1 Section of Endocrinology and Metabolism, McGuire Veterans Administration Medical Center and 2 Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23249
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ABSTRACT |
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The
interrelationship between insulin and leptin resistance in young
Fischer 344 (F344) rats was studied. Young F344 and Sprague-Dawley (SD)
rats were fed regular chow. F344 animals had two- to threefold higher
insulin and triglyceride concentrations and increased stores of
triglycerides within liver and muscle. F344 animals gained more body
fat. Both acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase I
gene expression were 20-50% less in F344 animals than in
age-matched SD animals. Peroxisome proliferator-activated receptor-
gene expression was reduced in 70-day-old F344 animals. Finally,
resistin gene expression was similar in 70-day-old SD and F344 animals. Resistin gene expression increased fivefold in F344 animals and twofold
in SD animals from 70 to 130 days, without a change in insulin
sensitivity. We conclude that young F344 animals have both insulin and
leptin resistance, which may lead to diminished fatty oxidation and
accumulation of triglycerides in insulin-sensitive target tissues. We
did not detect a role for resistin in the etiology of insulin
resistance in F344 animals.
Fischer 344 rats; acyl-coenzyme A oxidase; carnitine
palmitoyltransferase I; peroxisome proliferator-activated receptor-
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INTRODUCTION |
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INSULIN AND LEPTIN, intimately involved with intermediary metabolism and body weight homeostasis, appear to be physiologically linked. Insulin and leptin are secreted in the peripheral circulation by pancreatic islets and adipocytes, respectively, and they cross the blood-brain barrier (19). Both hormones have receptors within appetite centers in the hypothalamus and inhibit feeding (22). Finally, the secretion of both hormones appears to be regulated by glucose and the generation of intracellular energy (14). A close relationship also exists between insulin and leptin resistance. Nearly all individuals with type 2 diabetes are markedly insulin resistant, and the majority of them are obese and leptin resistant (2, 17). Most animal models of insulin resistance and type 2 diabetes mellitus have defects either in leptin secretion (e.g., as in the ob/ob mouse) or in leptin sensitivity (e.g., as in the db/db mouse, Zucker fa/fa rat, diet-induced obesity; see Ref. 10). Morbid obesity and glucose intolerance are noted early in the life span of the animals that display these monogenetic mutations; therefore, they do not adequately represent the majority of human type 2 diabetes subjects in whom these diseases develop later in life.
The Fischer 344 (F344) rat has been used as a model of aging-induced insulin resistance (3). This animal strain was believed to become insulin resistant with aging, but it did not appear to gain appreciable amounts of weight or of body fat. However, recent studies in our laboratory disclosed that F344 animals gained more body fat than did a commonly studied insulin-sensitive animal strain [Sprague-Dawley (SD); see Ref. 15]. Not only did F344 rats ingest more calories per gram body weight but also they stored more calories as weight and they converted ingested calories into fat more efficiently than did the SD rats. The propensity of the F344 rats to gain body fat occurred at young ages (70 days), and it occurred despite higher fasting and meal-induced concentrations of leptin. These studies suggested to us that the F344 animals were resistant to the two main biological responses to leptin, namely the inhibition of appetite and the enhancement of energy expenditure.
Therefore, it appears that the F344 strain may be a good model of human diabetes mellitus. These F344 animals have leptin resistance without developing morbid obesity, and they develop diabetes late in their life span. The purpose of the present study was to define more rigorously the insulin sensitivity of young Fischer rats and to study the interrelationship between insulin resistance and leptin resistance. Several studies have suggested that physiological and cellular mechanisms that lead to the accumulation of lipids in insulin-sensitive target tissues (16, 18, 5) and in the pancreatic islets (12) may produce a clinical syndrome of insulin resistance and declining insulin secretory capacity; this syndrome is typical of type 2 diabetes mellitus. Leptin reduces intracellular accumulation of lipids in liver, muscle, and in the pancreatic islet (1, 8, 13, 20). Therefore, leptin resistance may exaggerate the lipid accumulation in adipose and nonadipose tissue and worsen insulin resistance.
We have measured indexes of lipid accumulation within insulin-sensitive target tissues and the gene expression of factors and enzymes involved with mitochondrial and peroxisomal fatty acid oxidation in the leptin-resistant F344 strain. Furthermore, we tested the hypothesis that the newly discovered resistin gene links obesity and insulin resistance (21). We have found that the F344 animals are both leptin and insulin resistant. We have also found that this strain accumulates lipid excessively in liver and muscle and that the gene expression of factors and enzymes involved with fatty acid oxidation are reduced. However, we did not find that resistin gene expression played a role in the insulin resistance observed in F344 animals.
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METHODS |
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Animals and diets. All animals were humanely treated, and the experimental protocols were reviewed and accepted by the Institutional Animal Care and Use Committee at Virginia Commonwealth University. Sixty-day-old SD and F344 rats were purchased from Harlan Sprague-Dawley (Indianapolis, IN) and housed in individual cages under controlled lighting conditions on a natural dark-light cycle (1800-0600). The animals were allowed free access to food and water. All animals were fed a regular chow diet (Purina).
Serum and tissue measurements.
Seventy- and 130-day-old SD (n = 10 at each age) and
F344 (n = 10 at each age) animals were fasted
overnight. One-half of the animals was killed (fasted), and the other
one-half of the animals was fed a regular powdered chow (total 8 g) for 3 h and then killed (refed). Therefore, there were five
animals in four experimental groups (70-day-old SD and F344 animals,
fasted; 130-day-old SD and F344 animals, refed). Invariably, the
animals ingested the entire 8 g of pelleted chow that were
supplied. All animals were anaesthetized with isoflurane before they
were decapitated. Blood was collected and saved on ice. After being
spun in a centrifuge, the serum was isolated and saved in a 80°C
freezer. Liver, abdominal muscle, and the epididymal fat pad were
quickly dissected and weighed, and then they were frozen in liquid
nitrogen and stored in a
80°C freezer.
Intravenous glucose tolerance test. Seventy- and 130-day old SD and F344 animals were anesthetized with isoflurane, and a catheter was inserted in the external jugular vein, as previously described (11). The infusion cannulas were tunneled subcutaneously to the back of the neck. The catheter was infused with heparin to prevent clot formation at the intravenous tip of the catheter, and the external end of the catheter was plugged. The animals were allowed to recover for 2 days. On the 3rd day, the animals were fasted overnight. The next morning, 0.5 ml of blood (for fasting glucose and insulin levels) was withdrawn through the catheter, and then 0.55 g/kg of glucose was infused through the catheter over a 1-min period, as previously described (4). After 5, 10, 15, 20, and 30 min, 0.5 ml of whole blood was again withdrawn through the catheter. Serum glucose and insulin were measured at the indicated times.
Gene expression by quantitative RT-PCR.
RNA was extracted from liver, muscle, and adipose tissue by the TRIzol
Reagent method, as described by the suppliers (GIBCO-BRL, Grand Island,
NY). cDNA synthesis was performed with an oligo(dT) primer and
Superscript reverse transcriptase, as described by the supplier
(GIBCO-BRL). Duplex PCR was performed in a solution with primer pairs
from a gene of interest and a housekeeping gene. The sense and
anti-sense primers for each gene are as follows: peroxisome
proliferator-activated receptor- (PPAR
), sense
5'-AAGCCATCTTCACGATGCTG-3' and anti-sense
5'-TCAGAGGTCCCTGAACAGTG-3' (25); acyl-CoA oxidase (ACO), sense 5'-GCCCTCAGCTATGGTATTAC-3' and anti-sense
5'-AGGAACTGCTCTCACAATGC-3' (25); carnitine
palmitoyltransferase I (CPT I), sense 5'-TATGTGAGGATGCTGCTTCC-3' and
anti-sense 5'-CTCGGAGAGCTAAGCTTGTC-3' (25); resistin,
sense 5'-GGGAGTTGTGCCCTGCT-3' and anti-sense
5'-CAGCACTCGGAGGGCAA-3' (9); enolase, sense
5'-TTCTCAAGATCCATGCCAGG-3' and anti-sense 5'-GCGTTCGCACCAAACTTAGA-3';
-actin, sense
5'-GTGACGAGGCCCAGAGCAAGAG-3' and anti-sense
5'-AGGGGCCGGACTCATCGTACTC-3'.
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Statistical analysis. We performed a two-way ANOVA (GraphPad Prism Version 3.0; GraphPad Software) to compare the effects of the fed state (fasting vs. refeeding) or strain (SD vs. F344) on various indexes of weight, body composition, and insulin sensitivity. We performed an unpaired t-test (GraphPad Prism version 3.0) when an experimental parameter in one strain of animal was compared with the other strain of animal.
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RESULTS |
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Seventy-day-old SD and F344 animals were fed regular rat chow ad
libitum for 60 days. Indexes of weight and body composition are shown
before (Table 1) and after (Table
2) the 60-day feeding period. In one-half
of the animals, measurements were obtained in animals fasted overnight
(fast). In the other one-half of the animals, measurements were
obtained in animals that were fasted overnight and then refed regular
chow for 3 h (refed). Age-matched SD rats are larger than F344
rats, and both strains gain ~1.5-fold their body weight in 60 days
when eating regular chow. However, the F344 animals are fatter than the
SD animals. At 60 days, the epididymal fat pad is ~15% larger in
F344 animals compared with SD animals (Table 1). In the 60-day
feeding period, the fat pad weight in SD animals increased by
~1.9-fold, whereas the fat pad weight in F344 animals increased
between 2.2- and 2.7-fold (Table 2). As previously demonstrated
in F344 animals by our laboratory, epididymal fat pad weight correlates
well with total body adiposity, as measured by dual-energy X-ray
absorptiometry scanning (15). Fat storage in nonadipocyte
tissue was also higher in F344 animals than in SD animals. Liver
triglyceride content was higher in 70-day-old F344 animals than in
age-matched SD animals (Table 1); after 60 days, the muscle and liver
triglyceride content increased fractionally more in F344 animals than
in SD animals. Muscle and liver triglyceride content were both higher
in 130-day-old F344 animals than in SD animals (Table 2).
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Also shown in Tables 1 and 2 are indexes of insulin and leptin sensitivity. Serum glucose concentrations were appropriately higher in refed animals compared with fasted animals. However, fasting glucose concentrations were minimally higher in 70-day-old F344 animals than in SD animals (Table 1) but were no different in 130-day-old animals (Table 2). However, the differences in insulin concentration were marked. Insulin concentrations in both fasted and refed F344 animals were approximately two- to threefold higher than in fasted and refed SD animals in both 70 (Table 1)- and 130 (Table 2)-day-old animals. Fasting serum triglyceride concentrations were higher in 70-day-old (Table 1) and 130-day-old (Table 2) F344 animals than in SD animals. In contrast to SD animals, the triglyceride concentration in F344 animals increased markedly with refeeding (Tables 1 and 2). In addition, fasting triglycerides in F344 animals increased over the 60-day experiment, whereas fasting triglycerides in SD animals did not change (compare Tables 1 and 2). Fasting free fatty acids were minimally elevated in 70-day-old SD animals compared with age-matched F344 animals (Table 1). There was no detectable difference in fasting free fatty acid between 130-day-old SD and F344 animals (Table 2). Serum free fatty acid decreased postprandially in both strains because of insulin-mediated inhibition of lipolysis. The serum leptin concentrations were not detectable in the young SD animals, which had small fat stores. This finding is consistent with our previous in vivo data (15). Serum leptin concentrations in 70-day-old F344 animals were measurable, and they increased by ~100% with refeeding (Table 1). After 60 days, the leptin concentration in F344 animals continued to a rise in fasted animals, and the concentration was responsive to refeeding. Note that, despite the high concentrations of this appetite-suppressing hormone, F344 animals still gained more triglyceride stores in both adipose and in nonadipose tissue than in SD animals. This observation is consistent with leptin resistance in the F344 animals.
To better characterize insulin sensitivity, intravenous glucose
tolerance tests were performed in 70- and 130-day-old animals from both
strains. The results are shown in Fig. 2.
Fasting and peak glucose concentrations were similar in 70-day-old SD
and F344 animals (Fig. 2, top left). Glucose concentrations
at 15 and 20 min were greater in 70-day-old SD than in age-matched F344 animals (Fig. 2, top left). The area under the curve (AUC)
for glucose was ~50% higher (P < 0.05) in SD
animals than in F344 animals (3,117.2 ± 94 vs. 2,124.5 ± 342 mg/dl, respectively). The insulin response to an intravenous bolus
of glucose was markedly different. Fasting insulin was approximately
threefold higher in the 70-day-old F344 rats than in age-matched SD
rats (Fig. 2, bottom left). Peak insulin concentrations were
approximately fivefold higher in the F344 than in the SD animals, and
the insulin AUC was ~2.7-fold higher (P < 0.001) in
the F344 animals than in the SD animals (66.8 ± 3.4 vs. 24.5 ± 1.9 ng/ml, respectively). The ratio of the insulin AUC to glucose
AUC in 70-day-old F344 animals vs. SD animals was 33 ± 4 vs.
7.7 ± 0.54 × 103 (P < 0.001). Therefore, to produce similar serum glucose concentrations after an intravenous glucose infusion, F344 animals require markedly higher insulin concentrations than do SD animals. This finding is
consistent with insulin resistance in the F344 animals, a state that
has not been recognized previously in these young animals. There were
no statistical differences in the glucose (Fig. 2, top
right) and insulin (Fig. 2, bottom right) responses to
intravenous glucose in 130-day old animals compared with 70-day-old
animals in both strains.
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A mechanistic link between the leptin and insulin resistance observed
in F344 animals may involve dysregulation of enzymes involved in fatty
acid oxidation. Therefore, we compared the relative gene expression of
transcription factors and enzymes involved with fatty acid oxidation in
the livers from fasted SD and F344 animals. The gene expression of the
transcription factor PPAR was ~1.8-fold greater in 70-day-old SD
rats than in age-matched F344 rats (Fig.
3). PPAR
stimulates the gene
expression of several enzymes involved with fatty acid oxidation. These
enzymes include the rate-limiting enzyme ACO in peroxisomal lipid
oxidation and the protein CPT I, which transports fatty acids for
oxidation in mitochondria. The ACO gene expression was somewhat less in 70-day-old F344 animals than in SD animals. The gene expression of CPT
I in 70-day-old SD animals was 1.5-fold greater than the CPT I gene
expression in age-matched F344 animals. In the 130-day-old animals,
PPAR
gene expression was greater in the F344 animals than in the SD
animals. However, the gene expression of ACO and CPT I in 130-day-old
SD animals was more than two times as great as the gene expression of
ACO and CPT I in age-matched F344 animals.
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The effects of fasting and refeeding on gene expression of proteins
involved in fatty acid oxidation were assessed in both 70-day-old
(Table 3) and 130-day-old (Table
4) animals. The gene expression of
PPAR in fasted animals was ~1.5- to 1.75-fold greater than the
gene expression of PPAR
in refed animals in both strains and ages of
rat. However, the ratio of fasted to refed ACO and CPT I gene
expression was significantly greater in SD animals than in age-matched
F344 animals.
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Finally, recent studies in experimental animals have shown that
resistin gene expression increases with adiposity and with insulin
resistance (21). We therefore measured the gene expression of resistin in the insulin- and leptin-resistant F344 strain and the
more insulin- and leptin-sensitive SD strain. As shown in Fig. 4,
left, resistin gene expression was slightly lower in fasted, 70-day-old F344 animals than in fasted, 70-day-old SD animals. We did
not detect a statistically significant difference in resistin gene
expression between fasted and refed 70-day old animals. After 2 mo, the
resistin gene expression increased by ~1.6-fold (P < 0.001) in SD animals. By contrast, in F344 animals, the resistin gene
expression increased by ~5.0-fold (P < 0.0001) in
the 130-day-old animals than in the 70-day-old animals. In 130-day-old
animals, resistin gene expression in the F344 strain was significantly greater than the resistin gene expression in the SD strain in the refed
state. In the fasted state, there was not a statistically significant
difference in resistin gene expression (P = 0.07).
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DISCUSSION |
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In the present study, we have characterized an inbred rodent strain that we believe represents a good model for typical type 2 diabetes in humans. We have found that young F344 animals with normal glucose tolerance have evidence of insulin resistance (Fig. 2), leptin resistance (Tables 1 and 2), dyslipidemia (fasting and postprandial hypertriglyceridemia; Tables 1 and 2), and excess triglyceride accumulation in insulin-sensitive target tissues such as liver and muscle (Tables 1 and 2). These constellations of findings are consistent with a metabolic syndrome that is observed in young animals with normal glucose tolerance, and they probably represent a genetic risk for diabetes mellitus that occurs later in life.
We also investigated the link between insulin resistance and the
propensity for obesity in F344 animals. Because leptin has been shown
to stimulate fatty acid oxidation and reduce triglyceride storage in
nonadipose tissue (23), we hypothesized that leptin resistance in F344 animals would diminish fatty acid oxidation and
enhance triglyceride storage in nonadipose tissue. Although we did not
directly measure fatty acid oxidation, we did measure the gene
expression of several key regulatory proteins in fatty acid oxidation.
We have demonstrated that the hepatic gene expression of ACO and CPT I
is consistently less in the leptin- and insulin-resistant F344 animals
than in age-matched SD animals (Fig. 3). ACO and CPT I are critical
regulatory proteins in the fatty acid oxidation pathway in peroxisomes
and mitochondria, respectively. The gene expression of both proteins is
regulated, in part, by the transcription factor PPAR. Consistent
with this observation, we have found that the gene expression of
PPAR
is less in 70-day-old F344 rats than in age-matched SD rats.
Diminished PPAR
gene expression in the leptin-resistant F344 animal
supports the findings by Zhou et al. (25) that leptin
normally stimulates PPAR
gene expression. However, we did not find
that PPAR
gene expression was less in the 130-day-old F344 rats than
in SD rats. The reason for this apparent discrepancy is unknown.
However, despite increased PPAR
gene expression, 130-day-old F344
animals had diminished downstream expression of regulatory proteins in
fatty acid oxidation. Two reasons might account for an increase in
PPAR
but a decrease in ACO and CPT I gene expression. First, PPAR
transcription activity not only depends on the amount of the gene
product but also on the binding of its endogenous ligand, purportedly a
fatty acid. PPAR
transcriptional activity could be reduced in the
130-day-old F344 animals if the intrahepatic fatty acid composition was
different and the activated PPAR
gene transcribed less well than
age-matched SD animals. Second, PPAR
is not the only transcriptional
activator of ACO and CPT I; other PPAR
-independent transcriptional
inhibitors may play a role in the gene expression of ACO and CPT I in
F344 animals.
We believe that the reduction in gene expression of ACO and CPT I in F344 animals probably reduced hepatic fatty acid oxidation and increased the propensity to store fatty acids as triglycerides. We found that liver contains more triglycerides in F344 animals than in SD animals (Tables 1 and 2). Muscle contains more triglycerides in 130-day old F344 animals than in age-matched SD animals (Table 2). The enhanced triglyceride storage in nonadipose tissue resulted in insulin resistance (Fig. 2) and its associated disturbance of hyperinsulinemia and hypertriglyceridemia (Tables 1 and 2).
The response of the gene expression of PPAR and its cognate genes to
fasting and refeeding was appropriate; the gene expression was higher
with fasting and was diminished with refeeding, as previously
demonstrated (7). However, the fractional decrease in
response to refeeding was not as great in F344 animals as in the SD
animals (see Tables 3 and 4). This phenomenon may be an example of what
Kelley and Mandarino (6) have referred to as "metabolic
inflexibility." In the lean, insulin-sensitive SD animals, energy
production during fasting conditions might rely predominantly on lipid
oxidation, with a rise in gene expression of proteins mediating lipid
oxidation. With refeeding, the gene expression of proteins involved in
lipid oxidation decreases as insulin-mediated glucose production likely
becomes predominant in the SD animals. In contrast, the obesity-prone,
insulin-resistant F344 animals likely manifest less lipid oxidation
with a fall in gene expression of proteins involved in lipid oxidation
during fasting conditions. However, lipid oxidation most likely plays a
greater role during insulin-stimulated refeeding in F344 animals, as
the fractional decline in gene expression of proteins mediating lipid
oxidation do not decline to the same degree as in SD animals. The
failure to augment lipid oxidation during fasting conditions likely is
a mechanism leading to lipid accumulation within insulin-sensitive target tissues, whereas the failure to fully suppress lipid oxidation during refeeding may be a manifestation of the relative resistance to insulin.
Finally, we have examined the role of resistin in the etiology of insulin resistance in F344 animals. Resistin gene expression and protein secretion are increased in both genetic and diet-induced models of obesity and diabetes (21). Furthermore, resistin appears to antagonize the effects of insulin both in vivo and in vitro (21). Such an antagonism might provide a link between obesity and insulin resistance. In vivo administration of resistin antiserum to diet-induced obese mice improved blood glucose levels and insulin sensitivity (21). Conversely, administration of recombinant resistin impairs glucose tolerance and insulin action in normal mice. Resistin's role in obesity and insulin resistance has not been confirmed by other investigators (24). We have hypothesized that resistin gene expression in the insulin-resistant, obesity-prone F344 rats would be higher than in SD rats. Our results do not support this hypothesis. The resistin gene expression in insulin-resistant, 70-day-old F344 animals was less than in age-matched SD animals (Fig. 4). At 70 days, the difference in the amount of stored fat in the epididymal fat pad (Table 1) or in total body adiposity (15) differs only slightly between the two strains. After 60 days of a low-fat diet, F344 rats gain markedly more fat, without much change in insulin resistance, as measured by the intravenous glucose tolerance test. Despite almost equal glucose tolerance between 70- and 130-day-old F344 animals, the expression of the resistin gene increases dramatically. From these observations, we must conclude that resistin gene expression is not involved in the etiology of insulin resistance in F344 animals. Resistin gene expression does increase proportionally to the gain in total body fat, but animals do not become progressively more insulin resistant in this 2-mo period. Resistin gene expression is another marker for total body adiposity in both SD and F344 strains.
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ACKNOWLEDGEMENTS |
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This work is supported by the Veterans Administration Merit Review (J. R. Levy).
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. R. Levy, McGuire Veterans Administration Medical Center 111-P, 1201 Broad Rock Blvd., Richmond, VA 23249 (E-mail: James.Levy{at}med.va.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00346.2001
Received 31 July 2001; accepted in final form 23 October 2001.
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