a diet abundant in lipids (HF diet), the male
Fabpi-/- mice tended to store more of this
energy in an organ that is easily or quickly accessible to metabolism
(liver). On a diet that is more restricted in lipids (LF diet), the
male Fabpi-/- mice tended to store energy in a
less accessible storage depot (fat). These effects would suggest that
I-FABP is somehow involved in determining the disposition of lipid
stores.
It was previously shown in mice that the loss of the adipocyte
FABP uncoupled obesity from insulin resistance and impaired fat cell
lipolysis (18
, 19)
, whereas deletion of heart FABP caused
a metabolic switch in the heart from mainly lipid metabolism toward
mainly glucose metabolism (20)
. I-FABP has been suggested
to be involved in the absorption of dietary fatty acids (4
, 5
, 12
, 13)
; however, the results of our study suggests that I-FABP
is not essential to this process. In fact, the higher concentration of
triacylglycerols in the plasma of male
Fabpi-/- mice (Table 1)
, which is consistent
with their greater weight gain, would imply that in male mice the rate
of dietary fat transfer into the plasma compartment is actually
increased in the absence of I-FABP. In support of this inhibitory role
for I-FABP, when the human intestinal cell line Caco-2 overexpressed
human I-FABP the cells showed a lower rate of fatty acid absorption,
which is consistent with I-FABP depressing cellular fat transfer
(21)
.
Elevated plasma insulin levels were the only parameter consistently
different between Fabpi-/- and
Fabpi+/+ mice regardless of sex, with
Fabpi-/- males showing the largest effect
(Table 1)
. However, this hyperinsulinemia was not accompanied by a
change in blood glucose when compared to the
Fabpi+/+ counterparts.
The alanine to threonine variant (A54T) of the human gene
for I-FABP was initially found in the Pima Indian population of the
American Southwest (12)
. This population is associated
with abnormal lipid metabolism and an increased incidence of obesity
and type II diabetes (22)
. This same mutation in a Finnish
population was associated with a defect in postprandial lipemia
(23)
and other dyslipidemias (24)
. The male
Fabpi-/- mice described here show features
that are similar to these human populations. Although the
hyperinsulinemic effect of I-FABP deficiency in mice was not
accompanied by hyperglycemia, a sustained elevation in plasma insulin
level may eventually lead to a true diabetic condition. Our
Fabpi-/- mice and the A54T human mutation
suggest to us that I-FABP functions physiologically as a lipid-sensing
component of energy homeostasis and not as a direct part of dietary
fatty acid absorption. I-FABP likely feeds information about dietary
lipid status into mechanisms that universally control energy
utilization, energy storage, and eventually body weight. The
gender-dependent dichotomies of the Fabpi-/-
mice also indicate that this lipid sensing function of I-FABP is
influenced by sex hormones, which may be relevant to the fat
distribution differences that is often observed between the
sexes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication November 9, 1999.
Revision received March 1, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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