(The FASEB Journal. 2001;15:108-114.)
© 2001 FASEB
The role of leptin resistance in the lipid abnormalities of aging
ZHUO-WEI WANG*,
WEN-TONG PAN*,
YOUNG LEE*,
TETSUYA KAKUMA*,
YAN-TING ZHOU* and
ROGER H. UNGER*,
1
* Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; and
VA North Texas Health Care System, Dallas, Texas 75216, USA
1Correspondence: Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8854, USA. E-Mail: Runger{at}mednet.Swmed.edu
 |
ABSTRACT
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Leptin resistance has been implicated in the pathogenesis of
obesity-related complications involving abnormalities of lipid
metabolism that resemble those of old age. To determine whether
development of leptin resistance in advancing age might account for
such abnormalities, we compared the effects of hyperleptinemia (>40
ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+)
Zucker diabetic fatty rats by adenovirus gene transfer. The decline in
food intake, body weight, and body fat in old rats was only 25%, 50%,
and 16%, respectively, of the young rats. Whereas in young rats plasma
free fatty acids fell 44% and triacylglycerol (TG) 94%, neither
changed in the rats. In hyperleptinemic young rats, adipocyte
expression of preadipocyte factor 1 increased dramatically and leptin
mRNA virtually disappeared; there was increased expression of acyl CoA
oxidase, carnitine palmitoyl transferase 1, and their transcription
factor peroxisome proliferator-activated receptor 
, accounting for
the reduction in body fat. These hyperleptinemia-induced changes were
profoundly reduced in the old rats. On a high-fat diet, old rats
consumed 28% more calories than the young and gained 1.5x as much
fat, despite greater endogenous hyperleptinemia. Expression of a
candidate leptin resistance factor, suppressor of cytokine signaling 3
(SOCS-3), was compared in the hypothalamus and white adipocytes of
young and old rats before and after induction of hyperleptinemia;
hypothalamic SOCS-3 mRNA was 
3x higher in old rats before, whereas
it was 3x higher in WAT after, hyperleptinemia. We conclude that the
anorexic and antilipopenic actions of leptin decline with age, possibly
through increased SOCS-3 expression, and that this could account for
the associated abnormalities in lipid metabolism of the elderly.—Wang,
Z.-W., Pan, W.-T., Lee, Y., Kakuma, T., Zhou, Y.-T., Unger, R. H.
The role of leptin resistance in the lipid abnormalities of aging.
Key Words: high-fat diet • hyperleptinemia • SOCS-3 • fatty acids • hypothalamus • lipotoxicity
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INTRODUCTION
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ALL CELLS HAVE a genetically programmed life span
(1
, 2)
, but longevity is also influenced by environmental
factors. Caloric restriction (3)
and exercise
(4)
appear to prolong life, whereas caloric excess,
physical inactivity, and obesity seem to shorten it. The benefits of
caloric restriction and exercise have been attributed to a reduction in
extramitochondrial metabolism of long-chain fatty acids (FA) (3
, 5)
.
Like exercise and caloric restriction, leptin lowers the lipid content
of cells (6)
. In the absence of leptin activity, FA
delivery to nonadipose tissues may exceed the oxidative requirements;
the resulting increase in nonoxidative metabolism may impair cell
functions and cause cell death through ‘lipoapoptosis’ (7
, 8)
. In the absence of leptin or its functional receptors, excess
FA fail to up-regulate peroxisome proliferator-activated receptor
(PPAR) and the enzymes of oxidation (9
, 10)
, thereby
eliminating a protective buffer against FA overload. Unoxidized FA
excess may then enter deleterious metabolic pathways, such as ceramide
formation (7
, 8)
, lipid peroxidation (11)
,
detergent action, or increased omega oxidation.
Because deficiency of and unresponsiveness to leptin result in the
ectopic overaccumulation of lipids secondary to underexpression of
PPAR and the enzymes of FA oxidation (10)
, it seemed
possible that loss of sensitivity to leptin might be a cause of
age-related ectopic accumulation of unoxidized lipids. The report that
activators of PPAR can correct age-related dysfunction of redox
balance (12)
would be consistent with the posit that the
cellular damage is, at least in part, the result of FA excess secondary
to leptin resistance. Consequently, this study was designed to
determine whether insensitivity to the lipopenic actions of leptin
might play a role in the age-related lipid abnormalities of nonadipose
tissues.
|
MATERIALS AND METHODS
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Animals
Lean wild-type (+/+) Zucker diabetic fatty (ZDF)
(fa/fa) were bred in our laboratory from ZDF/Drt-fa (F10)
rats purchased from R. Peterson (University of Indiana School of
Medicine, Indianapolis). Twenty-four 2-month-old and 18-month-old male
rats were studied.
Adenovirus treatment
Recombinant adenovirus containing the leptin (AdCMV-leptin) and
the bacterial galactosidase (AdCMV-ß-gal) cDNAs were prepared as
described previously (13
, 14)
. Polyethylene tubing (PE-50;
Becton Dickinson, Rutherford, N.J.) was anchored in the right jugular
vein under anesthesia. Before infusion, adenovirus samples were
suspended in saline and filtered through a 0.2 µm filter. Two
milliliters of AdCMV-leptin or AdCMV-ß-gal containing 1–2 x
1012 plaque-forming units of virus were infused
into animals over a 10 min period. Animals were studied in individual
metabolic cages (Nalgene Labware, Rochester, N.Y.). The food intake by
AdCMV-ß-gal-infused control animals in each age group was matched to
the AdCMV-leptin-infused rats; food intake and body weight were
measured daily. Nine old rats and 12 young rats were treated with
AdCMV-ß-gal, and 9 old and 12 young received AdCMV-leptin. Three rats
from each treatment set in the old group were killed 3 days after
treatment and six at 7 days. In the young group, six rats from each
treatment set were killed at 3 days and at 7 days.
Leptin measurements
Blood samples were collected from the tail vein in capillary
tubes coated with ethylenediaminetetraacetic acid. Plasma was stored at
-20°C. Plasma leptin was assayed using the Linco leptin assay kit
(Linco Research, St. Charles, Mo.).
Estimation of body fat by magnetic nuclear resonance
spectrophotometry (MRS)
Using the method of Stein et al. (15)
, proton MRS
data were obtained with 4.7-T 40 cm bore system [Omega chemical shift
imaging (CSI) model; Bruker Instruments, Fremont, Calif.] using a 6 in
diameter birdcage coil. Rats were placed supine within the coil and
positioned in the center of the magnet. Proton spectra of each rat were
resolved into water and fat resonances, the areas of which were
quantified using the nuclear magnetic resonance (NRM-1) software
program (Tripos Associates, St. Louis, Mo.), assuming equal line widths
for both resonances.
Expression profiles of relevant genes
mRNA for acyl CoA oxidase (ACO), carnitine palmitoyl transferase
1 (CPT-1), preadipocyte factor 1 (Pref-1), and leptin mRNA and
suppression of cytokine signaling (SOCS-3) were semiquantified by
reverse transcription polymerase chain reaction (RT-PCR) in adipose
tissue from the epididymal fat pad. Briefly, total RNA was extracted
using TRIzol isolation kit (Life Technologies) and treated with
RNAase-free DNAase. First-strand cDNA was obtained using the
first-strand cDNA synthesis kit (Clontech, Palo Alto, Calif.).
Linearity of the PCR was tested by amplification of 200 ng per reaction
from 20–45 cycles. The linear range was found to be between 20 and 40
cycles. The products were electrophoresed on a 1.2% agarose gel. After
transferring to Hybond-N Nylon membrane (Amersham, Arlington Heights,
Ill.), DNA samples were hybridized with
32P-ATP-labeled specific probes and analyzed in
the Molecular imager (Bio-Rad Laboratories, Richmond, Calif.). Data
were expressed as the ratio of the mRNA to ß-actin mRNA. All sense,
antisense, and internal primers are listed in Table 1
.
Triglyceride content of liver, skeletal muscle, heart, and plasma
For TG measurements of liver, heart, and skeletal muscle, total
lipids were extracted from 
100 mg of tissue as described. TG was
extracted with 30 µl of tert-butyl alcohol and 20 µl of
a Triton X-100/methyl alcohol mixture (1:1 v/v). Plasma and tissue TG
content were measured by Sigma Triglyceride (GPO-Trinder) kit as
described previously (16)
.
Plasma free fatty acid (FFA) measurement
Plasma FFAs were determined using the Boehringer Mannheim kit
(Ingelheim, Germany) according to manufacturer’s instructions.
Statistical analyses
All values shown are expressed as mean ± SE.
Satistical analysis was performed by two-tailed unpaired with unequal
variance Student’s t test.
|
RESULTS
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Effects of age on the reduction of body fat by hyperleptinemia
Treatment of rats with AdCMV-leptin resulted in marked elevations
of plasma leptin, which averaged 48 ± 16 ng/ml in the 2-month-old
and 44 ± 10 ng/ml in the 18-month-old rats (N.S.). In young rats
food intake during the 7 post-treatment days decreased by 37.5% and
body weight by 10.6% compared to a decrease of only 9% and 5.3%,
respectively, in the old rats (Table 2
). Estimation of total body fat mass by MRS revealed a 94% decline from
prehyperleptinemic levels in the young animals compared to a 15%
reduction in the old group (P<0.01) (Table 2)
. Plasma FFA
and TG levels, which fell by 44 and 94%, respectively, in the young
did not decline significantly in the older rats (Table 2)
. Thus, in
older rats with a comparable level of hyperleptinemia, the reductions
of food intake, body weight, body fat, and plasma lipid levels were far
less than in young rats.
Effect of age on hyperleptinemia-induced changes in the mRNA of
Pref-1 and leptin
During adenovirus-induced hyperleptinemia in young rats, dramatic
changes in gene expression occur in white adipose tissue (WAT) as TG
disappear (13)
. Among these changes are the up-regulation
of expression of Pref-1, a preadipocyte marker (17)
, and
the virtual disappearance of endogenous leptin mRNA (18)
.
In the WAT of 8-wk-old rats used here, once again Pref-1 mRNA increased
(Fig. 1A
), whereas leptin mRNA disappeared by the seventh day after
the infusion of Ad-CMV-leptin (Fig. 1B
). However, these
dramatic effects were markedly attenuated in the WAT of 18-month-old
rats made similarly hyperleptinemic: the increase in Pref-1 mRNA
measured only 1% (P<0.01), and the suppression of leptin
expression only 37%, of the changes in young rats. Thus, although
leptin did exert a significant effect on the expression profile of
adipocytes of elderly rats, the effect was but a small fraction of that
observed in young rats.
The effect of aging on leptin-induced up-regulation of PPAR- and
enzymes of FA oxidation in white adipose tissue
In young rats, the dramatic disappearance of adipocyte TG that
accompanies the weight loss of adenovirus-induced hyperleptinemia has
been attributed in part to up-regulation in WAT of the enzymes of fatty
acid oxidation, ACO and CPT-1, mediated through increased expression of
their transcription factor, PPAR (18)
. The age-related
resistance of WAT to the lipopenic action of the hyperleptinemia could
reflect failure to up-regulate PPAR and its target enzymes of FA
oxidation. To test this, we compared expression profiles of the FA
oxidation machinery of the two groups. Treatment of 8-wk-old rats with
AdCMV-leptin again resulted in up-regulation of the expression of all
three genes in the virtually unrecognizable remnant of the epididymal
fat pad (P<0.01) (Fig. 2
). In 18-month-old rats, by contrast, up-regulation of these genes,
although statistically significant (P<0.05), was 50% or
less than in the young rats. Thus, the ability of hyperleptinemia to
up-regulate FA oxidation in white adipose tissue is attenuated in
elderly rats.
Effects of age on the lipopenic effect of hyperleptinemia on
nonadipose tissue
In young rats, adenovirus-induced hyperleptinemia causes a marked
reduction in TG content in nonadipose tissues (10)
. In the
8-wk-old rats studied here, adenovirus-induced hyperleptinemia again
reduced the TG content in liver (P<0.01), heart
(P<0.01) and skeletal muscle (P<0.01)
(Fig. 3
). In 18-month-old rats with comparable hyperleptinemia, no significant
reduction in TG content was observed in any of these tissues. Thus, in
elderly rats there is marked resistance to the lipopenic action of
leptin in the nonadipose tissues that are prominently involved in the
pathophysiology of aging. This raises the possibility that certain of
the cardiac, muscular, and metabolic abnormalities of aging result at
least in part from lipotoxicity consequent to leptin resistance.
Effect of aging on the response to a high-fat diet
Body fat generally increases with age. Although this is almost
certainly multifactorial in etiology, the age-related reduction in
leptin sensitivity demonstrated here could well be a contributing
factor. Consequently, we compared body fat gain in 8-wk-old and
18-month-old rats presented with the same high-fat diet for 8 wk.
Actual caloric intake was 96 Kcal/day in the young rats and 132
Kcal/day in the old. Body fat measured by MRS increased by 46.7 ±
4.3 g (13.8±0.95% of body weight) in the young and by 79.2 ± 5.4 g (9.01±0.54% of body weight) in the old
(P<0.001). Leptin levels rose by 8.3 ± 1.5 ng/ml in
the young and by 14.0 ± 1.1 ng/ml in the old
(P<0.01). Relative hypoleptinemia (inappropriately low
level of hyperleptinemia relative to the expanded mass of body fat) was
excluded by calculating the ratios of 
leptin/ body fat, which
were 0.18 ± 0.03 in the young rats and 0.18 ± 0.04 in the
old rats.
Thus, since old rats on a high-fat diet exhibited greater gain in body
fat without absolute or relative hypoleptinemia, the greater food
intake and weight gain in the older rats must be the result of
hyposensitivity to the higher levels of endogenous leptin.
SOCS-3 levels in aging rats
SOCS-3 has been identified as a possible cause of leptin
resistance (19
, 20)
. To determine whether the age-related
resistance to the effects of diet-induced hyperleptinemia could be the
result of increased expression of this putative leptin resistance
factor, SOCS-3 mRNA was semiquantified in the hypothalamus of young and
old rats with normal leptin levels (Fig. 4
). The mean pretreatment level was almost 3x greater in the old group
(P<0.01), implying that this factor might have dampened the
hypothalamic response to the anorexic action of endogenous leptin and
contributed to the greater food intake and weight gain. However, after
induction of hyperleptinemia by AdCMV-leptin infusion in young rats,
SOCS-3 mRNA increased to the pretreatment level of the untreated old
rats. This may account for the improvement in food intake observed
after 4 days of hyperleptinemia (13)
.
To examine the possibility that an increase in locally expressed SOCS-3
in adipocytes of older rats plays a role in their marked resistance to
the lipopenic action of adenovirus-induced hyperleptinemia, we
contrasted the SOCS-3 expression level in epididymal fat pads of old
and young rats with comparable elevations in plasma level of leptin. In
epididymal fat of young rats made hyperleptinemic, SOCS-3 was no higher
than in normoleptinemic controls, but in old rats it was threefold
greater (P<0.01) 3 days after AdCMV-leptin treatment before
the adipose tissue became unidentifiable (Fig. 4)
. Thus, the rapid
increase in SOCS-3 expression in adipose tissue of the old rats may
have limited the effects of the hyperleptinemia on their involution and
dedifferentiation.
|
DISCUSSION
|
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Caloric restriction has been reported to extend life in a variety
of species (1
, 3)
. Barzilai and Gupta (3)
proposed the possibility that these life-extending effects are the
result of a diminution in body fat. Conversely, recent work from our
group suggests that many of the morbid complications of obesity in the
ZDF (fa/fa) rat are the result of enhanced nonoxidative
metabolism in nonadipose tissues, a consequence of increased FA flux
from the expanded adipocyte mass at rates that exceed the oxidative
capacities of the tissues (10)
. The fact that the
leptin-unresponsive tissues of ZDF rats are fat-laden led to the
hypothesis that the role of leptin is to protect nonadipocytes from
overaccumulation of FA when FA influx exceeds caloric needs, as during
the development of obesity (10)
. According to this
concept, adipocytes function not only as storage depots for FA, but
also as protectors of nonadipocytes from the deleterious consequences
of lipid overload. These consequences include diabetes
(21)
, impaired cardiac function (22)
, insulin
resistance (23
, 24)
, and sarcopenia.
Impairment of ß cell (25)
and cardiac function
(26)
, together with insulin resistance and sarcopenia
(27)
, are also observed in old age without obesity, and
both aging (28)
and obesity are associated with leptin
resistance. In the young, leptin-mediated antilipogenic protection
permits TG stores to expand in adipocytes without their
overaccumulation in nonadipose tissues. In the elderly, however, this
protective action wanes and there is a predilection for a gain in
overall body fat and for a shift of lipids into nonadipocytes. We
speculate that increased nonoxidative metabolism of unoxidized FA may
be a factor in dysfunction and death of cells during the aging process
and that the salutary effect of caloric restriction may simply be the
result of reduced spillover of surplus FA into nonadipocytes. The
efficacy of troglitazone treatment of obese rats in preventing
dysfunction and apoptosis in islets (29)
and heart
(22)
may be due to relocation of lipids into adipocytes
with reduced ectopic lipid accumulation in those tissues.
The present study extends an earlier report of age-related leptin
resistance (28)
by implicating it as a causative factor in
the accumulation of lipids in nonadipose tissues and in the functional
consequences thereof. In 18-month-old rats with adenovirus-induced
hyperleptinemia in excess of 40 ng/ml, the reduction in food intake and
loss of body fat was only a fraction of that observed in 2-month-old
rats with comparable hyperleptinemia. Plasma FFA and TG, which declined
dramatically in the young rats, were unchanged in the old. In the old
rats, hyperleptinemia failed to lower the TG content in liver, cardiac,
or skeletal muscle as it did in the young. This is attributed to the
fact that in old rats the marked hyperleptinemia failed to up-regulate
the enzymes of FA oxidation—ACO and CPT-1—and their transcription
factor, PPAR, to the levels observed in the young rats.
Finally, the tendency of the elderly to gain weight may be explained by
the observation that despite higher plasma leptin levels, the caloric
intake of old rats fed a high-fat diet for 8 wk was greater than in
young rats fed the same diet and they gained 60% more body weight.
Thus, if a role of leptin is to limit food intake, the older rats were
leptin resistant. This could perhaps be ascribed to the greater
expression of SOCS-3, a putative inhibitor of leptin action (19
, 20)
, in the hypothalamus of old rats. In the young rats the
SOCS-3 level in the hypothalamus increased 3 days after induction of
hyperleptinemia as food intake rose toward normal. In adipose tissues
of old rats, the rapid increase in SOCS-3 mRNA 3 days after induction
of hyperleptinemia may have accounted for a resistance to the lipopenic
actions of leptin subsequent to that time. In young rats, by contrast,
SOCS-3 expression remained unchanged by hyperleptinemia and
identifiable fat disappeared.
In summary, these findings point to leptin resistance as a cause of
certain components of the phenotype of old age, such as the overall
increase in total body TG and the distributional shift in TG from
adipose to nonadipose tissues. Failure to protect nonadipose tissues
from lipotoxicity may underlie the pathogenesis of abnormalities that
occur both in obesity and in old age, such as ß cell failure and
myocardial dysfunction. Since the antilipogenic thiazolidinedione
troglitazone prevents ß cell dysfunction (29)
and
cardiac dysfunction (22)
in rats with obesity secondary to
a leptin receptor defect, it may be that pharmacologic reduction of
ectopic lipid accumulation would be beneficial in reducing certain
morbid manifestations of old age.
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ACKNOWLEDGMENTS
|
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We acknowledge the grant support of the Department of Veterans
Affairs Institutional Support, the National Institutes of Health
(DK02700–37), The National Institutes of Health/Juvenile Diabetes
Foundation Diabetes Interdisciplinary Research Program, and
Novo-Nordisk Corporation. We thank Susan Kennedy for outstanding
secretarial work and Kay McCorkle for excellent technical help.
Received for publication May 9, 2000.
Revision received June 21, 2000.
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TOP
ABSTRACT
INTRODUCTION
on
the mRNA of the preadipocyte marker Pref-1 and of leptin in white
adipose tissue of young and old rats. Recombinant adenovirus containing
the cDNA of ß-galactosidase 
was infused as a control.
n = 6; *P<0.01.
