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Faculty of Human and Cultural Studies, Tezukayama Gakuin University, 4–2-2 Harumidai, Sakai, Osaka 590-0113, Japan
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • gene expression • leptin • insulin • insulin receptors • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Gene expression is
very low in the starved or diabetic rats, and insulin treatment of
diabetic rats quickly increases expression. The mechanisms of
stimulation and suppression of lipogenic enzyme gene expression have
been elucidated, and the cis-acting elements of genes are
involved (Bai et al. 1996
, Fukuda and Iritani 1999b
, Fukuda et al. 1996a
, 1996b
, 1997a
, 1997b
, and 1999
, Moustaid et al. 1994
, Towle et al. 1997
).
In vitro studies have raised the possibility that leptin modulates
insulin activities in obese human hepatic cells (Cohen et al. 1996
). Leptin impairs several metabolic actions of insulin,
namely stimulation of glucose transport, glycogen synthesis,
lipogenesis, inhibition of isoproterenol-induced lipolysis and
protein synthesis. Moreover, leptin diminishes insulin secretion of
pancreatic beta cells and induces insulin resistance (Remesar et al. 1997
). Muller et al. (1997)
reported that
insulin effects were reduced by leptin (2 nmol/L), which has a
half-life of about 8 h in rat adipocytes. At higher
concentrations this responsiveness was diminished, resulting in nearly
complete inhibition of insulin effects at >30 nmol/L leptin.
Barr et al. (1997)
reported that insulin increased both
leptin secretion and production by rat white adipose tissue when
epididymal fat pads were incubated in vitro in the presence or absence
of insulin. Insulin deficiency provoked by streptozotocin also markedly
down-regulated leptin mRNA, and this suppression was rapidly
reversed by insulin (MacDougald et al. 1995
). Other
groups also reported that the mRNA levels for leptin in fully
differentiated adipocytes were increased by insulin (Leroy et al. 1996
, Rentsch and Chiesi 1996
). In adipose
cells, the level of leptin mRNA is sensitive to insulin in the
nanomolar range of concentrations with an increase from an average of l
copy to 5–10 copies/cell (Becker et al. 1995
). The
effect of insulin was fully reversible and occurred primarily at a
transcription level. These results suggest that insulin is an important
regulator of leptin gene expression.
We previously mapped the sequences responsible for
insulin/glucose-stimulation and polyunsaturated fatty acids
(PUFA)3
-suppression in the proximal region from nucleotide -57 to -35 of the
fatty acid synthase gene of rat liver (Fukuda et al. 1996a
). When a synthetic nucleotide probe of the
FAS(-57/-35) gene linked to a reporter gene was used
for transfection, the reporter activity was significantly increased in
response to insulin/glucose-treatment in hepatocytes compared to
glucose treatment (Fukuda et al. 1997a
). We found that
the insulin stimulation was suppressed by addition of PUFA
(Fukuda et al. 1997a
) or leptin (Fukuda et al. 1999
). Bai et al. (1996)
reported that leptin
gene expression in 30A5 preadipocytes suppressed the acetyl-CoA
carboxylase mRNA level and lipid synthesis induced by hormone
treatment. It appeared that leptin may be involved in lipogenic enzyme
gene expression.
Leptin controls food intake and body weight at the level of the
brain (Campfield et al. 1995
, Halaas et al. 1995
, Pelleymounter et al. 1995
). In contrast to
these centrally mediated effects of leptin, we investigated the DNA
regulatory sequences required for stimulation and suppression of leptin
gene expression (Fukuda and Iritani 1999a
). Primary
cultured hepatocytes and adipocytes of rats were transfected with
plasmids containing the 5'-flanking sequences of the rat leptin gene
fused to the luciferase gene. When two copies of the sequences spanning
nucleotides -101 to -83 of the leptin promoter were used for
transfection, the reporter activity significantly increased in the
presence of insulin and glucose in comparison with glucose alone. These
findings were similar to those found for the transcription of the fatty
acid synthase(-57/-35) and ATP citrate-lyase (-64/-41) genes.
Moreover, the DNA-protein complexes were common to the
glucose/insulin regions of the leptin, fatty acid synthase and ATP
citrate-lyase genes, suggesting that these genes are coordinately
regulated. Therefore, we investigated the diet and insulin regulation
of expressions of leptin, lipogenic enzymes and insulin receptors in in
vivo experiment using rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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[
32P]dCTP (111 TBq/mmol) was purchased from ICN
Pharmaceuticals, (Costa Mesa, CA). Nylon filter (Hybond N) was
purchased from Amersham (Buckinghamshire, United Kingdom). Insulin
assay kit was obtained from Eiken Chemical Company (Tokyo, Japan). Rat
leptin assay kit was from Linco Research (St. Charles, MO). Recombinant
mouse leptin was from R and D System, (Minneapolis, MN). Most other
reagents were obtained from Sigma (St. Louis, MO) and Wako (Osaka,
Japan).
Animals.
Male Wistar rats (Japan SLC, Hamamatsu, Japan), 7-wk-old, fed on a
commercially available nonpurified diet (No. MF, Oriental Shiryou,
Osaka, Japan) were food-deprived overnight and then fed a
fat-free diet or a 10 g/100 g corn oil diet. Table 1
shows the diet compositions and the fatty acid compositions of corn
oil. Corn oil replaced sugar. Rats were individually housed in
wire-bottomed cages in a temperature-controlled room (24°C)
under an automatic lighting schedule (0800–2000 h). Each rat had free
access to water and was fed an equal amount of energy-containing
diet/body weight/day. Different amounts of the diets were given to
equalize energy between the two dietary groups. The amount of
diet consumed by a rat was measured at 1700 h every day. Based on
the measurement, the expected amount of diet consumed was given the
following day. Only the rats with equal energy intakes were used in the
experiment. In time-course studies, rats were killed at 0, 0.5, 1,
2, 4, 8, 16, 24 or 48 h after feeding.
|
) of the effect of leptin treatment on lipogenic enzyme expression, some
rats were intraperitoneally injected with recombinant mouse leptin
[0.3 mg in 0.2 mL of phosphate buffered saline (PBS)/kg body] at
1 h of feeding after being food-deprived overnight. They were
then killed to measure the mRNA concentrations of lipogenic enzymes
16 h after feeding between 0900 and 1000 h. For the control,
other rats were similarly injected with 0.2 mL PBS/kg body. The rats
with and without leptin treatment were each given equal amounts of
energy-containing diet per body weight during the feeding
period. Only the rats which consumed equal
energy-containing diet were used for the experiment.
|
). Dot blot and Northern blot hybridization assays.
Human insulin receptor cDNA (Ebina et al. 1985
) was a
generous gift from Professor Y. Ebina (Institute for Enzyme Research,
University of Tokushima, Japan). A rat leptin cDNA fragment spanning
nucleotides -59 to +540 was cloned from adipose tissue by reverse
transcription and polymerase chain reaction amplification according to
Murakami and Shima (1995)
. The genomic clone of rat rRNA
was obtained from the Japanese Cancer Research Resources Bank (Mishima,
Japan). About a 1-kb BamHI/EcoRI fragment of this clone was isolated
and used as a probe for 18S rRNA. Total RNA was isolated from liver or
white adipose tissue by acid guanidium thiocyanate-phenol-chloroform
extraction (Chomczynski and Sacchi 1987
). To measure the
mRNA concentrations of insulin receptors, leptin gene and lipogenic
enzymes, the total RNA (20–50 µg) was denatured with formamide,
spotted on a nylon filter and then radiated with UV light for 5 min.
The filter was prehybridized and then hybridized with
32P-labeled cDNA as described previously (Katsurada et al. 1990
). Relative densities of the hybridization signals
were determined by scanning the autoradiograms at 525 nm and normalized
to the values of 18S rRNA. The mRNA concentrations were measured by the
dot blot hybridization method, and many of them were confirmed by
Northern blot analysis.
Northern blot analysis of RNA was performed as described by
Gonzales and Kasper (1982)
. Total RNA was denatured and
electrophoresed on a 0.8% agarose gel containing 2.2 mol/L
formaldehyde. The gel was blotted onto a nylon filter according to
Thomas (1980)
. Prehybridization, hybridization and
autoradiography were carried out by using the dot blot hybridization.
Details were as described previously (Katsurada et al. 1990
). The autoradiograms of Northern blot analysis of leptin
and insulin receptors were shown in Figure 1
. One broad band was found for leptin. Several bands were found for
insulin receptors. The radioautograms of Northern blot analysis of
acetyl-CoA carboxylase and fatty acid synthase were shown
previously (Iritani et al. 1996a
and 1996b
).
|
Isolated epididymal fat cells were prepared by shaking adipose tissue
at 37°C for 60 min in Krebs-Ringer bicarbonate buffer containing
collagenase (2 g/L) and albumin (30 g/L), according to the method of
Rodbell (1964)
. Adipocytes were incubated in Krebs
Ringer buffer [50 g/L bovine serum albumin (BSA), pH 7.4] containing
[125I]-labeled insulin and varying concentrations of
unlabeled insulin for 45 min at 25°C. Incubations were terminated by
the oil flotation method, and the incorporations of radiolabeled
insulin by adipocytes were measured using a gamma counter
(Gammeltoft and Gliemann 1973
, Olefsky and Reaven 1975
).
Preparation and insulin binding assay of liver.
Insulin receptors were purified from livers using an agarose column
according to the method of Kadowaki et al. (1984)
.
Purified insulin receptors were incubated with
[125I]-labeled insulin at 4°C for 16 h in the
presence of varying concentrations of unlabeled insulin
(Kadowaki et al. 1984
). With human gamma globulin as the
carrier protein, receptor-bound insulin was precipitated with
polyethylene glycol (Hedo et al. 1981
).
Analyses.
Plasma glucose concentrations were determined by the
glucose-oxidase method (Werner et al. 1970
). Plasma
and pancreas insulin concentrations were measured by a two-antibody
system radioimmunoassay according to the method of Morgan and Lazarow (1963)
. Pancreas was homogenized and insulin was
extracted with a cold solution of ethanol/2 mol/L HCl/water
(75:1.5:23.5, by vol). Plasma leptin concentrations were measured by a
two-antibody system radioimmunoassay according to the method of
Maffei et al. (1995)
.
Statistical analysis.
Two-way ANOVA was followed by inspection of all differences between
pairs of means by using the least significant difference test
(Snedecor and Cochran 1967
). Differences were
considered significant at P < 0.05.
|
RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasma glucose concentrations were significantly greater in rats at 30
min after the feeding than in food-deprived rats, and even greater
in rats at 8 h after the feeding (Fig. 2
). Plasma insulin concentrations were also significantly greater in rats
at 30 min after the feeding, and reached maximal level at 8 h. In
contrast, the pancreas insulin concentrations had rapidly decreased at
1 h after feeding, and continued to gradually decrease for the
next 15 h until reaching about 50% (Fig. 3
). The glucose and insulin concentrations did not differ between the
rats fed the fat-free diet and those fed the corn oil diet. The
concentrations of plasma free fatty acids were immediately and markedly
decreased in contrast to those of glucose and insulin, and reached
about 50% in both groups 1–2 h after feeding (Fig. 2)
. The
concentrations were significantly lower in rats fed the corn oil diet
than in those fed the fat-free diet at 30 min. After 30 min,
concentrations did not differ between groups.
|
|
The plasma leptin concentrations had not changed at 4 h after
feeding but reached maximal level in rats at 8 h (Fig. 4
). The plasma leptin concentrations were increased about two- and
fourfold in rats at 8 h after feeding the fat-free diet and
the 10% corn oil diet, respectively. Plasma leptin concentrations were
elevated by the dietary corn oil (P < 0.001).
|
The leptin gene mRNA concentrations in adipose tissue began to increase
30 min after feeding and reached maximal level at 8–16 h after feeding
(Fig. 4)
. The expression of leptin mRNA and plasma leptin
concentrations generally were higher in rats fed the corn oil diet than
in those fed the fat-free diet. The autoradiograms of Northern blot
analysis of leptin are shown in Figure 1
. One broad band was found for
leptin. The intensities of the bands at 16 h were higher in rats
fed the corn oil diet than in those fed the fat-free diet and
supported differences in mRNA concentrations measured by dot blot
hybridization assay in Figure 4
.
Insulin receptor mRNA concentrations after feeding.
The insulin receptor gene expression was the reverse of the plasma
insulin concentrations in liver and adipose tissue. The insulin
receptor mRNA concentrations in the livers began to decrease 30 min
after feeding, were greatly decreased at 2 h and further decreased
to about half of the starved level at 8–16 h (Fig. 5
). Insulin receptor mRNA concentrations in the adipose tissue decreased
after the feeding similarly in the liver and had reached 50% levels at
16 h in both dietary groups. The autoradiograms for liver are not
shown but are similar to those for adipose tissue (Fig. 1)
. The
intensities of the bands at 2 h were not different in rats fed the
fat-free or corn oil diets and supported the mRNA concentrations
measured by dot blot hybridization assay (Fig. 5)
.
|
The insulin-binding capacities were high in the food-deprived
rats (Fig. 6
). The insulin-binding capacities in liver were markedly
(P < 0.001) decreased at 30 min after feeding and
partially recovered to about half of the food-deprived level at
2 h. The capacities in liver were significantly lower in rats fed
the corn oil diet compared to those fed the fat-free diet at 1 h after the feeding, but no differences were evident between the groups
after recovery. The capacities in adipocytes also markedly decreased at
30 min to about 50% levels in both dietary groups, but no differences
were evident between groups.
|
The mRNA concentrations in adipose tissue were significantly increased
at 16 h after feeding and reached maximal levels at 24 h,
while the mRNA concentrations in liver increased after 8 h and
reached maximal level at 16 h (Fig. 7
). The expression of acetyl-CoA carboxylase and fatty acid synthase
mRNA was suppressed by feeding the PUFA-containing, corn oil diet.
The lag time for mRNA induction after refeeding was longer in adipose
tissue than in liver.
|
Leptin was intraperitoneally injected into the rats at 1 h of
feeding. The rats were killed 16 h after the feeding to measure
the mRNA concentrations of their highest levels. Food consumption was
not significantly different between rats with and without leptin
treatment (Table 2)
and was not reduced for 16 h after
feeding and leptin treatment. Leptin treatment significantly suppressed
the mRNA concentrations in rats fed the fat-free diet, but not in
those fed the corn oil diet. The plasma insulin levels were not
significantly changed by the leptin treatment in either dietary group,
when the rats were killed 16 h after the feeding. When the plasma
insulin levels were followed after the leptin treatment, the levels at
2, 4, 6 and 8 h after the treatment were not significantly changed
in either dietary group and also did not differ between groups (data
not shown). Because effects of leptin treatment on plasma insulin
levels were not found, it is not clear whether insulin participates in
the effects of leptin treatment on lipogenic enzyme gene expression.
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Leptin mRNA concentrations in adipose tissue began to increase at
30 min after diet feeding diet and reached maximal levels 8–16 h after
refeeding (Fig. 4)
. Becker et al. (1995)
reported that
food deprivation produced a sharp decrease in leptin mRNA in epididymal
and inguinal fat pads of rats from 24 h onward, and that feeding
rapidly (3–6 h) induced leptin gene expression. They also reported
that the leptin mRNA level showed a rapid turnover, with a
half-life of approximately 2 h in the absence or presence of
insulin. A similar result was seen in the present experiment. The
expression of leptin mRNA was higher in rats fed the corn oil diet than
in those fed the fat-free diet. Thus, leptin gene was regulated by
variations in the nutritional state.
The mRNA concentrations of lipogenic enzymes were maximal after 16 h in liver and after 24 h in adipose tissue. The enzyme activities
were maximal after 48–72 h (Iritani 1992
,
Iritani et al. 1996a
). Leptin was expressed before
lipogenic enzymes after feeding. Lipogenic enzyme gene expression was
suppressed by dietary PUFA in the liver and adipose tissue, while
leptin gene expression was not suppressed in the adipose tissue but
rather was stimulated. Plasma leptin concentrations were increased by
dietary PUFA. For leptin to suppress lipogenic enzyme expression, it is
advantageous that the genes of both lipogenic enzymes and leptin were
coordinately changed by manipulation of insulin and dietary fat level.
The leptin treatment significantly suppressed the expression of
lipogenic enzyme mRNA in rats fed the fat-free diet, but not in
those fed the corn oil diet (Table 2)
. The leptin treatment had no
additive effect with dietary PUFA in suppressing lipogenic enzyme
expression. It is possible that leptin did not influence lipogenic mRNA
expression in corn oil-fed rats because leptin was already higher
in these animals and therefore already maximally active.
We previously investigated the insulin-induced stimulation of the
genes of ATP citrate-lyase (ACL) and fatty acid synthase in primary
cultured hepatocytes or adipocytes. The sequence from -64 to -41 of
the ACL gene, which is responsible for stimulation by insulin and
glucose and for suppression by PUFA in hepatocytes (Fukuda et al. 1996b
), was linked to a reporter gene and transfected into
rat hepatocytes or adipocytes. Liver and epididymal adipose tissues are
the major tissues where lipogenic enzyme genes are expressed. The CAT
activities of the ACL gene expressed in the presence of glucose alone
were low in these cells (Fukuda and Iritani 1999b
). In
the presence of insulin and glucose, however, the CAT activities were
markedly increased. A similar result was previously obtained for the
CAT activities of the sequence from -57 to -35 of the FAS gene
(Fukuda et al. 1996a
).
The stimulation of the CAT activities of FAS (-57/-35) by insulin and
glucose was reduced in PUFA-treated adipocytes and hepatocytes.
Stimulation was also reduced in the leptin-treated cells or leptin
gene expression vector-containing cells (Fukuda et al. 1999
). In the presence of PUFA or leptin, the
insulin-binding capacities of partially purified insulin receptors
from liver and isolated adipocytes of the rat were decreased
(Fukuda and Iritani 1999a
). Walder et al. (1997)
also reported that leptin decreased maximal insulin
binding in a dose-dependent manner. Leptin and PUFA appeared to
suppress the insulin stimulation of transcription of lipogenic enzymes,
possibly due to the reduction of insulin action. Cohen et al. (1996)
also demonstrated that leptin may attenuate insulin
activity in isolated hepatocytes.
Bai et al. (1996)
reported that leptin gene
expression in 30A5 preadipocytes suppressed the acetyl-CoA
carboxylase mRNA level and lipid synthesis induced by insulin. They
observed that leptin suppressed the accumulation of lipid droplets that
occurs in the adipocytes. Leptin appeared to suppress lipid synthesis
and lipid levels without the participation of the brain.
Previous results in hepatocytes (Fukuda et al. 1996a
, 1996b
, 1997a
and 1997b
) support the present results of this animal
study. Thus, the expressions of leptin, insulin receptors and lipogenic
enzymes are coordinately and/or mutually regulated by glucose and
insulin levels during dietary manipulation.
|
FOOTNOTES |
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3 Abbreviations used: ACL, ATP citrate-lyase; BSA,
bovine serum albumin; FAS, fatty acid synthase; PBS, phosphate
buffered saline; PUFA, polyunsaturated fatty acids.
Manuscript received August 30, 1999. Initial review completed October 5, 1999. Revision accepted January 10, 2000.
|
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