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1
* 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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 TOP ABSTRACT INTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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Key Words: lipotoxicity • lipoapoptosis • complications of obesity • noninsulin-dependent diabetes • cardiomyopathy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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. 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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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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). 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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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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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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, 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.
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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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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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, 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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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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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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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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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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, 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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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
.
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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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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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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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). 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
).
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TRANSLATING 20th CENTURY SCIENCE INTO 21st CENTURY MEDICINE |
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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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, 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.
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ACKNOWLEDGMENTS |
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Received for publication August 23, 2000. Accepted for publication September 15, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONNORMAL FATTY ACID (FA)...ABNORMAL FA HOMEOSTASISMECHANISMS OF LIPOTOXICITYGENETIC AND NONGENETIC CAUSES...LIPOTOXIC DISORDERS: DO THEY...PREVENTION OF LIPOTOXICITY AND...TRANSLATING 20th CENTURY SCIENCE...REFERENCES |
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through the production of endogenous ligand. Proc. Natl. Acad. Sci. USA 95,4333-4337 in disease of pancreatic ß cells. Proc. Natl. Acad. Sci. USA 95,8898-8903
proline) of the leptin receptor (OB-R) cDNA is the only mutation found in the Zucker fatty (fa/fa) rat. Biochem. Biophys. Res. Commun. 224,597-604[Medline]
B activation in cytokine- and sphingomyelinase-stimulated inducible nitric oxide synthase gene expression in vascular smooth muscle cells. Endocrinology 139,4506-4512 in metabolic disease, inflammation, atherosclerosis and aging. Curr. Opin. Lipidol. 10,151-159[Medline]
activation modulates cellular redox status, represses nuclear factor-B signaling, and reduces inflammatory cytokine production in aging. J. Biol. Chem. 273,32833-32841This article has been cited by other articles:
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  D. J. Foster, P. Ravikumar, D. J. Bellotto, R. H. Unger, and C. C. W. Hsia Fatty diabetic lung: altered alveolar structure and surfactant protein expression Am J Physiol Lung Cell Mol Physiol, March 1, 2010; 298(3): L392 - L403. [Abstract] [Full Text] [PDF]
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 J. Suzuki, M. Ueno, M. Uno, Y. Hirose, Y. Zenimaru, S. Takahashi, J.-i. Osuga, S. Ishibashi, M. Takahashi, M. Hirose, et al. Effects of hormone-sensitive lipase disruption on cardiac energy metabolism in response to fasting and refeeding Am J Physiol Endocrinol Metab, November 1, 2009; 297(5): E1115 - E1124. [Abstract] [Full Text] [PDF]
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 M. E. Young Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function J Appl Physiol, October 1, 2009; 107(4): 1339 - 1347. [Abstract] [Full Text] [PDF]
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A. Lombardi, P. de Lange, E. Silvestri, R. A. Busiello, A. Lanni, F. Goglia, and M. Moreno 3,5-Diiodo-L-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement Am J Physiol Endocrinol Metab, March 1, 2009; 296(3): E497 - E502. [Abstract] [Full Text] [PDF]
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 A. Akki and A.-M. L. Seymour Western diet impairs metabolic remodelling and contractile efficiency in cardiac hypertrophy Cardiovasc Res, February 15, 2009; 81(3): 610 - 617. [Abstract] [Full Text] [PDF]
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 S. Hammer, M. Snel, H. J. Lamb, I. M. Jazet, R. W. van der Meer, H. Pijl, E. A. Meinders, J. A. Romijn, A. de Roos, and J. W.A. Smit Prolonged Caloric Restriction in Obese Patients With Type 2 Diabetes Mellitus Decreases Myocardial Triglyceride Content and Improves Myocardial Function J. Am. Coll. Cardiol., September 16, 2008; 52(12): 1006 - 1012. [Abstract] [Full Text] [PDF]
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H. Li, P. N. Black, A. Chokshi, A. Sandoval-Alvarez, R. Vatsyayan, W. Sealls, and C. C. DiRusso High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias J. Lipid Res., January 1, 2008; 49(1): 230 - 244. [Abstract] [Full Text] [PDF]
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C. Blume, P. M. Benz, U. Walter, J. Ha, B. E. Kemp, and T. Renne AMP-activated Protein Kinase Impairs Endothelial Actin Cytoskeleton Assembly by Phosphorylating Vasodilator-stimulated Phosphoprotein J. Biol. Chem., February 16, 2007; 282(7): 4601 - 4612. [Abstract] [Full Text] [PDF]
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S. E. Schadinger, N. L. R. Bucher, B. M. Schreiber, and S. R. Farmer PPAR{gamma}2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1195 - E1205. [Abstract] [Full Text] [PDF]
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W. J. Fu, T. E. Haynes, R. Kohli, J. Hu, W. Shi, T. E. Spencer, R. J. Carroll, C. J. Meininger, and G. Wu Dietary L-Arginine Supplementation Reduces Fat Mass in Zucker Diabetic Fatty Rats J. Nutr., April 1, 2005; 135(4): 714 - 721. [Abstract] [Full Text] [PDF]
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K. L. Pappan, Z. Pan, G. Kwon, C. A. Marshall, T. Coleman, I. J. Goldberg, M. L. McDaniel, and C. F. Semenkovich Pancreatic {beta}-Cell Lipoprotein Lipase Independently Regulates Islet Glucose Metabolism and Normal Insulin Secretion J. Biol. Chem., March 11, 2005; 280(10): 9023 - 9029. [Abstract] [Full Text] [PDF]
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M. Z. Tucker and L. P. Turcotte Brief Food Restriction in Old Animals Decreases Triglyceride Content and Insulin-Stimulated Triglyceride Synthesis J Gerontol A Biol Sci Med Sci, February 1, 2005; 60(2): 157 - 164. [Abstract] [Full Text] [PDF]
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I. Briaud, L. M. Dickson, M. K. Lingohr, J. F. McCuaig, J. C. Lawrence, and C. J. Rhodes Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in {beta}-Cells J. Biol. Chem., January 21, 2005; 280(3): 2282 - 2293. [Abstract] [Full Text] [PDF]
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C. Cruciani-Guglielmacci, M. Vincent-Lamon, C. Rouch, M. Orosco, A. Ktorza, and C. Magnan Early changes in insulin secretion and action induced by high-fat diet are related to a decreased sympathetic tone Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E148 - E154. [Abstract] [Full Text] [PDF]
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M.-y. Wang and R. H. Unger Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E216 - E221. [Abstract] [Full Text] [PDF]
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C. M. Jenkins, D. J. Mancuso, W. Yan, H. F. Sims, B. Gibson, and R. W. Gross Identification, Cloning, Expression, and Purification of Three Novel Human Calcium-independent Phospholipase A2 Family Members Possessing Triacylglycerol Lipase and Acylglycerol Transacylase Activities J. Biol. Chem., November 19, 2004; 279(47): 48968 - 48975. [Abstract] [Full Text] [PDF]
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J. A. Villena, S. Roy, E. Sarkadi-Nagy, K.-H. Kim, and H. S. Sul Desnutrin, an Adipocyte Gene Encoding a Novel Patatin Domain-containing Protein, Is Induced by Fasting and Glucocorticoids: ECTOPIC EXPRESSION OF DESNUTRIN INCREASES TRIGLYCERIDE HYDROLYSIS J. Biol. Chem., November 5, 2004; 279(45): 47066 - 47075. [Abstract] [Full Text] [PDF]
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B.-H. Park, Y. Lee, M. Walton, L. Duplomb, and R. H. Unger Demonstration of reverse fatty acid transport from rat cardiomyocytes J. Lipid Res., November 1, 2004; 45(11): 1992 - 1999. [Abstract] [Full Text] [PDF]
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L. M. Dickson and C. J. Rhodes Pancreatic {beta}-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt? Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E192 - E198. [Abstract] [Full Text] [PDF]
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S. L.M. Coort, D. M. Hasselbaink, D. P.Y. Koonen, J. Willems, W. A. Coumans, A. Chabowski, G. J. van der Vusse, A. Bonen, J. F.C. Glatz, and J. J.F.P. Luiken Enhanced Sarcolemmal FAT/CD36 Content and Triacylglycerol Storage in Cardiac Myocytes From Obese Zucker Rats Diabetes, July 1, 2004; 53(7): 1655 - 1663. [Abstract] [Full Text] [PDF]
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C. Ascencio, N. Torres, F. Isoard-Acosta, F. J. Gomez-Perez, R. Hernandez-Pando, and A. R. Tovar Soy Protein Affects Serum Insulin and Hepatic SREBP-1 mRNA and Reduces Fatty Liver in Rats J. Nutr., March 1, 2004; 134(3): 522 - 529. [Abstract] [Full Text] [PDF]
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S. Gobin, L. Thuillier, G. Jogl, A. Faye, L. Tong, M. Chi, J.-P. Bonnefont, J. Girard, and C. Prip-Buus Functional and Structural Basis of Carnitine Palmitoyltransferase 1A Deficiency J. Biol. Chem., December 12, 2003; 278(50): 50428 - 50434. [Abstract] [Full Text] [PDF]
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R. H. Unger Minireview: Weapons of Lean Body Mass Destruction: The Role of Ectopic Lipids in the Metabolic Syndrome Endocrinology, December 1, 2003; 144(12): 5159 - 5165. [Abstract] [Full Text] [PDF]
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D. Pighin, L. Karabatas, A. Rossi, A. Chicco, J. C. Basabe, and Y. B. Lombardo Fish Oil Affects Pancreatic Fat Storage, Pyruvate Dehydrogenase Complex Activity and Insulin Secretion in Rats Fed a Sucrose-Rich Diet J. Nutr., December 1, 2003; 133(12): 4095 - 4101. [Abstract] [Full Text] [PDF]
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M. Sorhede Winzell, H. Svensson, S. Enerback, K. Ravnskjaer, S. Mandrup, V. Esser, P. Arner, M.-C. Alves-Guerra, B. Miroux, F. Sundler, et al. Pancreatic {beta}-Cell Lipotoxicity Induced by Overexpression of Hormone-Sensitive Lipase Diabetes, August 1, 2003; 52(8): 2057 - 2065. [Abstract] [Full Text] [PDF]
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J. Tordjman, G. Chauvet, J. Quette, E. G. Beale, C. Forest, and B. Antoine Thiazolidinediones Block Fatty Acid Release by Inducing Glyceroneogenesis in Fat Cells J. Biol. Chem., May 23, 2003; 278(21): 18785 - 18790. [Abstract] [Full Text] [PDF]
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T. Abiko, A. Abiko, A. C. Clermont, B. Shoelson, N. Horio, J. Takahashi, A. P. Adamis, G. L. King, and S.-E. Bursell Characterization of Retinal Leukostasis and Hemodynamics in Insulin Resistance and Diabetes: Role of Oxidants and Protein Kinase-C Activation Diabetes, March 1, 2003; 52(3): 829 - 837. [Abstract] [Full Text] [PDF]
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J. Kuhlmann, C. Neumann-Haefelin, U. Belz, J. Kalisch, H.-P. Juretschke, M. Stein, E. Kleinschmidt, W. Kramer, and A. W. Herling Intramyocellular Lipid and Insulin Resistance: A Longitudinal In Vivo 1H-Spectroscopic Study in Zucker Diabetic Fatty Rats Diabetes, January 1, 2003; 52(1): 138 - 144. [Abstract] [Full Text] [PDF]
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A. Chicco, M. E. D'Alessandro, L. Karabatas, C. Pastorale, J. C. Basabe, and Y. B. Lombardo Muscle Lipid Metabolism and Insulin Secretion Are Altered in Insulin-Resistant Rats Fed a High Sucrose Diet J. Nutr., January 1, 2003; 133(1): 127 - 133. [Abstract] [Full Text] [PDF]
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C. E. Wrede, L. M. Dickson, M. K. Lingohr, I. Briaud, and C. J. Rhodes Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic beta -Cells (INS-1) J. Biol. Chem., December 13, 2002; 277(51): 49676 - 49684. [Abstract] [Full Text] [PDF]
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Y. Pan, I. Cohen, F. Guillerault, B. Feve, J. Girard, and C. Prip-Buus The Extreme C Terminus of Rat Liver Carnitine Palmitoyltransferase I Is Not Involved in Malonyl-CoA Sensitivity but in Initial Protein Folding J. Biol. Chem., November 27, 2002; 277(49): 47184 - 47189. [Abstract] [Full Text] [PDF]
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B. Ljung, K. Bamberg, B. Dahllof, A. Kjellstedt, N. D. Oakes, J. Ostling, L. Svensson, and G. Camejo AZ 242, a novel PPAR{alpha}/{gamma} agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats J. Lipid Res., November 1, 2002; 43(11): 1855 - 1863. [Abstract] [Full Text] [PDF]
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J. J.F.P. Luiken, D. P.Y. Koonen, J. Willems, A. Zorzano, C. Becker, Y. Fischer, N. N. Tandon, G. J. van der Vusse, A. Bonen, and J. F.C. Glatz Insulin Stimulates Long-Chain Fatty Acid Utilization by Rat Cardiac Myocytes Through Cellular Redistribution of FAT/CD36 Diabetes, October 1, 2002; 51(10): 3113 - 3119. [Abstract] [Full Text] [PDF]
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C. Andreolas, G. da Silva Xavier, F. Diraison, C. Zhao, A. Varadi, F. Lopez-Casillas, P. Ferre, F. Foufelle, and G. A. Rutter Stimulation of Acetyl-CoA Carboxylase Gene Expression by Glucose Requires Insulin Release and Sterol Regulatory Element Binding Protein 1c in Pancreatic MIN6 {beta}-Cells Diabetes, August 1, 2002; 51(8): 2536 - 2545. [Abstract] [Full Text] [PDF]
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M. E. Young, P. H. Guthrie, P. Razeghi, B. Leighton, S. Abbasi, S. Patil, K. A. Youker, and H. Taegtmeyer Impaired Long-Chain Fatty Acid Oxidation and Contractile Dysfunction in the Obese Zucker Rat Heart Diabetes, August 1, 2002; 51(8): 2587 - 2595. [Abstract] [Full Text] [PDF]
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L. B. Nielsen, E. D. Bartels, and E. Bollano Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice J. Biol. Chem., July 19, 2002; 277(30): 27014 - 27020. [Abstract] [Full Text] [PDF]
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D. M. Muoio, P. S. MacLean, D. B. Lang, S. Li, J. A. Houmard, J. M. Way, D. A. Winegar, J. C. Corton, G. L. Dohm, and W. E. Kraus Fatty Acid Homeostasis and Induction of Lipid Regulatory Genes in Skeletal Muscles of Peroxisome Proliferator-activated Receptor (PPAR) alpha Knock-out Mice. EVIDENCE FOR COMPENSATORY REGULATION BY PPARdelta J. Biol. Chem., July 12, 2002; 277(29): 26089 - 26097. [Abstract] [Full Text] [PDF]
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J. Li, X. Yu, W. Pan, and R. H. Unger Gene expression profile of rat adipose tissue at the onset of high-fat-diet obesity Am J Physiol Endocrinol Metab, June 1, 2002; 282(6): E1334 - E1341. [Abstract] [Full Text] [PDF]
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C. Sewter, D. Berger, R. V. Considine, G. Medina, J. Rochford, T. Ciaraldi, R. Henry, L. Dohm, J. S. Flier, S. O'Rahilly, et al. Human Obesity and Type 2 Diabetes Are Associated With Alterations in SREBP1 Isoform Expression That Are Reproduced Ex Vivo by Tumor Necrosis Factor-{alpha} Diabetes, April 1, 2002; 51(4): 1035 - 1041. [Abstract] [Full Text] [PDF]
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A. J. G. Hanley, G. McKeown-Eyssen, S. B. Harris, R. A. Hegele, T. M. S. Wolever, J. Kwan, and B. Zinman Cross-Sectional and Prospective Associations between Abdominal Adiposity and Proinsulin Concentration J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 77 - 83. [Abstract] [Full Text] [PDF]
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J. D. McGarry Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes Diabetes, January 1, 2002; 51(1): 7 - 18. [Full Text] [PDF]
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C. Magnan, C. Cruciani, L. Clement, P. Adnot, M. Vincent, M. Kergoat, A. Girard, J.-L. Elghozi, G. Velho, N. Beressi, et al. Glucose-Induced Insulin Hypersecretion in Lipid-Infused Healthy Subjects Is Associated with a Decrease in Plasma Norepinephrine Concentration and Urinary Excretion J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4901 - 4907. [Abstract] [Full Text] [PDF]
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). SREBP-1c and
lipogenic enzymes increase and TG (yellow dots) accumulates in excess
in skeletal muscle, ß cells, myocardium, and other nonadipose
tissues.
