Insulin Resistance and Obesity in Lupus

Insulin Resistance and Obesity in a Mouse Model of

Systemic Lupus Erythematosus
Michael J. Ryan, Gerald R. McLemore Jr, Steven T. Hendrix

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AbstractAccumulating data indicate that metabolic syndrome is an inflammatory condition. Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with nephritis and cardiovascular disease. Evidence suggests that
individuals with SLE are at risk for developing insulin resistance; however, this has not been directly examined. Using
an established mouse strain with SLE (NZBWF1), we examined whether SLE is associated with increased body weight
and fat deposition. Mean arterial pressure was significantly increased (1404 versus 1142 mm Hg; n5) in SLE mice
by 36 weeks of age compared with control mice (NZW/LacJ). Body weight in SLE mice was higher at each age
compared with controls by 12%, 22%, and 34% (n30). Visceral adipose tissue weight was increased in SLE by 44%,
74%, and 117% at 8, 20, and 36 weeks, respectively (n12). Plasma leptin was increased in SLE mice (8.61.0 versus
24.72.2 ng/mL; n5), and renal and adipose tissue exhibited macrophage infiltration. Fasted insulin was higher in
SLE mice (0.60.1 versus 1.40.3 ng/mL; n10), but fasted glucose was not different (945 versus 809; n9). A
glucose tolerance test caused a significantly greater and longer increase in blood glucose from mice with SLE compared
with control mice. Food intake was not different between control and SLE mice. However, mice with SLE demonstrated
lower levels of nighttime activity than controls. These data show that the NZBWF1 strain may be an important model
to study the effects of obesity and insulin resistance on SLE-associated hypertension. (Hypertension. 2006;48:988-993.)
Key Words: SLE autoimmune inflammation insulin adipose leptin glucose

etabolic syndrome can be characterized by a group of

metabolic risk factors that includes central obesity,
insulin resistance, dyslipidemia, increased blood pressure,
and endothelial dysfunction.1 Individuals with metabolic
syndrome are at a markedly increased risk for developing
hypertension and renal disease. Recent evidence indicates
that inflammatory cytokines are elevated in patients with
metabolic syndrome,2 4 thus suggesting a role for chronic
inflammation as an underlying mechanism for progression of
this disease.
Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that predominantly affects women during
their reproductive years. The presence of autoantibodies
(typically antinuclear antibodies) is used diagnostically, and
although SLE can influence many organ systems, the skin,
joints, and kidneys are typically affected. Like metabolic
syndrome, a large percentage of individuals with SLE are
hypertensive. Evidence suggests that individuals with SLE
are also at increased risk for developing insulin resistance5
and changes in body mass composition6; however, this has
not been adequately examined.
The purpose of the present study was to test whether the
progression of SLE is associated with changes in body
composition, insulin sensitivity, and other characteristics of

the metabolic syndrome. To examine this, we used a genetic

mouse model of SLE (NZBWF1) that exhibits many features
of human SLE, including a complex genetic origin, a bias for
the female sex, immune complex glomerulonephritis, and the
presence of antinuclear antibodies. We reported recently that
these mice have hypertension and impaired endothelialdependent relaxation.7 The results of the present study show
that NZBWF1 mice also have several other characteristics of
the metabolic syndrome that may contribute to the hypertension, including central obesity, insulin resistance, and hyperleptinemia. These data show that the NZBWF1 strain may be
an important model to study the effects of obesity and insulin
resistance on SLE-associated hypertension.

Methods
Animals
Female NZBWF1 (SLE) and NZW/LacJ (control) obtained from
Jackson Laboratories (Bar Harbor, ME) were maintained on a
12-hour light/dark cycle, normal chow, and water ad libitum. Mice
were studied at 8 (7.80.7 weeks), 20 (21.20.3 weeks), and 36
(36.40.1 week) weeks of age. These ages correspond with the onset
of sexual maturity, pre-SLE, and full SLE, respectively. At 36 weeks
of age, female mice are fully capable of reproduction, and a decline
in ovarian hormones would be expected to improve or delay the
onset of SLE in NZBWF1 females. All of the studies were performed

Received July 26, 2006; first decision August 13, 2006; revision accepted August 21, 2006.
This paper was sent to Ernesto L. Schiffrin, associate editor, for review by expert referees, editorial decision, and final disposition.
From the Department of Physiology, University of Mississippi Medical Center, Jackson, Miss.
Correspondence to Michael J. Ryan, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St,
Jackson, MS 39216. E-mail [email protected]
2006 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org

DOI: 10.1161/01.HYP.0000243612.02929.df

988

Ryan et al

Insulin Resistance, Obesity, and SLE

989

with the approval of the University of Mississippi Medical Center

Institutional Animal Care and Use Committee and in accordance
with National Institutes of Health guidelines.

Physical Characteristics
Body weight (in grams) was measured for all of the mice. A
subgroup was euthanized and dissected for measurement of total
visceral adipose (omentalovarian/uterineretroperitoneal) and to
weigh individual adipose depots (ovarian/uterine, retroperitoneal,
and thermogenic). Mice were acclimated for 5 days to being individually housed before daily food intake was measured (in grams)
and normalized to grams per 24 hours. The effect of leptin on food
intake was also measured in 36-week-old mice. Mouse leptin (R&D
Systems) was administered via intraperitoneal injection (30 g,
twice daily) for 3 days. Intraperitoneal injection of vehicle (saline)
was used as a control.

Blood Glucose, Insulin, and Leptin

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Thirty-six-week-old NZBWF1 and NZW/LacJ mice were fasted for

6 hours before collecting blood samples with EDTA through
retro-orbital punctures in lightly anesthetized animals (isoflurane).
Fifteen microliters were used with the Accuchek Advantage glucometer (Roche) to measure blood glucose in milligrams per deciliter.
Remaining blood samples were centrifuged, and plasma samples
were stored at 80C.
Fasted insulin (nanograms per milliliter) was measured using a
Rat/Mouse Insulin ELISA kit (Linco Research). Plasma leptin levels
(nanograms per milliliter) were measured using the Quantikine
Mouse Leptin Immunoassay (R&D Systems).
Glucose tolerance was tested in 36-week-old NZBWF1 and
NZW/LacJ mice. Carotid artery catheters were implanted as described previously.8 10 The next day mice were fasted for 6 hours at
which time a 15-L sample of blood was analyzed for basal blood
glucose levels. Each mouse was administered an intraperitoneal
injection of isosmotic glucose (317 mmol/L). Fifteen-microliter
blood samples were taken through the carotid catheter, and glucose
was measured at 20, 40, 60, 120, and 180 minutes postinjection. This
method has been reported previously.11

Mean Arterial Pressure

Mean arterial pressure (MAP) was measured with indwelling carotid artery catheters attached to an external force displacement
transducer as described previously.9,12 Mice were allowed 48 hours
to recover before measurements were made. Surgeries were performed under isoflurane anesthesia, and bupivacaine (subcutaneous)
was used postoperatively as an analgesic.

Animal Activity
Radiotelemeters (PAC10 or PAC20, DSI) were implanted in
NZBWF1 and NZW/LacJ mice at 8, 20, and 36 weeks of age as
described previously.7 Mice recovered for 1 week before measuring activity continuously (24 hours per day) for 4 consecutive days.
Measurements are a relative measure of locomotor activity (high
counts means the animal was active) and cannot be used to calculate
distance or type of activity.

Figure 1. MAP is increased at 36 weeks of age in SLE mice

compared with controls. Pressure was measured by indwelling
carotid artery catheters in conscious freely moving mice.
(*P0.05, 1-way ANOVA).

control and 6 SLE mice were incubated with Oil-Red-O to test for
the presence of hepatic liver accumulation. Sections were counterstained with hematoxylin/eosin.

Statistics
A 1-way ANOVA with StudentNewmanKeuls post hoc test for all
of the pairwise comparisons was used to assess differences across
different age groups and between control and SLE animals. A
Student t test was used to assess statistical significance when
comparing only control and SLE groups. Significance was accepted
at P0.05.

Results
As we have reported recently,7 SLE mice are hypertensive
compared with control animals by 36 weeks of age (Figure 1).
Body weight in female SLE (NZBWF1) mice at 8, 20, and 36
weeks of age was significantly greater than control mice
(NZW/LacJ) and by a progressively larger margin (12%,
21%, and 34%) at each age (Figure 2 and Table). Weights,
indexed for body length (excluding tail), were significantly
higher in SLE mice compared with controls at 36 weeks of
age (0.360.00 versus 0.400.02 g/cm2; P0.01, Student
t test). Visceral adipose tissue from SLE mice was significantly increased by 20 weeks of age with a progressively
larger margin (73% to 117%; Table). Adipose tissue weight
from individual depots, including ovarian/uterine, retroperitoneal, and thermogenic (brown), was also measured. Thermogenic adipose tissue was not different between control and

Histology
Ovarian/uterine adipose or kidneys were fixed in 10% neutral
buffered formalin and paraffin embedded for histological analysis.
Sections were incubated with F4/80 rat anti-mouse antigen (1:10 in
normal rabbit serum overnight, Serotec), biotinylated with rabbit
anti-rat IgG, incubated with avidin-biotin complex (mouse avidin
biotin Vectastain, Vector), and visualized with diaminobenzidine
substrate (Vector) to detect the presence of monocytes/macrophage.
Slides were counterstained with Harris hematoxylin. At least 10
randomly selected fields were analyzed per slide from each animal,
and data are presented as a percentage (total number of macrophage/
total number of adipose cells counted). Frozen liver sections from 6

Figure 2. Body weight in control and SLE mice at 8, 20, and 36

weeks of age. *8-week control mice, #greater than all groups
except 36-week SLE, greater than all groups (P0.01, 1-way
ANOVA). Control body weight was not different from 20 to 36
weeks of age.

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Body Weight, Food Intake, Activity, and Adipose Weight

Age,
wk

Strain

Weight, g

Food Intake,
g per 24 h

Activity, Counts
per min

Visceral
Fat, g

Uterine/Ovarian
Fat, g

RP
Fat, g

Brown
Fat, g

NZW/LacJ

24.10.4

3.90.1

10.01.5

0.90.1

0.60.1

0.110.01

0.110.01

n33

n5

n5

n10

n4

n4

n4

27.10.5

3.90.1

7.50.9

1.30.1

1.00.1

0.170.01

0.130.01

n34*

n5

n4

n12

n5

n5

n5

32.30.3

3.10.2

6.90.6

1.90.2

1.20.1

0.210.02

0.280.03

n55

n5

n5

n15

n4

n4

n4

39.30.8

3.00.2

5.70.5

3.30.2

3.80.3

0.480.06

0.270.04

n48*

n5

n13*

n5*

n5*

n5

34.10.4

3.20.1

8.50.7

2.30.2

2.60.2

0.470.08

0.170.02

n79

n5

n7

n31

n4

n4

n4

45.70.6

3.30.2

5.50.7

5.00.3

5.70.6

0.870.08

0.320.09

n97*

n5

n8*

n46*

n5*

n5*

n5

NZBWF1
20

NZW/LacJ
NZBWF1

36

NZW/LacJ
NZBWF1

n5

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RP indicates retroperitoneal.
*P0.05, 1-way ANOVA, vs age-matched NZW/LacJ.

SLE; however, reproductive and retroperitoneal adipose depots were significantly greater beginning at 20 weeks of age
in SLE compared with controls (Table).
Food intake was not different between control and SLE
mice at any age tested (Table). Data using radiotelemeters
indicate that locomotor activity (during the night cycle)
tended to be lower in SLE mice at 8 (P0.14) and 20
(P0.11) weeks of age. At 36 weeks, the age with the
greatest disparity in weight and adipose, activity is significantly lower in SLE mice (P0.02). Activity data in the
Table represent the average nighttime activity over the course
of the 4 days. Because the greatest differences in activity,
body, and adipose weight were observed at 36 weeks, the
remaining experiments were performed at this age.
Given the increased central adiposity, it was not surprising
to find that plasma leptin levels in 36-week-old mice were
significantly elevated compared with controls (Figure 3a).
The elevated leptin and similar food intake led to the con-

sideration of leptin resistance, at least centrally. To assess

this, the effect of intraperitoneal leptin administration on food
intake was tested in 36-week-old mice (Figure 3b). Leptin
significantly reduced food intake to the same degree in both
control and SLE mice, suggesting that the SLE mice are not
resistant to its appetite-suppressing effects. In addition, the
reduction in body weight caused by leptin injection was not
different between control and SLE mice (2.60.2 g versus
3.00.4 g; n5; P0.33 Student t test). Injection of
vehicle (saline) did not affect food intake in either strain (data
not shown).
The ovarian/uterine adipose tissue depot isolated from
36-week-old SLE mice had significant macrophage infiltration, an indication of inflammation, when compared with
control mice (Figure 4). Similarly, sections of renal cortex
from SLE mice exhibited macrophage infiltration, whereas
those from control mice did not (Figure 5). Macrophage
infiltration was not notable in the medulla (data not shown).

Figure 3. Plasma leptin levels are increased

in 36-week SLE mice compared with controls. (A) P0.001 compared with control
(Student t test). Twice daily intraperitoneal
injections of 30 g of leptin in saline lead to
a similar reduction in food intake in both
control and SLE mice. (B) P0.05 compared
with basal food intake (1-way ANOVA).

Ryan et al

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Figure 4. Visceral adipose tissue from 36-week-old SLE mice

(B) had macrophage infiltration, whereas control adipose tissue
did not (A). Percentage of macrophage (per total number of
cells) was significantly increased in SLE mice compared with
controls (C). P0.03.

Frozen liver sections from SLE mice exhibited marked lipid

accumulation in 5 of 6 mice studied compared with 0 of 6
controls (Figure 6).
Although fasted blood glucose levels were not different
(Figure 7a), fasted insulin levels were significantly increased
in SLE mice when compared with controls (Figure 7b).
Moreover, when isosmotic glucose was administered after a
6-hour fast, SLE mice demonstrated a greater increase in
blood glucose that took longer to return to basal levels
(Figure 7c). These data indicate that the SLE mice are insulin
resistant.

Discussion
The major new finding of this study is that an established
model of SLE with hypertension has several characteristics of
the metabolic syndrome. Therefore, the NZBWF1 strain may
prove to be an important model for examining the connection
between chronic inflammation and the metabolic syndrome.
Specific findings include the following: (1) a hypertensive
mouse model of SLE has increased body weight and central
adiposity; (2) adipose tissue from SLE mice has monocyte/
macrophage infiltrates as a marker of inflammation; (3)
reduced physical activity may contribute to the increased
body weight and adipose, but increased food intake does not;
(4) SLE mice do not seem to be resistant to the satiating

Insulin Resistance, Obesity, and SLE

991

effects of leptin; and (5) the NZBWF1 model of SLE is insulin

resistant.
Several risk factors comprise metabolic syndrome, including central obesity, insulin resistance, endothelial dysfunction, hypertension, inflammation, and dyslipidemia. The
present data demonstrate that this model of SLE exhibits
many of these features. For example, numerous other studies
have reported an important role for inflammatory cytokines in
the progression of SLE in NZBWF1 mice.1315 Recent evidence from our laboratory demonstrated that NZBWF1 mice
are hypertensive, have impaired endothelial dependent relaxation, and have albuminuria by 36 weeks of age.7 The
pressure data from the present study measured by indwelling
carotid catheters are consistent with the recently reported
telemetry pressures. Although it is not yet clear, the impaired
endothelial function7 and elevated circulating leptin may be
potential contributors to elevated blood pressure in this
model. Although they were not measured in the present
experiments, data from the literature indicate that these mice
have dyslipoproteinemia.16 The NZBWF1 strain has been
widely used to examine the progression of SLE. These mice
closely mimic human SLE, including the presence of antinuclear antibodies, glomerulonephritis, inflammatory cytokines,
and a female predilection.13,15,17,18, Despite 4 decades of
experimentation, this is the first study to report characteristics of the metabolic syndrome in this model. One potential
limitation of this model is that the obesity and insulin
resistance may be comorbid with SLE. Further examination
will be required to establish a link between chronic inflammation in this model and the metabolic syndrome.
The relationship between SLE and changes in glucose
handling or body composition has not been widely studied. In
rare clinical cases, patients with SLE develop antibodies to
the insulin receptor, which cause insulin resistance (type B
insulin resistance).19 Independent of these case studies, currently available data suggest that humans with SLE are at an
increased risk to develop insulin resistance and obesity. For
example, it has been reported that individuals with SLE
have significantly increased body mass index at a 10-year
follow-up compared with healthy controls.20 In addition,
women with SLE have an increased likelihood of developing
insulin resistance5 and changes in body fat distribution and
composition.6,20 The reason for increased body weight and
adiposity in the NZBWF1 model is not yet clear; however,
one possible mechanism seems to be a reduced physical
activity level.

Figure 5. The renal cortex from

36-week-old SLE mice (B) exhibit macrophage infiltration, whereas the renal cortex from control mice did not.

992

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November 2006

Figure 6. Liver sections from 3 control (A

to C) and 3 SLE mice (D and E) stained
with Oil-Red-O show increased hepatic
lipid accumulation (red droplets) in SLE
mice.

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This new model of metabolic syndrome is potentially interesting, because previous genetic models typically have
alterations in the leptin gene, its receptor, or its signaling
pathways in the brain.2124 The NZBWF1 model of SLE is
unique in that the cause of the metabolic syndrome is not
clear. Although the present data suggest that the satiety actions of leptin in the brain are not different between control
and SLE, the data do not rule out the possibility of selective
leptin resistance.25 In addition, it is equally plausible that the
increased leptin may provide some benefit by maintaining
normal blood glucose26,27 and preventing even greater lipid
accumulation in nonadipose tissues.25 The findings of hepatic
lipid accumulation are consistent with what has been observed in human metabolic syndrome.
The role of leptin and its contributions to obesity in rodent
models has been studied extensively. Interestingly, leptin is
important for promoting immune system function. Leptin
(ob/ob) or leptin receptor (db/db) knockout mice are protected against the development of autoimmune diseases,
including arthritis, inflammatory bowel disease, and multiple
sclerosis.28 30 There is also compelling evidence in humans
that leptin may be important for the pathogenesis of autoimmune disease. For example, after a 7-day fasting period, 10
individuals with rheumatoid arthritis showed significant clinical improvement.31 Another study demonstrated that women
with SLE have significantly elevated plasma leptin when
compared with age-, sex-, and body mass indexmatched
controls.32 Therefore, it is possible that the elevated leptin in
NZBWF1 may be a contributing factor to the chronic inflam-

mation and progression of SLE in this model. Future studies

will be required to determine the role of leptin in promoting
autoimmunity and SLE hypertension.

Perspectives
Chronic inflammation is increasingly considered as a potential underlying mechanism for the progression of hypertension, insulin resistance, and the metabolic syndrome. SLE is
a chronic autoimmune inflammatory disorder with a high
incidence of hypertension. Evidence suggests that the incidence of insulin resistance, obesity, and lipodystrophy is
higher in individuals with SLE; however, the mechanisms for
this have not been investigated. The present study shows for
the first time that a widely used mouse model of SLE has
characteristics of the metabolic syndrome, including central
adiposity, fatty liver, elevated leptin, and insulin resistance.
Therefore, NZBWF1 may be an important model to examine
the relationship between chronic inflammation during SLE
and how this leads to insulin resistance and altered body
composition.

Acknowledgments
We acknowledge the University of Mississippi Medical Center
Department of Physiology Histology Core (Lisa Henegar and
Stephanie Evans) for assistance with adipose tissue and liver
histology.

Sources of Funding
This work was supported by an American Heart Association Scientist Development Grant to M.J.R (0630089N), as well as the National
Institutes of Health (PO1HL-51971).

Figure 7. Fasted blood glucose was not

different between 36-week-old control
and SLE mice (A). Fasted plasma insulin
was significantly increased in 36-week
SLE mice vs controls (B). P0.05. A glucose tolerance test showed that fasted
glucose was significantly greater in
36-week SLE mice after an intraperitoneal injection of isosmotic glucose and
took longer to return to basal levels (C).
P0.05 vs time-matched control (1-way
ANOVA).

Ryan et al

Disclosures
None.

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Insulin Resistance and Obesity in a Mouse Model of Systemic Lupus Erythematosus

Michael J. Ryan, Gerald R. McLemore, Jr and Steven T. Hendrix

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Hypertension. 2006;48:988-993; originally published online September 18, 2006;

doi: 10.1161/01.HYP.0000243612.02929.df
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2006 American Heart Association, Inc. All rights reserved.
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