Nutrition and Gene Regulation Desaturase-1 (SCD-1) Paul Cohen* and Jeffrey M. Friedman*

Nutrition and Gene Regulation
Leptin and the Control of Metabolism: Role for Stearoyl-CoA
Desaturase-1 (SCD-1)1
Paul Cohen* and Jeffrey M. Friedman*†2
*Laboratory of Molecular Genetics and †Howard Hughes Medical Institute, The Rockefeller University,
New York, NY 10021
KEY WORDS:
●
leptin
●
obesity
●
Metabolic Syndrome
●
stearoyl-CoA desaturase
obesity is BMI, which is equal to weight in kilograms, divided
by the square of height in meters. According to this measure,
a BMI ⱖ 25.0 is considered overweight and a BMI ⱖ 30.0 is
considered obese. Obesity is not only affecting adults in greater
numbers, but is an increasing concern in children and adolescents as well. Since 1976, the prevalence of overweight among
children and adolescents in the US has more than doubled
(7,8). This trend has been linked to a rise in the incidence of
Type 2 diabetes and other sequellae of increased body weight
in this age group (9).
The close association between obesity and the disorders
characteristic of the Metabolic Syndrome implies that effective treatment of obesity will provide marked health benefits
by reducing the incidence of diabetes, coronary artery disease,
and hypertension. While the public would welcome a therapy
that could eradicate obesity, recent studies have shown that
relatively modest weight loss in obese individuals, on the order
of ⬃10 pounds, significantly reduces the severity of diabetes
and other comorbid conditions (10,11). In addition to the well
known components of the Metabolic Syndrome, obesity is also
associated with an increased likelihood of osteoarthritis, cholelithiasis, sleep apnea, and cancer (5,12). A more recently
appreciated component of the Metabolic Syndrome is nonalcoholic fatty liver disease (NAFLD),3 with a ⬎30-fold relative
risk in obese individuals (13). While NAFLD is estimated to
A growing health problem
The effects of obesity have now permeated society, precipitating a public health emergency. Over 30% of adults in the
United States report attempting to lose weight, and the diet
industry generates billions of dollars in revenue each year
(1,2). Obesity not only confers a painful social stigma, but is
closely associated with morbidity and mortality (3,4). Data
from actuarial tables and the Nurses Health Study have found
a direct relationship between body weight and overall mortality (4). The relative risk of type II diabetes, coronary artery
disease, and hypertension is closely linked to indices of obesity,
and these disorders are so frequently found in association with
obesity that the constellation of conditions has been called the
Metabolic Syndrome or Syndrome X (5).
In the United States, where the situation is perhaps most
dire, nearly 30% of adults meet the cutoff for obesity and over
60% of adults meet the criteria for either overweight or obesity
(6). The most widely used metric for assessing overweight and
1
Presented at the 6th Postgraduate Course on Nutrition entitled “Nutrition
and Gene Regulation” Symposium at Harvard Medical School, Boston, MA,
March 13–14, 2003. This symposium was supported by Conrad Taff Nutrition
Educational Fund, ConAgra Foods, GlaxoSmithKline Consumer Healthcare, McNeil Nutritionals, Nestle Nutrition Institute, The Peanut Institute, Procter & Gamble
Company Nutrition Science Institute, Ross Products Division–Abbott Laboratories, and Slim Fast Foods Company. The proceedings of this symposium are
published as a supplement to The Journal of Nutrition. Guest editors for the
supplement publication were: W. Allan Walker, Harvard Medical School, George
Blackburn, Harvard Medical School, Edward Giovanucci, Harvard School of
Public Health, Boston, MA, and Ian Sanderson, University of London, London, UK.
2
To whom correspondence should be addressed.
E-mail: friedj@mail.rockefeller.edu.
3
Abbreviations used: ACAT, acyl CoA:cholesterol acyltransferase; ACC,
acetyl CoA carboxylase; CPT-1, carnityl palmitoyltransferase-1; DGAT, acyl CoA:
diacylglycerol acyltransferase; NAFLD, nonalcoholic fatty liver disease; PPAR␣,
peroxisome proliferator-activated receptor ␣; SCD-1, stearoyl-CoA desaturase-1;
SREBP-1, sterol regulatory element-binding protein-1.
0022-3166/04 $8.00 © 2004 American Society for Nutritional Sciences.
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ABSTRACT The incidence of obesity has increased sharply in recent years, making it one of the most urgent
public health concerns worldwide. The hormone leptin is the central mediator in a negative feedback loop
regulating energy homeostasis. Leptin administration leads to reduced food intake, increased energy expenditure,
and weight loss. Leptin also mediates unique metabolic effects, specifically depleting lipid from liver and other
peripheral tissues. While elucidation of leptin’s role has permitted a more detailed view of the biology underlying
energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular
components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic
Syndrome. We review here studies on the identification of one such component, stearoyl-CoA desaturase-1
(SCD-1), as a gene specifically repressed by leptin and discuss the role of this process in mediating the metabolic
effects of leptin. Data indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of
obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.
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affect 10 –24% of the population, the prevalence among obese
individuals has been estimated to be as high as 74% (14).
NAFLD, which is believed to be the most prevalent form of
liver disease worldwide, can cause hepatic steatosis or fatty
liver in its most benign form, but can progress to hepatitis,
fibrosis, cirrhosis, and liver failure (14). Given the myriad
health problems associated with obesity and the huge burden
it places on obese individuals and society as a whole, finding
new, effective treatments is imperative.
A biological basis for body weight
Metabolic effects of leptin
Leptin regulates energy expenditure and metabolism by
exerting specific and unique metabolic effects. Several lines of
evidence indicate that leptin’s actions are not the result of its
anorectic effects alone. For instance, ob/ob mice that have
been food restricted to the level that leptin treated mice
voluntarily consume (pair-fed) show smaller decreases in body
weight and size of adipose depots (31,46). Moreover, leptin
treatment causes the specific loss of fat mass, whereas food
restriction depletes both lean and fat mass (31,32). In addition, food restriction is associated with a compensatory decrease in energy expenditure, which does not occur in response
to leptin-induced hypophagia (47). Leptin-deficient humans
and ob/ob mice not only accumulate significant amounts of
triglyceride in adipose tissue, but also in liver, muscle, and
other peripheral tissues. The build-up of lipid in nonadipose
sites, such as liver, contributes to many of the health consequences of obesity such as insulin resistance and NAFLD, and
has been termed lipotoxic disease (48 –50). Leptin, much more
potently than pair-feeding, depletes lipid from these sites and
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In basic terms, obesity, a disorder of energy homeostasis,
develops when energy intake exceeds energy expenditure. One
view, popular among the public, is that obesity is the result of
a lack of willpower and gluttony, coupled with extreme laziness. An alternative theory posits that weight is maintained by
a precise physiological mechanism and that obesity is the
result of alterations in this biological pathway. The latter view
has been validated by the discovery of a homeostatic circuit
regulating appetite and body weight (1). The biological basis
of this endocrine pathway is best appreciated by the case
history that follows. A child from a consanguineous Pakastani
pedigree developed morbid obesity, marked hyperphagia, and
severe hyperinsulinemia beginning in infancy. By age 4 y, he
weighed over 90 pounds and had 57% body fat. This child was
found to have a homozygous mutation in the gene encoding
leptin (see below), an adipose tissue derived hormone (15,16).
Replacement of leptin produced profound effects. After 2 years
of leptin therapy, this child was transformed from a morbidly
obese 4-y-old to a moderately overweight 6-y-old, weighing
just over 70 pounds with 35.5% body fat (6,16). The effects of
leptin on this child, and his older, equally affected first cousin,
provide irrefutable evidence that body weight is under biological control (17).
Leptin, the hormone that these children congenitally lack,
is now appreciated to be the central mediator in an endocrine
circuit regulating energy homeostasis (18). Parabiosis studies
on the morbidly obese ob/ob and db/db mouse strains indicated
that ob/ob mice lacked a circulating factor regulating appetite
and energy expenditure and that db/db mice lacked the ability
to respond to that factor (19). This hypothesis was validated
with the positional cloning of the mutant gene product in
ob/ob mice in 1994, which was shown to encode an adipose
tissue-derived hormone, named leptin (20). Like the human
counterparts, ob/ob mice are morbidly obese and massively
hyperphagic, with an approximately 3-fold increase in body
weight and 2-fold increase in food intake relative to lean
littermates. In addition, these animals are insulin resistant and
diabetic, and accumulate massive amounts of lipid in peripheral tissues including the liver. Cloning of the mutant gene in
db/db mice showed that these mice had defects in the leptin
receptor, which has 5 splice variants (ObRa– e) (21–24). The
signaling form of the leptin receptor, Ob-Rb, is expressed at
highest levels in hypothalamic nuclei (25–28). Lesioning studies performed over 50 y ago identified these same nuclei as
serving a critical role in energy balance (29). In normal
individuals, leptin is secreted from adipose tissue and communicates the body’s nutritional status to the hypothalamus,
which coordinates food intake and energy expenditure appropriately. Leptin administration in ob/ob and wild-type mice
showed that leptin acts as an afferent signal in a negative
feedback loop regulating adiposity, leading to decreased food
intake, increased energy expenditure, and weight loss (30 –33).
Leptin also acts as a signal of nutritional deprivation, with low
leptin levels initiating an adaptive response to conserve en-
ergy, manifested by hyperphagia, decreased energy expenditure, and shutdown of the reproductive and other endocrine
axes (34). Thus, ob/ob mice, as well as leptin-deficient humans,
exist in a state of perceived starvation, characterized by hyperphagia without satiety.
Since the identification of leptin and its receptor, the
physiological circuit controlling energy homeostasis has become increasingly well understood, and the major features of
this pathway are summarized here (35). Leptin, acting via its
receptor in the hypothalamus, activates an anorexigenic pathway mediated by neurons producing pro-opiomelanocortin and
cocaine and amphetamine related transcript and inhibits an
orexigenic pathway mediated by neurons producing neuropeptide Y and agouti related protein (33,36 –39). These pathways
interact with other brain centers and metabolic circuitry to
coordinate appetite and modulate efferent signals to the periphery regulating metabolism and energy expenditure (40).
While elucidation of the role of leptin has permitted a
progressively more detailed view of the biology underlying
energy homeostasis, studies in humans indicate that most
overweight and obese individuals will not respond as potently
to leptin as ob/ob mice or the child described above. Only
about 10 humans with mutations in the leptin gene leading to
total leptin deficiency have been described (15,41). An additional unknown number of individuals have insufficient leptin
production resulting from heterozygous mutations in the leptin
gene (42). In general, however, plasma leptin levels are increased proportionately to body mass and fall following weight
loss (43,44). For the most part, the highest leptin levels are
found in the most obese individuals. While about 5–10% of
obese individuals are thought to be obese due to insufficent
leptin production, the remaining 90 –95% are believed to be
leptin resistant (43). Clinical trials of leptin have shown that
obese individuals do lose weight in a dose-dependent manner.
However, its effects are highly variable with certain patients
losing as much as 15–20 kg and others losing no weight at all
(45). Considering that most obese humans are leptin resistant,
these findings are to be expected. While leptin resistant patients may still prove to benefit from leptin, as insulin-resistant
diabetics can benefit from insulin, on its own, leptin is not
likely to significantly alleviate obesity. Thus, the development
of novel therapies for obesity, which are so urgently needed,
requires a fuller understanding of the molecular components of
the leptin pathway.
ROLE FOR SCD-1 IN MEDIATING THE METABOLIC EFFECTS OF LEPTIN
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Leptin-specific repression of stearoyl-CoA desaturase-1
(SCD-1) in liver
To elucidate the mechanism whereby leptin reduces hepatic lipid content, we used microarrays to identify genes in
liver whose expression was specifically modulated by leptin
treatment, hypothesizing that this set of genes would include
molecules involved in leptin’s metabolic effects (55). To that
end, ob/ob mice were followed over a time course of weight loss
induced by either leptin administration or saline treatment
with pair-feeding for 2, 4, or 12 d. As an additional control,
free-fed ob/ob mice treated with saline were also studied. As
described before, leptin treated mice lost significantly more
weight and showed a much more dramatic correction of hepatic steatosis than pair-fed mice, providing gross evidence of
the metabolic actions of leptin that we wished to uncover at
the molecular level. Liver RNA was isolated from each of
these groups and hybridized to Affymetrix oligonucleotide
microarrays, containing 6500 murine genes. The data from
these 8 experiments generated over 52,000 data points, necessitating novel analytical approaches to find meaningful trends
in this data set (Fig. 1). Previous work from our group and
others has shown that cluster analysis is a highly robust
method for identifying groups of genes with coordinate patterns of expression from these, and far larger data sets (56,57).
Fifteen clusters of genes with distinct patterns of expression
were identified in this data set, 6 of which correspond to genes
specifically regulated by leptin, but not pair- feeding. While
cluster analysis was able to determine groups of liver genes
specifically modulated by leptin administration, this list still
contained a few hundred genes. Therefore, to identify specific
genes for further functional analysis, we used a more directed
computational approach to select genes that are particularly
repressed during leptin-mediated weight loss (Fig. 1). An algorithm was created that ranked genes based on the extent to
which their expression was (1) increased in ob/ob liver compared to wild-type (2) repressed by leptin treatment, and (3)
maximally different between leptin treatment and pair-feeding
FIGURE 1 Algorithm for identifying and ranking leptin repressed
genes. To explore gene expression in response to leptin administration,
ob/ob mice were treated with either leptin or saline with pair-feeding
over a time course of 2, 4, or 12 d. As additional controls, free fed saline
treated and free fed untreated ob/ob and wild-type mice were also
studied. Liver RNA was isolated from each of these groups and hybridized to Affymetrix murine 6500 gene oligonucleotide arrays. The data
from each of the 8 ob/ob experiments was referenced to untreated
wild-type liver generating a total of 52,000 data points. To extract
biologically meaningful data from this massive data set we developed
an algorithm that identified and ranked genes specifically repressed by
leptin, based on how closely they adhered to the following criteria: (1)
increased expression in ob/ob liver, (2) reduced expression upon leptin
administration, and (3) maximally different expression between leptin
and pair-feeding. This approach generated a prioritized list of genes
uniquely repressed by leptin, which may be involved in mediating the
novel metabolic actions of the hormone.
(55). Specifically, we selected genes whose expression was
increased in ob/ob relative to wild-type and corrected by leptin
administration. This approach allowed us to generate a prioritized list of genes uniquely repressed by leptin, which were
candidates for mediating the novel metabolic actions of the
hormone.
The gene encoding SCD-1 ranked the highest in this
analysis. SCD-1 is the rate limiting enzyme in the biosynthesis
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thereby reverses the associated adverse effects (51). Whereas
food restriction leads to a rise in serum free fatty acids, leptinmediated weight loss is not associated with a rise in free fatty
acids or ketones, suggesting a unique mechanism of fatty acid
oxidation (51,52). In aggregate, these findings suggest that
leptin causes weight loss by enacting a novel metabolic program, distinct from food restriction on both a physiological
and molecular basis. Central administration of leptin and
generation of mice with a neuron-specific knockout of ObR
indicate that these metabolic effects are largely mediated by a
still uncharacterized efferent signal emanating from the central
nervous system, though direct effects on peripheral tissues may
also be important (30,33,47,53).
In the absence of leptin, ob/ob mice develop massively
enlarged livers engorged with lipid, and leptin replacement
preferentially corrects the liver pathology in these mice, much
more potently than food restriction (46). Leptin significantly
reduces hepatomegaly and liver triglyceride levels, and after
12 d of leptin replacement, an ob/ob liver is histologically
virtually indistinguishable from wild-type. An equivalent period of pair-feeding, however, leads to a much less dramatic
reduction in triglyceride, with a moderate amount of lipid
vacuolation still evident on histology (54). These dramatic
effects of leptin prompted us to examine the molecular basis by
which leptin specifically depletes hepatic lipid. We reasoned
that molecules involved in this pathway might be broadly
relevant to body weight homeostasis.
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SCD-1 repression is crucial in mediating the metabolic
effects of leptin
To determine the extent to which leptin’s metabolic effects
are mediated by repression of SCD-1, we studied asebia mice
(abJ/abJ) (71). Positional cloning of the mutant gene in these
mice identified a genomic deletion of the first 4 exons of the
SCD-1 gene (72). These mice produce no functional SCD-1
mRNA or protein, though expression of SCD-2 remains unaltered. Mice lacking SCD-1 have also been generated by
targeted deletion (SCD-1⫺/⫺), and the phenotype of abJ/abJ
and SCD-1⫺/⫺ mice is nearly indistinguishable (73,74). The
asebia mutants, first described in 1965, have ocular and cutaneous abnormalities, including an absence of sebaceous glands,
believed to be secondary to defective synthesis of wax esters
and other lipids (71). More recently these animals were shown
to have markedly decreased synthesis of palmitoleic and oleic
acid and subsequent reductions in hepatic triglycerides, cholesterol esters, and VLDL synthesis (75). The monounsaturated fatty acid products of SCD-1 are among the most abundant lipids in rodent and human diets, and thus, these findings
were initially puzzling. However, further study confirmed a
strict requirement for endogenous synthesis of these lipids, as
even diets supplemented with high levels of monounsaturated
fats could not correct the defects in asebia mice (76).
While the eye and skin phenotypes in these mice were
striking, we immediately appreciated that SCD-1 deficient
mice appeared visibly lean relative to their littermates. Despite
normal body weight, asebia mice have significant reductions in
body fat relative to littermate controls. In keeping with their
reduced adiposity, these mice also have decreased plasma
leptin levels (55). Next, we asked whether the absence of
SCD-1 could correct the genetic obesity resulting from leptin
deficiency. Because suppression of hepatic SCD-1 RNA levels
and enzymatic activity was found to be one of the markers of
leptin treatment, we hypothesized that ob/ob mice lacking
SCD-1 (abJ/abJ;ob/ob) would resemble leptin treated ob/ob
mice. Double mutant abJ/abJ;ob/ob mice showed a dramatic
reduction in body weight at all ages compared to ob/ob littermate controls, weighing 30% less by 16 wk of age (55). Leptin
treatment of ob/ob mice for 12 d produced a similar decrease in
body weight.
Body composition analysis showed a dramatic reduction in
percent body fat in double mutant animals, though they remained significantly more obese than wild-type littermates.
abJ/abJ;ob/ob mice also showed a significant increase in lean
body mass relative to ob/ob mice (55). This observation confirmed that the reduced adiposity in ob/ob mice lacking SCD-1
was not the result of a more general defect in growth or
development. Mice lacking SCD-1 are also protected from
dietary obesity, as shown by studies in SCD-1⫺/⫺ knockout
mice. The weight of every adipose depot, with the exception
of brown fat, was significantly lower in high-fat fed knockout
mice than in high-fat fed controls (74).
To explore the mechanism by which mice lacking SCD-1
are resistant to obesity, we evaluated the 2 most obvious
possibilities, decreased food intake and/or increased energy
expenditure. Unexpectedly, we found that mice lacking
SCD-1 ate significantly more than littermate controls (55).
Asebia mice ate a similar amount of food as ob/ob mice, which
weigh approximately twice as much. Double mutant abJ/abJ;
ob/ob mice ate even more still, consuming ⬎9 g/d. The finding
of significantly increased food intake, in the setting of reduced
adiposity, led us to predict that mice lacking SCD-1 were
burning more energy. We measured energy expenditure by
indirect calorimetry. Asebia mice of both sexes demonstrated
significantly greater total and resting oxygen consumption
(surrogates for total and basal metabolic rate) than littermate
controls (55). ob/ob mice are known to be markedly hypometabolic, since in the absence of leptin, they exist in a state of
perceived starvation and actively conserve energy. However,
we found that ob/ob mice lacking SCD-1 had a complete
correction of this hypometabolic phenotype, with energy expenditure equivalent to, or even greater than, wild-type littermates.
SCD-1 and fatty liver
SCD-1 was identified via a screen to elucidate the molecular basis by which leptin specifically depletes hepatic lipid. As
leptin administration potently reduces hepatic lipid while repressing the expression of a number of genes including SCD-1,
we analyzed to what extent the absence of SCD-1 alone could
protect ob/ob mice from fatty liver disease (55). Livers from
double mutant abJ/abJ;ob/ob mice were grossly and histologically indistinguishable from those of wild-type mice. In addition, triglyceride levels were reduced more than 3-fold in
abJ/abJ;ob/ob livers relative to ob/ob, to an amount equivalent
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of monounsaturated fats, which in conjunction with NADPH,
cytochrome b5 reductase, and cytochrome b5 introduces a
single double bond into its substrates palmitic (16:0) and
stearic acid (18:0) to generate the products palmitoleic (16:1)
and oleic acid (18:1) (58,59). These products are the most
abundant fatty acids found in triglycerides, cholesterol esters,
and phospholipids. SCD-1 is predominantly located in the
endoplasmic reticulum, where it undergoes rapid turnover in
response to a variety of nutritional and hormonal signals (60).
The gene is also transcriptionally regulated by a number of
factors including sterol regulatory element-binding protein-1
(SREBP-1) and PUFA (62,63). SCD-1, which is widely expressed, is one of four characterized SCD genes in mice, which
are arranged in a cluster on chromosome 19 (63). Humans
have a single characterized SCD gene, with 85% homology to
murine SCD-1 (64). SCD homologs have also been identified
in yeast, flies, and worms, indicating that this gene has served
a vital metabolic function during evolution (65– 67).
To confirm that this algorithm accurately identified leptin
repressed genes, SCD-1 RNA levels, enzymatic activity, and
enzymatic product levels were measured in an identical but
independent time course (55). SCD-1 RNA levels were highly
elevated in untreated ob/ob liver. SCD-1 RNA levels in leptin
treated ob/ob mice were normalized at 2 d and by 4 d fell to
levels below that of lean controls, a result consistent with
previous studies (68,69). Pair-fed mice showed a smaller and
delayed decrease in SCD-1 gene expression. These trends were
further reflected in measures of enzymatic activity. SCD enzymatic activity was elevated over 7-fold in livers of untreated
ob/ob mice relative to wild-type. Leptin treatment normalized
SCD enzymatic activity, while pair-feeding reduced enzymatic
activity to a lesser extent. Levels of hepatic monounsaturated
16:1 and 18:1 fatty acids, the products of SCD-1, were elevated
in ob/ob mice and normalized by 12 d of leptin treatment, but
not by pair-feeding. Leptin also preferentially normalized desaturation indices (ratios of 16:1/16:0 and 18:1/18:0 levels),
which are indicators of SCD enzymatic activity. These findings confirmed that we had identified a molecular target of the
metabolic effects of leptin. While the effects of leptin on
SCD-1 may be downstream of the hormone’s effects on insulin
and/or neuroendocrine function, leptin also represses SCD-1
in wild-type rodents, suggesting that the regulation of this
enzyme by leptin may be relatively specific (70).
ROLE FOR SCD-1 IN MEDIATING THE METABOLIC EFFECTS OF LEPTIN
of SCD-1, are required for triglyceride and cholesterol ester
synthesis and VLDL production (75). We hypothesized that in
the absence of SCD-1, lipid synthesis and VLDL production
are blocked, and that as a default, fat is oxidized. Histological
and quantitative analysis confirmed that hepatic lipid storage
was significantly reduced in abJ/abJ;ob/ob mice. We next assessed hepatic VLDL production by injecting mice with tyloxapol, an inhibitor of VLDL hydrolysis, and measuring plasma
triglyceride levels over time (55,88). Since VLDL hydrolysis is
inhibited by tyloxapol, plasma triglycerides rise in a linear
fashion over time, with the slope of the line denoting VLDL
production. While VLDL synthesis is markedly increased in
ob/ob mice, its production is reduced in abJ/abJ;ob/ob mice to
levels comparable to littermate controls. Therefore, in the
absence of SCD-1, hepatic lipid storage and VLDL production
are impaired, and as a default, fatty acids are oxidized. The
finding of reduced adiposity and increased energy expenditure,
in the setting of normal to increased food intake, is suggestive
of enhanced fatty acid oxidation. In addition, mice lacking
SCD-1 have increased plasma ketone bodies, another marker
of increased fatty acid oxidation (55). Moreover, expression
profiling of SCD-1⫺/⫺ mice demonstrated increased expression of genes encoding enzymes involved in fatty acid oxidation (74).
The schematic in Figure 2 illustrates one mechanism
whereby a deficiency in SCD-1 might lead to increased fatty
acid oxidation. In the absence of SCD-1, or when SCD-1 is
repressed by leptin treatment, saturated fatty acyl CoAs cannot be desaturated into monounsaturated fatty acyl CoAs, and
would be expected to accumulate. Saturated, but not monounsaturated, fatty acyl CoAs potently allosterically inhibit
acetyl CoA carboxylase (ACC), the enzyme that converts
acetyl CoA into malonyl CoA, an intermediate in fatty acid
Mechanism by which SCD-1 deficiency protects against
obesity and fatty liver
SCD-1 appears to be a pivotal metabolic control point, and
mice deficient in this enzyme are resistant to both hepatic
steatosis and obesity. These findings are due to markedly
increased energy expenditure in SCD-1 deficient mice. To
gain a deeper understanding of this process, we have been
studying the mechanism underlying increased energy expenditure in animals lacking SCD-1. As a starting point, we
considered the possible fates of hepatic fatty acids. In the liver,
fatty acids, which are esterified to glycerol in triglycerides or
cholesterol in cholesterol esters, can either 1) accumulate
leading to increased hepatic lipid content or steatosis, 2) be
packaged into VLDL for transport to other tissues, or 3) be
oxidized. Monounsaturated fatty acids, the enzymatic products
FIGURE 2 Basis for increased energy expenditure in mice lacking
SCD-1. Proposed mechanism for the metabolic effects mediated by
SCD-1 deficiency. In the absence of SCD-1, synthesis of triglycerides
and VLDL is blocked, leading to decreased hepatic lipid storage and
export. A lack of SCD-1 causes an increase in the pool of saturated
fatty acyl CoAs, which allosterically inhibit acetyl CoA carboxylase
(ACC). Inhibition of ACC reduces levels of malonyl CoA, a metabolite
which normally inhibits the mitochondrial carnityl palmitoyl shuttle system, the rate-limiting step in the import and oxidation of fatty acids in
mitochondria. Decreased malonyl CoA thus de-represses fatty acid
oxidation, leading to increased burning of fat.
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to that in wild-type livers. Triglyceride levels in abJ/abJ mice
were reduced still further to levels below that of wild-type.
Thus, downregulation of SCD-1 expression and activity plays
a major role in leptin-mediated depletion of hepatic lipid.
The resistance to hepatic lipid accumulation in ob/ob mice
lacking SCD-1 prompted us to examine whether hepatic steatosis in other clinical settings can be suppressed by SCD-1
deficiency. Lipodystrophy, defined by the partial or complete
absence of adipose tissue, is associated with hepatic steatosis,
severe insulin resistance, diabetes, and leptin deficiency
(77,78). Human lipodystrophy can be either congenital or
acquired, and is emerging as a significant problem in a substantial number of HIV patients, likely as a secondary effect of
highly active antiretroviral therapy (79). In the absence of
adipose tissue, triglyceride accumulates in liver, heart, muscle,
and other tissues. A number of mouse models of lipodystrophy
exist, with the best characterized being the aP2-nSREBP-1c
transgenic and the A-ZIP fatless mice (80,81). The existence
of these mouse models allowed scientists to determine whether
the metabolic defects in lipodystrophy were specifically due to
the absence of adipose tissue as a triglyceride storage depot or
due to the absence of an adipose-derived factor. The answer
appears to be the latter as leptin administration markedly
improved insulin resistance and diabetes in both lipodystrophic mice and humans (82,83). In addition, fat cell transplants
from wild-type, but not ob/ob, mice into lipodystrophic mice
ameliorated the diabetic phenotype (84,85). Furthermore, in
lipodystrophic mice and humans, physiological doses of leptin
also correct the enlarged fatty liver (86).
We therefore examined whether SCD-1 overexpression
contributes to the hepatic steatosis of lipodystrophy. We found
that liver SCD-1 expression and activity were increased in
aP2-nSREBP-1c transgenic mice and repressed by leptin in a
dose-dependent manner (87). Intracerebroventricular administration of leptin, at a dose that had no effect when delivered
peripherally, completely normalized SCD activity in lipodystrophic mice, indicating that the effects of leptin on liver
SCD-1 are likely mediated by central action (87). In a previous study, SCD-1 among several other lipid biosynthetic genes
was also found to be overexpressed in aP2-nSREBP-1c transgenic liver and repressed by leptin (82). To assess the specific
role for SCD-1 in the hepatic steatosis of lipodystrophy double
mutant, lipodystrophic mice lacking SCD-1 (abJ/abJ;aP2nSREBP-1c tg) were generated. Analysis of these mice found
that SCD-1 deficiency significantly improves, but does not
completely correct, the fatty liver associated with lipodystrophy (87). Additional studies are underway to evaluate the
importance of SCD-1 in other models of hepatic steatosis,
such as alcohol-induced fatty liver.
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for triglyceride hydrolysis, also display reduced body weight
and fat mass (103). Finally, ob/ob mice overexpressing apolipoprotein C1, which has been proposed to inhibit hydrolysis of
VLDL triglyceride, demonstrate a nearly total correction in
obesity (104).
A role for SCD-1 in other components of the
metabolic syndrome
Given the effects of SCD-1 on lipid metabolism and obesity, repression of this enzyme may also protect from other
components of the Metabolic Syndrome, such as diabetes and
atherosclerosis. While diabetes has traditionally been considered a disorder of carbohydrate metabolism, more recent work
has indicated that diabetes is fundamentally a disease of lipid
metabolism (48,49). Increased deposition of lipid in tissues
other than white fat contributes to the development of insulin
resistance and diabetes (50). SCD-1⫺/⫺ mice show increased
glucose and insulin tolerance, indicating that an inhibition of
SCD-1 activity may be protective against diabetes (74). However, SCD-1 deletion on its own does not appear to improve
the severe form of diabetes seen in lipodystrophic animals
(87). Studies are currently in progress to determine the effects
of SCD-1 repression in other insulin-sensitive tissues and the
specific effects of SCD-1 deficiency on the insulin signaling
cascade.
Mice lacking SCD-1 have markedly reduced rates of both
triglyceride and cholesterol ester synthesis as well as reduced
levels of VLDL production (75). While effects on triglyceride
metabolism appear to confer protection from obesity in the
absence of SCD-1, the effects on cholesterol and lipoprotein
metabolism suggest that SCD-1 deficiency may also stave off
atherosclerosis. Oleic acid, the product of SCD-1, is the preferred substrate for acyl CoA:cholesterol acyltransferase
(ACAT), the rate-limiting enzyme in cholesterol esterification (105). Mice lacking SCD-1 have decreased synthesis of
cholesterol esters despite normal ACAT activity (75). In
addition, hypertriglyceridemia is associated with increased
SCD-1 activity in the hyplip mouse, a model of hyperlipidemia, which has increased SCD-1 activity (106). Furthermore,
in a human cohort, differences in SCD-1 activity explained
44% of the variance in triglyceride levels (106). These findings
suggest that increased SCD levels and activity might promote
atherosclerosis, whereas inhibition of SCD-1 may protect
against atherosclerosis. This hypothesis is supported by the
finding that increased levels of SCD-1 inhibit ABCA1-mediated cholesterol efflux (107). However, to formally demonstrate a role for SCD-1 in atherosclerosis, genetic studies are in
progress in which mice lacking SCD-1 are being bred to mouse
models of atherosclerosis such as apoE or LDL receptor knockout mice.
Importance of stearoyl-CoA desaturases in other tissues
While repression of SCD-1 has been shown to be an important component of leptin’s metabolic actions, leptin may
also have effects on SCD-1 and other SCD isoforms in other
tissues. Leptin administration in ob/ob mice results in the
reduction of lipid in tissues other than liver, such as heart and
skeletal muscle (94,108). During a survey of the effects of
leptin in other tissues, we found that while the RNA levels of
SCD-1 and SCD-2 were not altered by leptin deficiency in
ob/ob hearts, SCD activity and levels of monounsaturated fatty
acids were increased. This observation led to the cloning of
SCD-4, a novel SCD isoform expressed exclusively in the
heart (109). SCD-4 RNA levels are elevated in ob/ob heart,
Downloaded from jn.nutrition.org by guest on June 9, 2014
biosynthesis (89 –91). This enzymatic reaction plays a critical
role in directing the cell towards either lipid synthesis or
oxidation. Malonyl CoA normally inhibits carnityl palmitoyltransferase-1 (CPT-1), the rate limiting enzyme in the shuttle
of fatty acids from the cytosol, where they are synthesized, into
the mitochondria, where they are oxidized (92). When malonyl CoA levels fall, however, CPT-1 is de-repressed and fatty
acids can enter mitochondria and be oxidized. As indicated in
Figure 2, saturated fatty acyl CoAs would be expected to
accumulate in the absence of SCD-1 and inhibit ACC. Inhibition of ACC would lead to a concomitant fall in malonyl
CoA, which would thereby relieve the inhibition of CPT-1
and direct fatty acids into mitochondria, where they are
burned for energy. In addition, a fall in malonyl CoA would
also decrease fatty acid biosynthesis.
Several alternative mechanisms could also account for the
increased energy expenditure in the setting of SCD-1 deficiency. Inhibition of SCD-1 could increase the levels of a
peroxisome proliferator-activated receptor ␣ (PPAR␣) ligand,
leading to increased peroxisomal fatty acid oxidation. In support of this possibility, expression analysis in SCD-1⫺/⫺ mice
detected increased levels of the mRNA encoding acyl CoA
oxidase, the rate-limiting enzyme in peroxisomal oxidation
(74). Moreover, PPAR␣ is required for leptin-mediated fatty
acid depletion in the liver (93). Decreased SCD-1 activity
could also alter the levels of ligands for other nuclear hormone
receptors important in lipid homeostasis. SCD-1 deficiency
may be associated with increased activity of AMP-activated
protein kinase, a signaling molecule that has been shown to
stimulate fatty acid oxidation following leptin administration
(94). SCD-1 deficiency could also alter phospholipid composition, thereby affecting membrane fluidity and signal transduction. Repression of SCD-1 could additionally be associated
with direct or indirect effects of fatty acids on uncoupling
proteins. Moreover, the fur and lipid abnormalities associated
with defects in SCD-1 could be associated with increased
energy dissipation. Experiments are currently underway to
evaluate each of these possibilities.
Interestingly, inhibition of other genes in the same metabolic pathway as SCD-1 is also associated with increased
energy expenditure and resistance to obesity, providing further
evidence that manipulation of this pathway may be therapeutically relevant. Mice with targeted mutations in ACC-2 have
decreased levels of malonyl CoA, increased fatty acid oxidation, and are protected from obesity (95). Furthermore, the
drug C75, which causes weight loss by both a central effect on
appetite and a peripheral effect on metabolism, is a fatty acid
synthase inhibitor, but also acts in part by directly de-repressing CPT-1 (96,97). Deletion of acyl CoA:diacylglycerol acyltransferase (DGAT), which catalyzes the final step in the
biosynthesis of triglycerides from fatty acids, also produces
sebaceous gland defects and leads to a phenotype very similar
to that of mice lacking SCD-1 (98,99). Interestingly, a polymorphism in the promoter of the DGAT gene, leading to
decreased expression, has been associated with reduced BMI in
Turkish women (100). Modulation of these gene products may
prevent obesity by a similar mechanism to that proposed for
SCD-1 in Figure 2.
In the liver, triglycerides formed via this pathway can be
packaged in VLDL and exported to adipose tissue and other
sites. A number of genetic alterations, inhibiting hydrolysis
and consequent delivery of VLDL triglyceride, also lead to
reduced adiposity. Mice lacking the VLDL receptor are lean,
and breeding of this mutation on to the ob/ob background
markedly corrects obesity (101,102). In addition, ob/ob mice
lacking adipose tissue lipoprotein lipase, an enzyme required
ROLE FOR SCD-1 IN MEDIATING THE METABOLIC EFFECTS OF LEPTIN
and leptin, more potently than pair-feeding, repressed SCD-4
RNA levels and monounsaturated fatty acids in these mice.
Studies are in progress to determine the specific role for SCD-4
in heart and the physiological consequences of elevated
SCD-4 in ob/ob mice. Furthermore, we are continuing to
examine the effects of leptin on SCD isoforms in a variety of
other metabolically important tissues.
Directions for the future
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This review has described recent work on SCD-1, which
was identified in a screen to elucidate the molecular basis for
leptin’s effects on liver. The work presented here indicates
that leptin’s metabolic effects are, to a large extent, mediated
by repression of this enzyme. The specific mechanism by which
leptin represses SCD-1 is currently unknown, but could involve both transcriptional and post-translational modulation.
Moreover, SCD-1 appears to be a critical metabolic control
point partitioning fats towards storage, when activity is high,
and towards oxidation, when activity is low. Future experiments are needed to determine whether SCD-1 or other SCD
isoforms are functionally important in other tissues. Studies
also need to further explore what role SCD-1 plays in other
aspects of the metabolic syndrome, such as diabetes and atherosclerosis. Further experimentation is necessary to determine
whether the absence of SCD-1 confers any adverse health
risks. Increased fatty acid oxidation may increase the levels of
toxic free radicals, which could predispose to cancer or reduced longevity (110). In addition, global deletion of SCD-1,
while beneficial from a metabolic standpoint, has deterimental
effects on the skin, hair, and eye. However, mice with heterozygous mutations in SCD-1 have none of these abnormalities, despite a 50% reduction in SCD activity, suggesting that
a partial reduction in SCD activity may be beneficial (73).
While the algorithm described above found SCD-1 to be the
most potently leptin-regulated gene, other genes identified as
being either specifically repressed or induced by leptin may
also have critical physiological roles. Future work will determine whether inhibition of SCD-1 could be a therapeutic
target in the treatment of obesity, hepatic steatosis, and other
components of the Metabolic Syndrome.
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