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deficiency and TZD treatment
on insulin resistance associated with age and high-fat feeding
Departments of 1 Surgery and 2 Medicine, University of California, San Diego, 3 San Diego Veterans Affairs Medical Center; 4 Whittier Diabetes Institute; and 5 Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute, La Jolla, California 92093
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Peroxisome proliferator-activated
receptor-
(PPAR) is the target receptor for
thiazolidinedione (TZD) compounds, which are a class of
insulin-sensitizing drugs used in the treatment of type 2 diabetes.
Paradoxically, however, mice deficient in PPAR (PPAR+/
) are more insulin sensitive than
their wild-type (WT) littermates, not less, as would be predicted. To
determine whether PPAR deficiency could prevent the development of
the insulin resistance associated with increasing age or high-fat (HF)
feeding, insulin sensitivity was assessed in
PPAR+/ and WT mice at 2, 4, and 8 mo of age
and in animals fed an HF diet. Because TZDs elicit their effect through
PPAR receptor, we also examined the effect of troglitazone (a TZD)
in these mice. Glucose metabolism was assessed by hyperinsulinemic
euglycemic clamp and oral glucose tolerance test. Insulin sensitivity
declined with age for both groups. However, the decline in the
PPAR+/ animals was substantially less than
that of the WT animals, such that, by 8 mo of age, the
PPAR+/ mice were markedly more insulin
sensitive than the WT mice. This greater sensitivity in
PPAR+/ mice was lost with TZD treatment. HF
feeding led to marked adipocyte hypertrophy and peripheral tissue and
hepatic insulin resistance in WT mice but also in
PPAR+/ mice. Treatment of these mice with
troglitazone completely prevented the adipocyte hypertrophy and
normalized insulin action. In conclusion, PPAR deficiency partially
protects against age-related insulin resistance but does not protect
against HF diet-induced insulin resistance.
peroxisome proliferator-activated receptor- deficiency; high-fat
diet; aging; insulin resistance; thiazolidinedione; mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THIAZOLIDINEDIONE (TZD)
COMPOUNDS are a new class of insulin-sensitizing drugs used in
the treatment of type 2 diabetes. They improve insulin sensitivity,
glucose tolerance, and the lipidemic profile in type 2 diabetic
patients (7, 28), as well as in obese nondiabetic subjects
(19). Similar findings have also been demonstrated in a
number of genetic and nongenetic animal models of diabetes/insulin
resistance (4, 5, 14). TZDs have been shown to elicit
their effect through peroxisome proliferator-activated receptor-
(PPAR) (15). PPAR belongs to a subfamily of nuclear receptors involved in the control of various aspects of lipid metabolism (10). These receptors function as heterodimers
with the retinoid X receptor (11, 12, 17) and bind to
cis-acting sequences (peroxisome proliferator response
element) on DNA to initiate transcription (16).
Adipogenesis (30) and other cellular processes of lipid
accumulation (31) are stimulated by PPAR through the
induction of genes mediating fatty acid metabolism (22, 23,
29). In addition, it plays a critical role in proper placental
vascularization, myocardial health, and embryonic development (1).
We previously studied mice heterozygous for PPAR to further
elucidate the physiological role of PPAR in glucose homeostasis (homozygous PPAR-null animals were not viable). Paradoxically, PPAR+/ mice displayed greater insulin
sensitivity than did their wild-type (WT) littermates
(18). These findings were unexpected and run contrary to
what might have been predicted on the basis of the known biological
effects and mechanism of action of TZDs. This suggests that the
inhibition of PPAR function could render individuals less
susceptible to the development of insulin resistance due to obesity,
type 2 diabetes, aging, or other factors.
Insulin sensitivity normally declines as rodents (2) and
humans (3) age, and this raises the question whether
PPAR+/ mice exhibit increased insulin
sensitivity at all stages of development or whether these animals are
relatively protected from the natural decline in insulin sensitivity
that occurs with increasing age. A diet high in fat causes insulin
resistance (26, 27), and we also sought to determine
whether PPAR+/ mice are protected from
high-fat diet-induced insulin resistance. To address these questions,
we measured insulin action in PPAR+/ and WT
mice from 2 to 8 mo of age and in mature mice fed a high-fat diet.
Last, it was of interest to assess the effects of TZD treatment in
PPAR+/ mice compared with WT littermates
under these various conditions.
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RESEARCH DESIGN AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Mice carrying the PPAR-null allele are described elsewhere
(1). Genotypes were determined by PCR of tail DNA
(1). Animals used in our physiological studies were
age-matched WT (PPAR+/+) and
PPAR+/ male offspring of eight consecutive
back-crosses onto a C57BL/6J strain background (30:1
C57BL/6J-to-129/SvJae allelic ratio). Mice were housed under controlled
light (12:12 h) and temperature conditions, and had free access to food
and water. All procedures were in accordance with the Guide for
the Care and Use of Laboratory Animals of the National Institutes
of Health and approved by the Animal Subjects Committee of the
University of California, San Diego.
Age-related study.
PPAR+/ and WT mice were studied at 2, 4, and 8 mo of age. In addition, 8-mo-old mice were treated with and
without troglitazone (a TZD) for 4 wk and underwent glucose clamp
testing and an oral glucose tolerance test (OGTT) according to methods
described previously (9). The drug was given as a 0.2%
food admixture and was freshly mixed with regular powdered rodent chow
(Rodent Diet no. 8604, Harlan Teklad, Madison, WI) in small amounts
every week and stored at 4°C. The 2-mo-old mice underwent a modified
glucose clamp, because their small size precluded the use of glucose tracer.
High-fat feeding study.
Eight-month-old PPAR+/ and WT mice were fed
regular chow or a high-fat diet (TD 85418; Harlan Teklad) with and
without troglitazone for 4 wk. Fifty-six percent of the calories of the
high-fat diet came from partially hydrogenated vegetable oil, and a
complete description of the diet is described elsewhere
(9). Troglitazone was given as a 0.2% admixture and was
freshly mixed with the fat diet or powdered rodent chow in small
amounts every week and stored at 4°C. Three weeks into the diet,
animals underwent an OGTT and, 1 wk later, a glucose clamp experiment
as described elsewhere (18). The epididymal fat pads were
harvested after the glucose clamp.
Assays. Plasma glucose concentration was measured with a YSI 2300 STAT Glucose/Lactate Analyzer (YSI, Yellow Springs, OH). Insulin and leptin were measured using radioimmunoassay kits (Linco, St. Charles, MO). Plasma glucose specific activity was measured after deproteinization with barium hydroxide and zinc sulfate (21). Epididymal fat cell size was determined using the osmium tetraoxide method after digestion with collagenase (6).
Calculations. Hepatic glucose production (HGP) and glucose disposal rate (GDR) were calculated for the basal period and the steady-state portion of the glucose clamp by use of the Steele equation for steady-state conditions (25). Values presented are means ± SE. Statistical analysis was performed by using a two-way analysis of variance (ANOVA) for unbalanced data. Significance was assumed at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Our studies were performed with WT and PPAR-heterozygous mice, and
animals were fully developed, fertile, and healthy. Due to effects of
sporadic genetic variations between different mouse strains on the
susceptibility to metabolic disorders, experiments were conducted on
animals back-crossed for eight consecutive generations against a
C57BL/6J strain background. The control group was comprised of WT
siblings of the heterozygous mice.
Age-related effects of PPAR deficiency: comparison of 2-, 4-, and 8-mo-old mice.
We have previously shown (18) that, in animals 8 mo of
age, heterozygous PPAR+/ mice show enhanced
peripheral and hepatic insulin sensitivity compared with WT mice. It is
known that insulin sensitivity normally declines as rodents and humans
age, and, because 8-mo-old mice are postmature, the question
arises whether PPAR+/ mice exhibit
increased insulin sensitivity at different stages of development or
whether these animals are relatively protected from the natural decline
in insulin sensitivity that occurs with age.
+/ mice were not different from WT mice
at all three ages, as seen in Table 1.
However, epididymal fat cell size (1,810 ± 180 vs. 2,240 ± 190 µm2, P < 0.05) was less in the
PPAR+/ group compared with WT. The fasting
plasma glucose concentrations of the PPAR+/
mice were comparable to those of the WT mice and did not change from 2 to 8 mo of age. The fasting insulin concentrations were similar at 2 and 4 mo of age, but at 8 mo of age, the insulin level of the WT mice
was significantly higher than that of the PPAR+/ mice (0.31 ± 0.07 vs.
0.45 ± 0.05 ng/ml, P < 0.05). We also measured in vivo insulin sensitivity in PPAR+/ and
WT animals at 2, 4, and 8 mo of age. For comparison purposes, insulin
sensitivity of the animals at the three different ages is expressed as
the exogenous glucose infusion rate (Glcinf) necessary to
maintain euglycemia, and the results are presented in Fig. 1. As can be seen in WT animals, there
was a marked and progressive decline in insulin-stimulated
Glcinf going from 2 to 4 to 8 mo of age, resulting in a
fall from 85.2 ± 8.1 to 32.7 ± 2.8 mg · kg1 · min1
from 2 to 8 mo. In the PPAR+/ animals,
insulin sensitivity was comparable to controls at 2 and 4 mo of age,
but the decline in insulin sensitivity going from 4 to 8 mo of age is
substantially less, such that, by 8 mo of age, the
PPAR+/ animals are more insulin sensitive
than WT controls (47.3 ± 5.3 vs. 32.7 ± 2.8 mg · kg1 · min1,
P < 0.01). These data indicate that heterozygosity for
the PPAR receptor provides partial protection from the age-related
physiological insulin resistance that occurs in mice.
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Effect of TZD treatment on 8-mo-old WT and
PPAR+/ mice.
The PPAR receptor is the target of insulin-sensitizing TZD agents,
and it is notable that animals with a 50% genetic deficiency of this
receptor display enhanced insulin action on glucose metabolism. It was,
therefore, of interest to assess the effects of TZD treatment in
PPAR+/ mice compared with WT littermates.
Accordingly, chow-fed 8-mo-old WT and
PPAR+/ animals were given troglitazone for
4 wk or not, and various measurements were made in these groups of animals.
+/ animals.
Body weight was the same in all animal groups under all conditions. In
WT animals, fat pad weight was unaffected by TZD treatment. However,
after TZD treatment, fat pad weight increased in the
PPAR+/ animals and was now more comparable
to values seen in WT littermates. The average fat cell size in the
epididymal fat pad was smaller in untreated
PPAR+/ animals compared with WT littermates
(P < 0.05) and was significantly increased after TZD
treatment to values comparable to those of controls. Fat cell size was
unaffected by TZD treatment in WT littermates. FFA and serum leptin
levels were not significantly different among the groups.
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+/ animals compared with WT
littermates, but after TZD treatment insulin levels increased to values
comparable to those observed in WT mice.
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+/ animals suggests the
opposite, i.e., a TZD-induced decrease in insulin sensitivity. To
directly assess this possibility, we conducted a series of
hyperinsulinemic euglycemic glucose clamps in the various animal study
groups, and these data are summarized in Fig.
4. TZD treatment had no effect on insulin
action in WT littermates, and these findings are consistent with
previous studies demonstrating that various TZDs are without effect on
insulin sensitivity in normal animals (4, 5) and humans
(19, 28). In the PPAR+/
animals, GDR values are 34% higher in untreated animals compared with
WT littermates at 8 mo, and TZD treatment leads to a significant reduction in GDR. Thus, after the period of drug treatment, the PPAR+/ animals are less insulin sensitive
than the untreated group, and the GDR values in the treated
PPAR+/ animals are now comparable to those
seen in WT littermates. Thus a 50% genetic deletion of the PPAR
receptor led to the unexpected finding of enhanced, rather than
diminished, insulin sensitivity in chow-fed untreated animals, and, in
keeping with this counterintuitive finding, TZD treatment has the
paradoxical effect of reducing insulin sensitivity in these animals,
bringing insulin-stimulated glucose uptake back to control values.
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+/ animals, HGP
suppression by insulin was greater in the untreated animals compared
with WT controls, and TZD treatment led to a blunting of this aspect of
insulin action so that HGP suppression was now comparable to WT controls.
Effect of PPAR deficiency on high-fat diet-induced insulin
resistance.
In 8-mo-old PPAR+/ and WT mice, a
diet high in fat increased body weight, fat pad weight, fat cell size,
and FFA and leptin levels compared with chow-fed mice (Fig.
5). Compared with the chow diet,
high-fat feeding also led to an increase in basal glucose and insulin
concentrations (t = 0) to similar levels in both groups (Fig. 6). During the OGTT (Fig. 6), both
groups showed a greater and equal increase in plasma glucose and
insulin concentrations compared with the chow-fed animals (compare Fig.
3 with Fig. 6). This suggests that
PPAR+/ and WT animals fed a high-fat diet
are equally insulin resistant. As seen in Fig.
7, basal glucose turnover in the
PPAR+/ and WT groups were slightly but
significantly elevated compared with the chow-fed groups. The
insulin-induced increase in GDR and decrease in HGP of the
PPAR+/ and WT groups were similar but
significantly less than those of the chow-fed groups (Fig. 7). These
results indicate that the liver and the peripheral tissues of
PPAR+/ and WT mice are equally insulin
resistant on a high-fat diet.
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Effect of TZD treatment on high-fat diet-induced insulin
resistance.
In 8-mo-old mice fed a high-fat diet, troglitazone treatment equally
decreased body weight, fat pad weight, fat cell size, and FFA and
leptin levels in both PPAR+/ and WT groups
(Fig. 5). Treatment also equally decreased basal and postglucose
challenge glucose and insulin levels to the values seen in chow-fed WT
mice (Fig. 6, bottom). Furthermore, troglitazone treatment
had a comparable effect of enhancing insulin sensitivity in both groups
(WT and PPAR+/) of high fat-fed mice. Thus
the insulin-induced increase in GDR and the suppression of HGP were
enhanced equally in both groups, and the values were comparable to
those seen in the chow-fed WT mice (Fig. 7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
RESEARCH DESIGN AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Insulin-sensitizing thiazolidinediones are high-affinity ligands
for the PPAR nuclear receptor (15), which regulates the transcription of genes involved in lipid and glucose metabolism (22, 23, 29). We have previously shown (18)
that a 50% reduction in PPAR receptor content did not result in
insulin resistance, as one might predict, but rather led to an increase in insulin sensitivity. Therefore, we postulated that PPAR
deficiency might prevent or attenuate the insulin resistance associated
with type 2 diabetes, obesity, aging, and other factors. In this study, we examined the effect of PPAR deficiency on two physiological causes of insulin resistance: increasing age and high-fat diet.
Age-related insulin resistance.
It is well established that insulin sensitivity normally declines with
age in both humans and animals (2, 3), and this may be due
to obesity, physical inactivity, or other age-related factors. The mice
in our study were no exception. At 2 mo of age, insulin sensitivity, as
measured by Glcinf values, of the
PPAR+/ and WT mice were similar and
progressively declined by 4 and 8 mo of age. The rate of decline of the
PPAR+/ mice, however, was less than that
for the WT mice, such that by 8 mo of age, insulin sensitivity of the
PPAR+/ mice was greater than in WT mice.
+/ mice occurred in peripheral tissue
(muscle and fat tissue) and in the liver, as reflected by the greater
insulin stimulation of GDR and suppression of HGP, respectively.
Furthermore, fat cell size in the PPAR+/
mice was smaller than in the WT littermates, and smaller fat cells have
been associated with insulin sensitivity (20).
The present studies show that PPAR receptor-deficient animals have
greater insulin sensitivity than WT controls but that this effect
occurs only in the postmature state. In other words, the
PPAR+/ animals are relatively protected
from the normal physiological decrease in insulin sensitivity, which
occurs when mice age from 2 to 8 mo. Although the mechanism(s) of this
"developmental" insulin resistance is not fully understood, in
addition to simple aging, as mice get older they become more obese and
less physically active, and a similar series of events occurs in
humans. Thus relative PPAR deficiency apparently mitigates these
physiological causes of insulin resistance, raising the possibility
that a therapeutic maneuver that could produce the same effect as
PPAR deficiency might be of clinical value in the treatment of
insulin resistance.
TZDs are traditionally used to increase insulin sensitivity. In normal
WT mice, TZD treatment had no effect on insulin action, consistent with
previous studies demonstrating that various TZDs are without effect on
insulin sensitivity in normal animals and humans (4, 5, 19,
28). In the PPAR+/ animals, however,
TZD treatment significantly lowered GDR and impaired insulin's
suppressive effects on HGP (increased HGP values during the clamp
study) compared with untreated animals. Thus, after the period of drug
treatment, the PPAR+/ animals are less
insulin sensitive than the untreated group, and the GDR and HGP values
in the treated PPAR+/ animals are now
comparable to those seen in WT littermates. Thus a 50% genetic
deletion of the PPAR receptor led to the unexpected finding of
enhanced, rather than diminished, insulin sensitivity in chow-fed
animals, and, in keeping with this counterintuitive finding, TZD
treatment reduced insulin sensitivity in these animals, bringing
insulin-stimulated glucose uptake back to control values. Troglitazone
also increased fat pad weight and fat cell size in PPAR+/ animals, and this may contribute to
the decreased insulin sensitivity.
PPAR deficiency and high-fat diet-induced insulin resistance.
Four weeks of high-fat diet feeding led to the expected effects of
glucose intolerance, increased adiposity, and both peripheral tissue
and hepatic insulin resistance in WT mice. Although the results in Fig.
1 show that PPAR deficiency confers protection against age-related
insulin resistance, it did not protect against high-fat diet-induced
insulin resistance. Thus the PPAR+/ mice
became just as glucose intolerant and insulin resistant as their WT
littermates fed a high-fat diet. In fact, because these animals were
more insulin sensitive before high-fat feeding was initiated, the
diet-induced decrease in peripheral and hepatic insulin sensitivity was
actually greater in the PPAR+/ animals.
Furthermore, fat pad weight and fat cell size, as well as circulating
FFA and leptin levels, were all comparable between TZD-treated WT and
PPAR+/ mice on the high-fat diet.
+/ groups. Leptin levels increased with
high-fat feeding in parallel with the onset of insulin resistance and
decreased after TZD treatment, and these effects go in the opposite
direction in changes in insulin sensitivity. However, it is important
to note that, in vivo, a major site of action of leptin is the central
nervous system (CNS), and intracerebroventricular administration of
leptin has been shown to increase insulin sensitivity (8).
Clearly, we did not measure cerebrospinal fluid levels of leptin in our
studies; therefore, concentrations of leptin that could exert central
effects or CNS leptin sensitivity are unknown in these animals.
The results of our high-fat feeding studies differ from the work of
Kubota et al. (13), who showed that PPAR
receptor-deficient mice did not display adipocyte hypertrophy and
appeared to be protected from insulin resistance while on a high-fat
diet. The reasons for the discrepancy between the two studies are not
clear, but several possibilities exist. For example, the physiological response of mice to a diet high in fat is highly dependent on the
background strain of the animal. In our studies, heterozygous PPAR
offspring were backcrossed eight times onto the C57BL/6J strain
background and for practical purposes can be considered a pure strain.
The purity of the mice used in the study by Kubota et al. is not
specified. It is also possible that the composition of the respective
high-fat diets is a factor. In the present study, the fat in the diet
came predominately from partially hydrogenated vegetable oil as opposed
to the polyunsaturated safflower oil used in the study by Kubota et al.
Although saturated fats tend to cause a greater degree of insulin
resistance than unsaturated fat, it has been reported that both result
in a substantial impairment of insulin action (26, 27).
However, the latter studies were conducted in normal animals, whereas
the present experiments and those of Kubota et al. were in genetically
altered animals. These findings raise the possibility that there may be
more than one mechanism by which a diet high in fat leads to insulin
resistance. In the present study, PPAR+/
mice fed saturated fat responded like WT mice and developed obesity and
insulin resistance, suggesting that the mechanism by which this
occurred was intact in PPAR+/ mice.
Conversely, the PPAR+/ mice fed
unsaturated fat in the study of Kubota et al. were protected from
adipocyte hypertrophy and insulin resistance, suggesting that the
mechanism by which unsaturated fat induces insulin resistance may
involve PPAR receptors. It is possible that different kinds of fat
diets influence production of endogenous PPAR ligands, and the
interaction of these ligands with PPAR receptors may be
quantitatively or qualitatively different in the presence of receptor deficiency.
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ACKNOWLEDGEMENTS |
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We thank Michael C. Nelson for excellent mouse colony management and genotyping.
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FOOTNOTES |
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Y. Barak was supported by a European Molecular Biology Organization fellowship and by funds from the Charles and Anna Stern Foundation. R. M. Evans is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in molecular and developmental biology. This work was supported in part by grants from the National Institutes of Health (DK-33651 and HD-27183) and the Veterans Administration Research Service, Department of Veterans Affairs.
Address for reprint requests and other correspondence: P. D. G. Miles, Dept. of Surgery (8400), UCSD Medical Center, 200 West Arbor Drive, San Diego, CA 92103 (E-mail: pmiles{at}ucsd.edu).
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.00312.2002
Received 12 July 2002; accepted in final form 14 November 2002.
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RESULTS
DISCUSSION
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