(The FASEB Journal. 2001;15:312-321.)
© 2001 FASEB
Diseases of liporegulation: new perspective on obesity and related disorders
ROGER H. UNGER*,
1 and
LELIO ORCI
* Gifford Laboratories, Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854, USA;
Veterans Affairs North Texas Health Care System, Dallas, Texas, USA; and
Department of Morphology, University of Geneva Medical School, Geneva, Switzerland
1Correspondence: Gifford Laboratories, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8854, USA. E-mail: runger{at}mednet.swmed.edu
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ABSTRACT
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Obesity-related diseases now threaten to reach epidemic proportions in
the United States. Here we review in a rodent model of genetic obesity,
the fa/fa Zucker diabetic fatty (ZDF) rat, the
mechanisms involved in the most common complications of diet-induced
human obesity, i.e., noninsulin-dependent diabetes mellitus, and
myocardial dysfunction. In ZDF rats, hyperphagia leads to
hyperinsulinemia, which up-regulates transcription factors that
stimulate lipogenesis. This causes ectopic deposition of
triacylglycerol in nonadipocytes, providing fatty acid (FA) substrate
for damaging pathways of nonoxidative metabolism, such as ceramide
synthesis. In ß cells and myocardium, the resulting functional
impairment and apoptosis cause diabetes and cardiomyopathy.
Interventions that lower ectopic lipid accumulation or block
nonoxidative metabolism of FA and ceramide formation completely prevent
these complications. Given the evidence for a similar etiology for the
complications of human obesity, it would be appropriate to develop
strategies to avert the predicted epidemic of lipotoxic
disorders.—Unger, R. H., Orci, L. Diseases of lipid overflow: new
perspective on obesity and related disorders.
Key Words: lipotoxicity • lipoapoptosis • complications of obesity • noninsulin-dependent diabetes • cardiomyopathy
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INTRODUCTION
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THROUGHOUT THE 2.5 MILLION YEAR history of human
development the principal threat to survival has been recurrent famine.
The evolution of adipocytes provided a means for coping with the cycles
of undernutrition by enabling the preloading of calories for subsequent
use (1)
. During the 20th century, however, an
unprecedented change in the pattern of caloric availability took place
in many Western countries. Recurrent undernutrition was replaced by
unending overnutrition, the consequences of which were greatly
amplified by the permanent state of underexertion imposed by sedentary
occupations and immobilizing technologies of modern life. Since the
compensatory mechanisms that buffer the metabolic consequences of
short-term overnutrition were incapable of compensating for such
chronic changes in caloric balance, diseases of overnutrition became
increasingly prevalent.
The first such disease to be identified was coronary artery disease
(2)
. Scientific advances of the past three decades have
elucidated its mechanisms (3)
and have reduced its health
consequences (4
, 5)
. A second group of disorders, the
complications of obesity, now threatens to replace it as a major health
problem in Westernized societies (6)
. These complications,
which include dyslipidemia, insulin resistance, noninsulin-dependent
diabetes mellitus (NIDDM), and heart disease, are often referred to
collectively as ‘metabolic syndrome X’, ‘insulin resistance
syndrome’, or ‘Reaven syndrome’ (6
7
8)
. Given the
inexorable increase in the prevalence of obesity, these complications
will constitute an ever-increasing cause of morbidity, mortality, and
health care costs in the United States and elsewhere (6)
.
A similar array of complications in genetically obese Zucker
diabetic fatty (ZDF) rats has been referred to as ‘lipotoxicity’
(9
10
11
12
13)
. This presumably monogenic disorder is far more
suitable for intensive study of obesity-related disease mechanisms than
is the environmentally induced, polygenic human counterpart, because
the complications appear by the 14th week of age in 
100% of male
homozygotes, provided that their diet contains at least 6% of the
calories as fat. The lipotoxicity is attributed to products of
excessive non-ß-oxidative metabolism of FA excess in skeletal muscle,
pancreatic islets, and myocardium (10
11
12)
. High levels of
these metabolic products are believed (13)
to cause the
common complications of obesity, insulin resistance, cardiovascular
disease, and diabetes by disrupting cell function and ultimately by
promoting programmed cell death (‘lipoapoptosis’) (11
, 12)
. These complications are completely preventable in rodents
by means of currently available pharmacologic interventions that
increase oxidative and reduce the nonoxidative metabolism of FA
(14
, 15)
.
The possibilities that the complications of human obesity are
mechanistically similar to those of obese ZDF rats and can be blocked
by the same interventions prompted this review of rodent lipotoxicity,
its prevention, and its relevance to human disease.
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NORMAL FATTY ACID (FA) HOMEOSTASIS
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Compensatory up-regulation of FA oxidation
Normally, FA delivery to nonadipose tissues is tightly coupled to
their need for fuel. Plasma free FA levels rise during exercise and
fasting to meet the metabolic requirements, leaving little or no
unoxidized FA in these cells (Fig. 1A
). During chronic overnutrition, however, FA influx into
tissues may exceed FA usage, in which case compensatory up-regulation
of FA oxidation is required to maintain intracellular FA homeostasis
(Fig. 1B
). The excess FA themselves probably provide the
signals for such metabolic adjustments by serving as ligands for
peroxisome proliferator-activated receptors (PPAR)
(16
17
18
19)
.
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Figure 1. Normal and abnormal fatty acid (FA) homeostasis in nonadipose
tissues. A) Caloric equilibrium: FA supplied and FA used
in nonadipose tissues are equal, leaving no unoxidized FA.
B) Compensated caloric excess. During chronic caloric
excess, the FA supply to nonadipose tissues may exceed their oxidative
needs; however, up-regulation of PPAR , the transcription factor for
enzymes of FA oxidation (CPT-1 and ACO) and uncoupling protein (UCP-2),
will promote compensatory oxidation of the surplus FA, and the unneeded
energy will be dissipated as heat. This compensatory system requires
leptin and a normal leptin receptor (OB-R). C)
Uncompensated caloric excess. In the absence of leptin or its receptor
OB-R, hyperphagia results in a caloric intake in excess of caloric
requirements. FA storage occurs not only in adipocytes, resulting in
obesity, but also in nonadipocytes, causing lipotoxicity. With PPAR
expression reduced, surplus FA influx presumably binds to the high
levels of PPAR , which up-regulates the lipogenic enzymes ACC and
FAS. This causes ectopic accumulation of TG, increased nonoxidative FA
metabolism, and lipoapoptosis (see Fig. 2
).
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PPAR is a transcription factor that up-regulates the oxidative
enzymes (Fig. 1B
) carnitine palmitoyl transferase-1 (CPT-1)
and acyl CoA oxidase (ACO) (18
19)
. Normally it is
expressed in nonadipose tissues at relatively high levels compared to
PPAR, the lipogenic transcription factor. It has been suggested that
surplus FA may up-regulate PPAR and the oxidative machinery, and
thus prevent the overaccumulation of unoxidized lipids
(20)
. The supplemental energy thereby generated is
presumably dissipated as heat (21)
, as inferred from
leptin-mediated up-regulation of uncoupling protein 2 (22
, 23)
and from earlier studies of the thermogenic effects of
nutrients (24)
.
In most normal nonadipose tissue, PPAR- and the enzymes of fatty
acid synthesis are expressed at low levels compared to adipocytes
(25)
, suggesting that they have relatively low lipogenic
capacities, an important factor in normal intracellular homeostasis.
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ABNORMAL FA HOMEOSTASIS
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Sources of FA excess
The putative liporegulatory system described above
is leptin-requiring, i.e., it exists only in tissues of normally
leptinized organisms. In leptin-unresponsive obese ZDF rats homozygous
for the fa mutation in the leptin receptor (OB-R) (26
, 27)
, FA-mediated up-regulation of oxidative enzymes does not
occur (20)
. The surplus FA may therefore enter pathways of
lipogenesis and nonoxidative metabolism (10
, 12)
such as
lipid peroxidation and ceramide-mediated apoptosis (Fig. 1C
). While this is, in part, the consequence of failure of
FA to up-regulate expression of PPAR and the enzymes of
ß-oxidation (10)
, the major cause of the excess lipid
deposition in nonadipocytes is the high rate of lipogenesis derived
from both elevated plasma free FA and triacylglycerol (TG) levels and
from increased intracellular FA synthesis (10)
.
PPAR, a lipogenic transcription factor normally expressed at
high levels in adipocytes, is also expressed at high levels in
nonadipose tissues of fa/fa rats (20)
. PPAR
up-regulates the lipogenic enzymes (17
18
19)
, acetyl CoA
carboxylase (ACC), and fatty acid synthase (FAS), which catalyze FA
synthesis, and glycerol-phosphate acyl transferase, which catalyzes FA
esterification. The high PPAR in nonadipocytes such as islets, in
turn, is accompanied by increased expression of the adipocyte
determination and differentiation factor 1 (ADD-1)/sterol regulatory
element binding protein (SREBP-1) (28
, 29)
in the affected
nonadipose tissues of the ZDF rat. SREBP-1 is a strong candidate for
the proximal transcription factor that increases lipogenic capacity,
because it can be up-regulated by hyperinsulinemia induced by
overnutrition (30
, 31)
. Figure 2
depicts a putative concept for diet-induced hypertrophy and hyperplasia
of adipocytes induced by overnutrition and ultimate ectopic lipogenesis
in nonadipocytes.
Although the abnormalities depicted in Fig. 1C
have so far
been identified only in pancreatic ß cells (11
, 33)
and
myocardium (34)
, they could also be a cause of other
complications of obesity (Table 1
).
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MECHANISMS OF LIPOTOXICITY
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The products of non-ß-oxidative FA metabolism that can
injure cells include TG (35)
, ceramide (12
, 36
, 37)
, and products of lipid peroxidation (38)
(Fig. 1C
). FA-induced damage through direct detergent action on
membranes, through omega oxidation or through inadequate stearoyl CoA
desaturase activity, have not yet been explored.
Triacylglycerol excess (steatosis)
TG are the most abundant products of excessive
non-ß-oxidative metabolism of FA, but they are probably relatively
inert and therefore not toxic in a direct sense. Marked TG excess in a
nonadipocyte could theoretically interfere directly with certain cell
functions, such as muscular contraction. For example, the high
incidence of gallstones in obese humans could conceivably be the result
of bile stasis due to impaired contractility of the gall bladder
secondary to steatosis of its wall, but this question has not been
addressed.
Excess TG may cause fibrosis in nonadipocytes. Hepatic fibrosis, a
common finding in alcohol-induced hepatic steatosis, also occurs in
obese nonalcoholic patients with excessive hepatic TG deposition
(35)
. Abnormal fibrosis also develops in the fat-laden
islets (14)
and heart (34)
of ZDF rats.
Although the mechanism of the poststeatotic fibrosis is unknown,
transforming growth factor ß is suspected (39
, 40)
.
Ceramide excess
An expanded reservoir of TG within nonadipocytes is a
potential source of excess FA that may enter the lipotoxic pathways of
de novo ceramide synthesis. Ceramide accumulation in ß
cells, long implicated in apoptotic pathway of autoimmune destruction
of ß cells and attributed to increased sphingomyelin breakdown
(41)
, can also be formed directly via de novo
synthesis from FA (12)
(Fig. 1C
). This pathway
appears to play a central role in FA-induced apoptosis (11
, 12)
(Fig. 3A
). The islets of obese fa/fa ZDF rats exhibit an
increase in de novo synthesis of
[3H]-ceramide from its precursors,
[3H]-palmitate and
[3H]-serine, compared to +/+ controls (Fig. 3B
). Moreover, the expression of serine palmitoyl
transferase, which catalyzes the first step in ceramide synthesis,
condensation of serine and palmitoyl CoA (42)
(Fig. 3A
), is increased in such islets (12)
(Fig. 3C
). Ceramide increases the expression of inducible nitric
oxide synthase (iNOS) through activation of nuclear factor 
B
(43)
, and thereby augments the production of nitric oxide
(NO) (44)
. NO forms potent oxidants, such as peroxynitrite
(45
, 46)
, that cause the apoptosis (Fig. 3B
).
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Figure 3. Role of de novo ceramide synthesis in
lipotoxicity. A) Simplified scheme showing fatty
acid-induced ceramide synthesis from condensation of palmitoyl CoA and
serine. Elevated ceramide is believed to be the cause of FA-induced
apoptosis of pancreatic ß cells. This pathway is distinct from
cytokine-induced breakdown of sphingomyelin, the mechanism proposed for
apoptosis of autoimmune diabetes. The validity of the fatty
acid-induced pathway is supported by the fact that ceramide formation,
iNOS up-regulation, and apoptosis can all be reduced or blocked by
L-cycloserine (CS) and by fumonisin B1 (FB-1), by
reducing islet lipid content (14)
, and by the experiments
in panel B. B) Comparison of de
novo [3H]-ceramide formation from
[3H]-serine or [3H]-palmitate in islets
isolated from normal lean ZDF rats (+/+) and obese diabetic ZDF rats
(fa/fa). C) The ratio of serine palmitoyl
transferase mRNA to ß-actin mRNA in islets isolated from normal lean
ZDF rats (+/+) or obese ZDF rats (fa/fa). At 7 wk of age
the obese rats are prediabetic; at 14 wk of age they are diabetic.
D) Apoptosis, as evidenced by DNA laddering, in the
pancreatic islets of obese prediabetic ZDF (fa/fa) rats
cultured in the absence or presence of 1 mM fatty acids (FA) and its
relationship to leptin action and Bcl2 expression. Prior to
culture, the islets were treated with either AdCMV-ß-gal (as a
control) or AdCMV-OB-Rb to cause transgenic overexpression of a normal
leptin receptor. In the AdCMV-ß-gal-treated islets cultured in 1 mM
FA, the already high level of DNA laddering, an index of apoptosis,
rose by twofold. Expression of the antiapoptotic factor
Bcl2 declined; the addition of leptin did not prevent these
changes. By contrast, in the AdCMV-leptin-treated islets in which the
normal leptin receptor is overexpressed, FA still increased DNA
laddering and reduced Bcl2 expression, but 20 ng/ml of
recombinant leptin completely blocked both the apoptotic effect of FA
and the FA-induced down-regulation of Bcl2. (Reprinted with
permission of Proceedings of the National Academy of Sciences
U.S.A.)
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Type 1 and 2 diabetes share a distal portion of the
apoptotic pathway
Obesity-related Type 2 diabetes of ZDF rats and autoimmune
Type 1 diabetes appear to share the apoptotic pathway mediated by
ceramide and iNOS (Fig. 3A
). However, in lipotoxic islet
disease only those ß cells with the highest fat content succumb to
lipoapoptosis; this leaves enough functioning ß cells to maintain
insulin independence, but not sufficient insulin-producing capacity to
compensate for the insulin resistance and prevent Type 2 diabetes. In
contrast, in cytokine-mediated apoptosis of autoimmunity, the
destruction of ß cells is indiscriminate and usually total, causing
insulin-dependent or Type 1 diabetes.
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GENETIC AND NONGENETIC CAUSES OF LIPOTOXICITY (TABLE 1)
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Congenital generalized lipodystrophy (CGL)
CGL is a rare genetic disorder characterized by absence of
adipocytes and deficiency of their secretory products. The leptin
deficiency (47)
causes hyperphagia (48)
,
whereas the lack of leptin-mediated protection against ectopic lipid
accumulation, coupled with a lack of adipocytes in which to store
excess TG, results in severe lipotoxicity in nonadipocytes. The
clinical manifestations of the disorder include a voracious appetite,
hypertriglyceridemia, severe insulin resistance, diabetes, hepatic
steatosis, and cardiac disorders such as hypertrophic cardiomyopathy
appearing in early adulthood (48
, 49)
. In mouse models of
CGL, leptin administration reduces the insulin resistance and hepatic
steatosis (50)
, as does transplantation of adipocytes
(51)
.
Based on this evidence of lipotoxicity in rodent CGL, it would seem
appropriate in human CGL patients to maintain equality between FA
influx and FA utilization by reducing their caloric intake and/or
increasing their FA utilization. Exercise and/or antisteatotic
treatment with leptin (50)
, or possibly troglitazone
(15)
, might also be helpful in protecting against
lipotoxicity.
Lack of leptin action
Loss-of-function mutations in the genes encoding
leptin (52)
or its receptor (26
, 27)
block
compensatory ß-oxidation of excess FA and enhance lipogenesis in
nonadipose tissues, thereby predisposing to lipotoxicity whenever
influx of FA exceeds intrinsic oxidative needs. Because leptin-mediated
regulation of hypothalamic appetite centers is absent in such rodents,
their caloric intake is high and they lack leptin-mediated protection
against the ectopic deposition of the increased FA and its consequences
(Fig. 1C
). Although such mutations are extremely rare in
humans, they have been reported (53
, 54)
.
Diet-induced obesity
The clinical course of the lipotoxicity complicating
diet-induced obesity is as different from the genetic obesity of
monogenic leptin-resistant ZDF fa/fa rats as is the course
of coronary artery disease of diet-induced hypercholesterolemia from
that of monogenic familial hypercholesterolemia. Diet-induced
lipotoxicity develops far more gradually, at widely varying rates, and
at a later age than genetic lipotoxicity. This is because normally the
protective action of the increasing hyperleptinemia (Fig. 1B
) will at first maintain normal FA homeostasis and
minimize ectopic TG deposition. Only later in the course of obesity,
for reasons that are not yet fully understood, does severe leptin
resistance appear. The causes of postreceptor leptin resistance are
under study (55)
. It is possible that aging itself
contributes to the leptin resistance and complications that appear
after decades of uncomplicated dietary obesity.
Aging
The increased morbidity and mortality of old age have
been attributed to increased oxidative stress and lipid peroxidation in
various tissues (56
57
58
59)
. Caloric restriction and exercise
are reputed to extend life by reducing non-ß-oxidative metabolism of
lipids (60
61
62)
, as leptin might be expected to do. It is
therefore noteworthy that as normal rats grow to maturity, they become
increasingly leptin resistant (63)
. In elderly rats the
effectiveness of leptin in reducing the TG content of nonadipose
tissues is less than 10% of young controls (64)
, raising
the possibility that leptin resistance contributes to the phenotype of
old age.
Impaired cardiac function and sarcopenia play central roles in the
‘dwindling’ of advanced age (65)
. These and other
abnormalities could be the consequence of an age-related lipotoxicity
in which leptin-mediated protective ß-oxidation is lost, permitting
lipids to shift into nonadipose tissues. Human ß cells have, in fact,
been reported to undergo an age-related accumulation of neutral lipids
(66)
, perhaps explaining the decline in ß cell function
in the elderly.
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LIPOTOXIC DISORDERS: DO THEY OCCUR IN HUMANS?
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Lipotoxic heart disease
In rodents
‘Lipid cardiomyopathy’ was identified more than 30
years ago in the hypertrophied heart of gold thioglucose obese mice
(67)
, and the deleterious effect of FA on myocytes has
subsequently been well documented (68
, 69)
. In ZDF
fa/fa rats, evidence of increased non-ß-oxidative FA
metabolism in the myocardium is reflected by elevations in myocardial
TG and ceramide content (34)
(Fig. 5A
) and by
increased myocardial oxidative stress (38)
. Myocardial
expression of iNOS expression is high (34)
, and the
increased nitric oxide is believed to interact with superoxide to
induce apoptosis (45)
, as reflected by the increase in DNA
laddering (34)
(Fig. 4B
). There is echocardiographic evidence of reduced myocardial
contractility (Fig. 4C
) attributed to loss of functioning
myocytes through apoptosis (34)
. These changes can be
completely prevented by treatment with troglitazone, which reduces the
myocardial TG and ceramide content and preserves the contractile
function of the heart (34)
.
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Figure 5. Oil red O staining for lipids in human and rat heart and rat skeletal
muscle showing similarity of excess lipid deposition in obesity. Frozen
sections. A) Upper panels: cardiac muscle samples from
(left) an untreated obese ZDF fa/fa rat or (right) from a
troglitazone (TGZ)-treated obese ZDF fa/fa rat. Lower
panels: skeletal muscle samples from (left) an untreated
fa/fa rat, or (right) from a TGZ-treated
fa/fa rat. B) Autopsy material from human
cardiac muscle from (left) a 57-year-old obese male [body mass index
(BMI) = 42] or (right) a 67-year-old lean male (BMI = 28). There is
accumulation of Oil red O-stained lipids in samples from both the obese
human, presumably diet-induced, and the untreated fa/fa ZDF
rat with monogenic obesity.
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Figure 4. A) Cardiac triacylglycerol (TG) and ceramide content
14-wk-old ZDF (fa/fa) rats and wild-type controls (+/+).
There is a statistically significant increase in both TG and ceramide
content. Troglitazone (TGZ) treatment for 6 wk significantly reduces TG
and ceramide content toward normal. *P<0.01.
B) DNA laddering, an index of apoptosis, is increased in
heart of obese fa/fa ZDF rats at age 14 wk. The increase
is entirely blocked by treatment of the rats for 6 wk with the
antisteatotic agent troglitazone (TGZ) beginning at 7 wk of age. Data
are expressed as fold change from the 7-wk-old baseline in
fa/fa rats, which is 10-fold that of lean +/+ rats at
that age. C) Left panel: echocardiographic images from a
normal lean (+/+) rat at age 20 wk and an obese fa/fa
age-matched ZDF rat. The dotted lines represent the cavity area for
end-diastole (left) and end-systole (right). Both the end-diastolic and
end-systolic areas are much larger in the fa/fa rat,
indicating a dilated ventricle with poor systolic contraction. Right
panel: quantification of circumferential fractional shortening, showing
functional loss in 20-wk-old fa/fa prevented by
treatment with the antisteatotic drug, troglitazone (TGZ).
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In humans
Dilated cardiomyopathy, sudden death, restrictive
cardiomyopathy, and congestive heart failure attributed to
lipid-related abnormalities have all been observed in obese humans
(70
71
72
73
74
75
76)
. In fact, obesity in asymptomatic young women is
associated with echocardiographic evidence of diastolic dysfunction
(76)
. Left ventricular dilatation, eccentric hypertrophy,
and diminished compensatory reserve, sometimes leading to overt
congestive failure, have been reported in obesity (76)
. It
appears that left ventricular abnormalities are greater in
visceral-type than in subcutaneous-type obesity (75)
, in
keeping with the greater metabolic activity of the former.
Despite the foregoing evidence that FA and ceramide may damage
cardiomyocytes, cardiac lipotoxicity is not currently recognized as a
clinical entity in the United States. When congestive failure, chest
pain, or arrhythmias occur in obese patients, they are usually
attributed to other coexisting diseases, such as coronary artery
disease and/or hypertension, rather than to lipotoxic dysfunction of
myocytes. Nonetheless, a reduction in the number of cardiac myocytes
through apoptosis is now a recognized cause of heart failure
(77)
, and lipotoxicity could well be an important
contributory cause of apoptosis. Figure 5B
provides the first preliminary morphological evidence that
lipid excess can occur in the myocardium of obese humans, as it does in
rodents. A human counterpart of the lipotoxic heart disease of obese
rodents is therefore a very real possibility.
Lipotoxic diabetes
In rodents
As mentioned, diabetes occurs before the age of 14 wk in
100% of male ZDF fa/fa rats, provided that 6% or more
of their caloric intake is derived from fat. Two weeks before the onset
of hyperglycemia (9)
, plasma levels of FFA and TG increase
dramatically. Islet TG content, which at first rises gradually,
increases abruptly 1 wk before the onset of hyperglycemia
(9)
. Ceramide also increases at this time. The chronologic
relationships of islet TG and ceramide content to the islet morphology
and the clinical course of the disorder are depicted in Fig. 6
.
In the preobese state, the islet morphology and the TG content appear
to be perfectly normal. During the prediabetic stage, as obesity
increases, islet TG content rises 10-fold, in association with a
4-fold increase in the ß cell mass and insulin production. Since
these same changes can be induced in vitro by culturing
normal islets in FA (78)
, it is assumed they are mediated
by the excess of FA. The increasing hyperinsulinemia parallels the
rising insulin requirements, thus keeping blood glucose levels within a
normal range. The insulin resistance has been attributed to lipid
excess in skeletal muscle (79
80
81
82)
, and this is readily
apparent on Oil Red O staining (14)
(Fig. 5A
).
By the age of 10 wk the obesity and insulin requirement have
progressed further, islet TG may be 50x normal, and ß cell
function has declined. The ceramide content has risen significantly,
accompanied by a 10-fold increase in DNA laddering
(11)
. The ß cell mass now begins to decrease and insulin
production is further reduced, essentially wiping out the earlier gain
of ß cells. Insulin production can no longer meet the increased
production required to compensate for the insulin resistance and
diabetes is now present (Fig. 6)
. Figure 7
displays the morphological changes that characterize the ß cells of
obese ZDF rats at the time of their failure.
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Figure 7. Upper panels: Immunofluorescent staining for insulin of an islet
of Langerhans in an untreated ZDF fa/fa rat (left) or in
a troglitazone (TGZ) -treated ZDF fa/fa rat (right).
Note the reduction and irregular distribution of the insulin cells in
the untreated islet. Middle panels: Immunofluorescent staining for
glucose transporter-2 (Glut-2) of an islet in an untreated
fa/fa rat (left) or in a TGZ-treated
fa/fa rat (right). Note the marked reduction of Glut-2
staining on the insulin cells in the untreated fa/fa
rat. Left upper and middle panels and right upper and middle panels are
consecutive serial sections. Lower panels: aldehyde-fuchsin and
Masson’s trichrome staining of islets in untreated, or TGZ-treated
fa/fa rats to compare fibrosis. The purple-stained
insulin cells are severely reduced in number in the islet of the
untreated fa/fa rat (left), accompanied by a marked
accumulation of collagen, which is stained in blue-green. The bars
represent 50 µm.
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In humans
Conclusive evidence that lipotoxic diabetes occurs in humans is
lacking because of the unavailability of islets and other tissues for
longitudinal measurements of TG. However, fat accumulation in human
islets was first reported in 1902 (83)
and found to be
greater in diabetic islets than in nondiabetic controls
(84)
. As mentioned, a recent study of human islets has
demonstrated increased neutral lipids in pancreatic sections and ß
cells of older humans (66)
. Furthermore, treatment with
the lipopenic drug troglitazone (85)
or with caloric
restriction (86)
, measures shown to lower the islet lipid
content in rats (14
, 51)
, improves glucose tolerance in
both humans (84)
and obese rats (14
, 86)
.
These findings are consistent with a common cause of disease in the two
species.
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PREVENTION OF LIPOTOXICITY AND LIPOAPOPTOSIS
|
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The dysfunctional and apoptotic consequences of lipotoxicity can
be blocked at multiple sites (Fig. 3A
). Restoration of
leptin action, reduction of the lipid excess, blockade of ceramide
formation, and inhibition of iNOS are all effective (11
, 12
, 43)
. Blocking the ectopic deposition of lipids by the daily
administration of troglitazone to prediabetic fa/fa ZDF rats
completely prevents both the diabetes (14)
and the heart
disease (33)
that otherwise occur in 100% of untreated
animals. Troglitazone appears to work by reducing lipogenesis in
nonadipose tissues such as the islets (14)
and heart
(34)
, while increasing lipogenesis in adipocytes. By
lowering plasma FFA, it not only reduces substrate overload to tissues
but also diminishes putative FA-mediated signals to nuclear receptors
(87). Moreover, it may improve insulin sensitivity by minimizing
activation of a serine/threonine kinase cascade postulated to block
insulin receptor substrate association with phosphotidylinositol
3-kinase, a key event in insulin action (88). By confining lipogenesis
to the adipocytes, the excessive apoptosis of ß-cells
(14)
and cardiac myocytes is prevented (34)
.
The iNOS inhibitors aminoguanidine and nicotinamide similarly prevent
the diabetes (44)
. Their efficacy in preventing lipotoxic
heart disease has not been studied.
Profound alterations in 85% of mitochondria have been observed
in ß cells of untreated rats (14); these are completely prevented by
troglitazone therapy, as is the accompanying fibrosis and deformation
of islets (Fig. 7C
). Loss of the ß cell glucose
transporter GLUT-2 (Fig. 4D
) and of glucose-responsive
insulin secretion (data not shown) is also prevented (14)
.
Similarly, the echocardiographic evidence of impaired myocardial
contractility and the increased apoptosis are completely prevented by
troglitazone treatment, in conjunction with a reduction of myocardial
TG and ceramide content and iNOS expression (34)
(Fig. 3A
).
|
TRANSLATING 20th CENTURY SCIENCE INTO 21st CENTURY MEDICINE
|
|---|
Here we have attempted to link important molecular discoveries of
the last century [leptin (52)
, ADD-1/SREBP-1
(29
30
31)
, PPAR, and (87)
] to an
impending health problem of the present century, the tissue disease and
clinical consequences resulting from abnormal FA homeostasis caused by
dietary excess. Although absolute proof is lacking, circumstantial
evidence suggests that the findings described in rats may be relevant
to human disease. The inexorable increase in the prevalence of human
obesity and the decrease in its age of onset predicts a rising
incidence of lipotoxic complications that could approach the 50% level
in Pima Indians (88)
. Since pharmacologic strategies that
effectively prevent lipotoxic complications in rodents now exist, a
concerted effort to minimize the impact of lipotoxic diseases in humans
is indicated until a means of controlling obesity becomes
available.
Note added in proof: The efficacy of troglitazone in
improving the metabolic control of patients with lipodystrophy and
diabetes. Ariuglu, E. et al. (2000) Ann. Int. Med.
133, 203–274.
|
ACKNOWLEDGMENTS
|
|---|
We thank Susan Kennedy for outstanding secretarial work, Kay
McCorkle, Nadine Dupont, Gérard Negro, and P.-Alain
Rüttimann for excellent assistance with the illustrations, and R.
Sanders Williams for critical review of the manuscript. This work
supported by the Department of Veterans Affairs Institutional Support,
the National Institutes of Health (NIH) (DK02700–37), the NIH/Juvenile
Diabetes Foundation Diabetes Interdisciplinary Research Program, the
Novo-Nordisk Corporation, and the Swiss National Science Foundation
(L.O.).
Received for publication August 23, 2000.
Accepted for publication September 15, 2000.
|
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TOP
ABSTRACT
INTRODUCTION
). SREBP-1c and
lipogenic enzymes increase and TG (yellow dots) accumulates in excess
in skeletal muscle, ß cells, myocardium, and other nonadipose
tissues.