International Journal of Obesity (2008) 32, 10761082

& 2008 Macmillan Publishers Limited All rights reserved 0307-0565/08 $30.00
www.nature.com/ijo

REVIEW
Role of stearoyl-CoA desaturases in obesity and the
metabolic syndrome
HE Popeijus1,2, WHM Saris2 and RP Mensink1,2
1
Nutrigenomics Consortium, Top Institute Food and Nutrition, Wageningen, the Netherlands and 2Department of Human
Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht,
the Netherlands

The prevalence of obesity and related metabolic disorders increases rapidly in western societies. A proper choice of foods may
now prevent or delay many of the health consequences related to these disorders. In this respect, replacing dietary saturated
fatty acids (SFAs) by cis-monounsaturated fatty acids (cis-MUFAs) has beneficial effects. In addition to diet-derived cis-MUFAs, the
human body can also generate cis-MUFAsfrom SFAs through the action of stearoyl-CoA desaturases (SCDs). SCDs may play an
adverse role in obesity and obesity-related insulin resistance. Here, we review the current knowledge on the molecular aspects
and the role of SCD1 in obesity and the metabolic syndrome (MS). In mice, many studies have suggested a negative role for
SCD1 in the development of obesity and insulin resistance. In humans, however, evidence is less convincing. If anything,
increased, rather than decreased, levels of SCD1 mRNA levels are negatively associated with MS-related diseases such as insulin
resistance. However, an unequivocal conclusion is currently not possible as the number of human studies is limited. Therefore,
more human studies are needed at the molecular as well as at the physiological level to understand the true role of SCD1 during
the development of obesity and the MS.
International Journal of Obesity (2008) 32, 10761082; doi:10.1038/ijo.2008.55; published online 22 April 2008
Keywords: stearoyl-CoA desaturase; regulation of expression; metabolic syndrome; cancer; insulin

Introduction
Obesity is a major risk factor for chronic diseases such as the
metabolic syndrome (MS), diabetes mellitus type 2, hypertension and cardiovascular diseases. Currently, obesity has
reached epidemic proportions and is globally recognized as a
growing medical problem.1 Over one billion adults are
overweighed and at least 300 million adults are obese.
Moreover, these numbers are increasing rapidly, not only in
adults but also in children.2,3 There is no common
denominator to explain these increasing numbers, though
it is has been observed that obesity is significantly associated
with an increased consumption of energy-dense food,
together with a reduced level of physical activity.47
Dietary fat is an important macronutrient in the diet. It is a
source of energy and it plays a pivotal role in many cellular
processes. Moreover, dietary fatty acids are able to affect gene

Correspondence: Dr HE Popeijus, Department of Human Biology, Maastricht

University, Universiteitssingel 50, P.O. Box 616, Maastricht, Limburg 6200
MD, The Netherlands.
E-mail: hepopeijus@hb.unimaas.nl
Received 21 October 2007; revised 15 February 2008; accepted 17 March
2008; published online 22 April 2008

expression, leading to pronounced changes in metabolism,

cell differentiation and growth.8 Replacing, for example,
cis-monounsaturated fatty acids (cis-MUFAs) with saturated
fatty acids (SFAs) in the diet may impair insulin sensitivity,
one of the characteristics of the MS, and may increase the
risk to develop type 2 diabetes.9,10 In addition, the proportions of the SFA palmitic acid (C16:0) and stearic acid (18:0)
of plasma phospholipids correlated positively with the
development of type 2 diabetes.11 Further, the SFA palmitic
acid (C16:0) and stearic acid (18:0) significantly downregulated levels of peroxisome proliferator-activated receptor
gamma coactivator-1a (PGC-1a) and peroxisome proliferator-activated receptor gamma coactivator-1b (PGC-1b)
mRNA, whereas the cis-MUFA, palmitoleic acid (C16:1) and
oleic acid (C18:1), did not change mRNA expression of PGC1a and PGC-1b.12 Changes in the regulation of PGC-1a and
PGC-1b in mice and human are associated with obesity and
the MS, but their precise roles are not fully understood and
may be tissue specific.1214
As desaturase enzymes modulate the fatty acid composition of cellular lipids, they can also indirectly influence gene
transcription, fat storage and insulin sensitivity. The human
desaturases comprises d5, d6 and d9 desaturases. Stearoyl-CoA
desaturases (SCDs; EC 1.14.19.1) belongs to the group of

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HE Popeijus et al

1077
enzymes that introduce a cis double bond between carbon
atoms C9 and C10 of the fatty acid chain, counted from the
carbon atom of the carboxyl end. Therefore, SCD is also
called d9 desaturase. The mammalian SCDs are located in the
membrane of the endoplasmatic reticulum. On the basis of
the topology of mouse SCD1, it is thought that the
N-terminus of the enzyme is in contact with the cytoplasm,
spans the endoplasmatic reticulum and also makes contact
with the endoplasmatic reticulum lumen.15 SCD works
together with NADH-cytochrome b5 reductase and cytochrome b5 to desaturate fatty acids.16,17 The availability of
SCD protein is rate limiting in the conversion of SFAs to
MUFAs.18 SCDs are widely found in various species such as
human, mice, rats, hamsters, sheep, fish, plants, fungi and
nematodes.1927
In humans, SCD1 is a key enzyme in the biosynthesis of
the cis-MUFA, palmitoleic acid (C16:1) and oleic acid (C18:1)
from its preferred SFA substrates palmitic acid (C16:0) and
stearic acid (C18:0), respectively28 (Figure 1). However,
considering that rat SCD can act on chain lengths from
C12:0 up to C19:0, other fatty acids may also serve as
substrate.28 In mice, four SCD isoforms have been identified.25,2931 Mouse SCD1, SCD2 and SCD4 desaturate both
stearic acid (C18:0) and palmitic acid (C16:0), but mouse
SCD3 utilizes only palmitic acid (C16:0).32 Mouse SCD1 is
mainly expressed in white adipose tissue, liver, lung, and
skin, whereas SCD2 is constitutively expressed in brain, at
much lower levels in adipose tissue, lung, skin and liver.30,33
SCD3 is expressed exclusively in skin31 and SCD4 predominately in heart.29 There are two SCD enzymes of human
origin; SCD1 and SCD2 (or SCD5).22,3436 The human SCD1
and SCD2 have similar desaturase activities toward
14
C-labeled stearic acid (C18:0) and palmitic acid (C16:0)
(35, 36). The human SCD1 mRNA is predominately
expressed in adipose tissue and liver and to a lesser extent
in lung, brain and the pancreas.35 SCD2 mRNA is mainly
expressed in brain, pancreas, kidneys and lungs. When
compared to these tissues, low expression levels of SCD1 and
SCD2 mRNA are detectable in human muscle and heart
tissue.35 This observation suggests that skeletal muscle and
heart muscle tissue depend for their necessary MUFAs and
PUFAs (polyunsaturated fatty acids) on the uptake of these

Figure 1 Action of stearoyl-CoA desaturases (SCDs) together with elongases. Palmitic acid (16:0) and palmitoleic acid (16:1) can be elongated by
elongases (Elovl) through the addition of two carbon atoms to stearic acid
(18:0) and oleic acid (18:1), respectively. SCD1 convert the unsaturated fatty
acids palmitic acid (16:0) and stearic acid (18:0) to the monounsaturated fatty
acids palmitoleic acid (16:1) and oleic acid (18:1). The resulting monounsaturated fatty acids can then be incorporated in membranes as
phospholipids or stored as triacylgycerols produced from diacylglycerols.

fatty acids from the environment. Another possibility is that

there might be a third or even fourth human SCD isoform.
However, as far as known, there are no studies that clearly
demonstrate desaturase activity in human muscle. In one
study, however, increased SCD1 mRNA levels were observed
in skeletal muscle tissue of morbid obese human when
compared to lean subjects, but it cannot be excluded that
this SCD1 mRNA originated from inter muscular fat cells.37
The role, function and regulation of SCD have been
studied in different processes. There are indications that
SCD plays an important role in membrane fluidity. In
addition, SCD expression may be changed during the
development of cancer.22,38 Interestingly, SCD1 mRNA and
protein upregulation correlates with neural regeneration in
rat.39 Also, in human SCD1 and especially SCD2 mRNA is
highly upregulated human fetal brain, suggesting a role for
SCD in human brain development.35 This is supported by
data derived from the nematode Caenorhabditis elegans. In
this nematode, the SCDs (fat-5, 6 and 7) are essential for
MUFA and PUFA production. Knockdown of the SCDs in this
worm results in growth retardation and shorter life span.19
Furthermore, research of the past decade in mice suggests an
important function of SCD in obesity, obesity-related insulin
resistance and diabetes mellitus type 2.
In this review, the regulation of SCD is first described,
followed by a discussion on the effects of SCD on membrane
fluidity and cancer development. Finally, an overview of the
role of SCD1 in relation to the MS and obesity is given.

Regulation of SCD
The human SCD family is composed of two genes, SCD1 and
SCD2. SCD1 is located on chromosome 1034 at 10q24.31 and
SCD2 on chromosome 4 at 4q21.22.36 Human SCD genes are
highly related to the SCD genes from other species and all
share three highly conserved histidine motives.40,41 These
histidine motives are thought to bind an iron atom and are
essential for the enzymatic activity.40 The consensus
sequence GE  (FYNW) HN (FYW)  (FY) P  D (YW) is
obtained using the ClustalW sequence alignment program
from the software package of Vector NTI Suite 10 (Invitrogen
Corporation, Carlsbad, USA) on all SCD from the EC
1.14.19.1 group (Figure 2). With this consensus sequence,
it might be possible to discover new SCD isoforms of human
origin and of other species.
Humans have two SCD1 genes, of which one is a pseudo
gene. The putative mRNA transcript that could arise from
this pseudo gene has two premature in-frame stop codons.
The pseudo gene has no introns and is located on chromosome 17 at 17p11.2, whereas the functional SCD1 gene is
located on chromosome 10.34 In contrast to the mRNA of the
SCD1 gene, the pseudogene mRNA could not be detected
in the brain and liver.34 Therefore, the SCD1 pseudogene is
considered to be transcriptional inactive or to produce an
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Figure 2 Alignment of stearoyl-CoA desaturases (SCDs): the sequences of the human SCDs are aligned with all the SCDs from the EC 1.14.19.1 group. A small part
of this alignment is shown (including both human SCD accession no.: O00767 and Q86SK9, a SCD of mouse, rat, chicken, carp, Helicoverpa assulta, Manduc sexta
(tobacco hawkmoth), Ashbya gossypii (yeast), Tetrahymena thermophilia (protozoan), Pichia angusta (yeast) and Choristoneura rosaceana (oblique banded leafroller)
with accession no.: P13516, P07308, Q9YGM2, CCU31864, Q8MZZ1, Q4A182, Q75F06, Q94824, Q1L856 and Q81ITE6, respectively. The completely conserved
amino acids are shaded in gray. The consensus sequence is shown below in which X stands for any amino acid.

unrelated transcript. Owing to the premature in-frame stop

codons, a transcript will not lead to a functional SCD
protein.
SCD genes are regulated at the transcriptional level by the
diet, hormones (for example, insulin), temperature, developmental processes, metals,and proliferators.34,35,39,4244 Sterol
regulatory element-binding protein (SREBP1) is a transcription factor involved in the regulation of metabolism-related
genes, such as the SCD genes. Upon activation, SREBP1 is
able to upregulate mouse SCD1 and SCD2. The human SCD1
promoter also contains putative SREBP1 binding sites and
has been activated by SREBP1 in transactivation experiments.45,46 Peroxisome proliferator-activated receptors
(PPARs) are another group of transcription factors involved
in lipid and glucose metabolism. Activation of PPARs reduces
the risk to develop atherosclerosis and has positive effects on
the lipid profile and insulin sensitivity. Importantly, the
human promoter of SCD145 contains also other binding sites
such as the binding site for the PPARs, which is similar to
the PPAR binding site in the mice SCD1 promotor.47 So far,
the postulated link between human SCD1 and its regulation
via the PPARs needs to be established. Considering that
PPARs are tightly linked to lipid and carbohydrate metabolism, it is plausible that these transcription factors are also
able to regulate SCD. This is supported by the finding that
PPAR agonists are able to increase the SCD1 mRNA levels in
humans, mouse and rats.4749 However, mouse SCD2 seems
to be regulated independent of PPARs.47
To modulate SCD expression and thereby its protein level
using diet or drugs, it is crucial to understand the regulation
of the synthesis and the activity of the SCD protein. The SCD
enzymes seem to be tightly regulated at both the transcriptional and protein level. SCD have a high turnover of
approximately 34 h.50,51 In rat, the N-terminus of SCD1
contains a sequence motive of 3366 residues that triggers
SCD1 for rapid degradation.52,53 More specifically, three lysyl
residues (positions 33, 35 and 36) may be essential for the
International Journal of Obesity

initiation of SCD degradation, whereas substitution of these

lysyl residues with alanyl residues resulted in stabilization of
the SCD protein without affecting its enzymatic activity.54 As
these amino acids are highly conserved in rat and humans,
it is likely that also the human SCD have a similar fast
turnover.
SCD1 degradation, which is likely to occur on the
cytoplasmic site of the endoplasmatic reticulum, is independent of the lysosome or proteosome as its degradation could
not be blocked by lysosomal or proteosome inhibitors.52,55
Therefore, it was suggested that degradation of SCD1 was
partially performed by a lysosome and proteosome independent serine or thiol protease, such as the plasminogen
(PGL)-like protein.56,57 However, both overexpression and
downregulation of PGL showed no changes in SCD1
degradation.53 Later studies from Kato et al.,53 however,
clearly indicated that the degradation of SCD1 is dependent
on ubiquitinization and is mediated via the proteosome. In
these later studies, SCD1 protein degradation was studied
using cells instead of microsomal fractions.5557 Considering
that these later studies used a more physiologically relevant
approach, these findings support the notion that SCD1 is
most likely subjected to ubiquitinization-mediated degradation rather than degradation by serine or thiol proteases.

Role of SCD1 in membrane fluidity

For a normal cellular function, it is necessary to maintain
proper cell membrane fluidity. By increasing the proportion
of unsaturated fatty acids, membranes become more fluid
thereby countering the increased membrane stiffness during
cold. In this way, the membrane fluidity can be maintained
under various temperatures. As recently reviewed by Aguilar
and De Mendoza,43 SCD together with other desaturases
such as d5 and d6 are thought to be involved in maintaining

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cell membrane fluidity. This view is supported by the
observation that SCD1 regulates membrane fluidity in
Simian vacuolating virus 40 (SV40) transformed human lung
fibroblasts.58 Additional evidence is derived from bacteria,
fungi, fish, and plants in which a decrease in temperature
induces the rapid transcriptional upregulation of the
SCD.20,5963 Other interesting findings are derived from
experiments with carp, a fish with two known SCD genes,
SCD1 and SCD2, respectively. In these fish, there is a
difference in upregulation of the SCD isoforms. Carp SCD1
is upregulated by a SFA-enriched diet, whereas Carp SCD2 is
upregulated by lowering the temperature of the water.44,61
However, it remains to be elucidated whether this role of
SCD is important in humans as well.

Role of SCD1 in the link between obesity and

cancer
Data from prospective epidemiological studies showed that
obesity was associated with an increased risk to develop
various from of cancers.64,65 Another study found that
obesity was positively associated with death due to prostate
cancer metastases.66 Hursting et al.67 2007 now suggested
that the observed increase in obesity associated cancers is the
result of chronic inflammation that follows obesity.
Also SCDs may play a role in cancer development.22 SV40
transformation leads to oncogenic transformation of primary fibroblasts. It has now been observed that SCD1 is
strongly upregulated in SV40-transformed fibroblasts.58
Therefore, SCD1 has been linked to increased neoplastic cell
transformation and to a process that protects the neoplastic
cell against apoptosis.58 In contrast, strongly downregulated
or even diminished SCD1 expression is often seen in human
prostate carcinoma.68 Interestingly, fatty acid synthase is
highly upregulated in both SV40 transformed fibroblast
and prostate carcinoma, as well as in many other tumor
types.22,58,69 Inhibition of fatty acid synthase is linked to
induced cell death,7072 whereas overexpression predicts
prostate cancer progression.73 Furthermore, recent data
indicated downregulation of SCD1 protein in some tumor
cell lines.38 SCD1 knockdown resulted in 40% cell survival in
the human non-small cell lung carcinoma cell line (H1299),
75% survival in human colon cancer cells, whereas human
breast carcinoma cell line MDA-MB-468 seemed unaffected.38 The decrease in cell survival through apoptosis
was thought to be mediated via upregulation of Caspase 3.38
Thus, it remains currently unclear whether SCD plays a key
role in tumor genesis.

The role of SCD in the metabolic syndrome and

obesity
Overweighed and obese subjects are at increased risk to
develop the MS. SCD1 is now thought to serve as a potential

molecular target to prevent or treat this highly prevalent

disease. SCD1 is thought to stimulate fat storage in adipose
tissue. Therefore, it has been postulated that inhibition of
the SCD1 activity could attenuate obesity through redistribution of fat toward utilization and blockage of fat storage.
Evidence for this hypothesis is mostly derived from mice.
The SCD1-null mice (abJ/abJ, SCD1 / ) are protected from
development of insulin resistance even after overfeeding
conditions.7476 These mice are insulin sensitive probably as
a consequence of their inability to become obese. In
contrast, their littermates, that did have a functional SCD1,
became obese and insulin insensitive.7476 In addition to
SCD1-null mice, normal mice treated with antisense oligos
to specifically downregulate SCD1 mRNA were also leaner,
more insulin sensitive and became resistant to diet-induced
obesity.77 The littermates of the SCD1-null mice and normal
mice that were treated with scrambled (nonsense) antisense
oligos became obese and insulin resistant following overfeeding.7577 Moreover, hepatic SCD1 mRNA levels were
elevated in insulin-resistant obese (ob/ob) mice and in
obesity prone mice.78,79 Furthermore, when mice were fed
a high-fat diet to induce insulin resistance, SCD1 mRNA
levels increased. These data have led to the hypothesis that
SCD genes are potential candidates to target with drugs or
diet to treat obesity and insulin resistance. However, contradictory evidence has been published. High fat-feeding in rats
resulted in SCD1 mRNA levels less than 20% of normal SCD1
mRNA levels.80 Furthermore, one study showed that overexpression of SCD1 protein in rat muscle cells, protected
them against fatty acid-induced insulin resistance.81 In
addition, in rats made diabetic with streptozotocin, SCD1
mRNA levels were significantly decreased.82 Furthermore, in
obese and insulin resistant aP2-nSREBP-1c mice, SCD1
mRNA levels and activity in liver are strongly upregulated.79
In these mice, leptin is able to completely reduce SCD1
mRNA levels and activity, comparable to wild-type levels. As
a result, these animals become insulin sensitive.79 Crossing
aP2-nSREBP-1c mice with SCD1-null (abJ/abJ, SCD1 / )
mice reduced their liver steatosis and diminished their white
adipose tissue.79 Interestingly, these mice were still diabetic
and had high plasma glucose levels, even higher than aP2nSREBP-1c mice, which was probably due to b-cell failure.79
Similar results were observed, when leptin null (ob/ob) mice
were crossed with SCD1-null (SCD1 / ) mice. Their offspring had reduced body weight and increased insulin
resistance.76 These data suggest that the positive effects of
leptin are uncoupled from SCD1 mRNA levels and activity,
and that the loss of SCD1 in these double knockout mice
enhance insulin resistance.
In humans, data concerning SCDs in relation to the MS is
scarce. As SCD genes are probably negatively related to
obesity, one could assume that genetic variation in these
genes would make one more or less susceptible to the
development of obesity. However, single nucleotide polymorphism analysis of the human SCD1 gene revealed no
association with BMI, waist-to-hip ratio and chromosome
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10-linked type 2 diabetes.83 However, recently eight single
nucleotide polymorphisms of the human SCD1 gene were
reported to be associated with obesity and obesity-related
insulin resistance.84 Other contradictory evidence emerged
from a study with obese diabetic patients treated with
rosiglitazone to counter their insulin resistance. In these
patients, SCD1 mRNA levels were elevated instead of downregulated.48 Obese and insulin-resistant patients treated with
rosiglitazone gain some weight as a consequence of the
treatment.85 However, their insulin resistance decreases
probably due to a lowering of circulating free fatty acid
levels. The latter may be related to increased SCD1 mRNA
levels and subsequent enhanced fat storage. Thus, these data
may indicate that SCD1 protects rather than induces obesity
and insulin resistance.
The contradictory evidence that increased SCD1 mRNA is
protective might be explained by differences in fat metabolism in mice compared to humans and rats. In SCD1
knockout mice, fat oxidation is increased probably via
uncoupling proteins present in the brown adipose tissue.
Similarly, when diet-induced obese and insulin-resistant
mice were treated with a PPARg antagonist, uncoupling
protein-2 levels and fat utilization increased, whereas SCD1
mRNA levels decreased in skeletal muscle and white adipose
tissue. In fact, these mice also lost weight and became less
insulin resistant.86 Therefore, despite similarities in genes,
mice handle fat metabolism by different mechanisms than
humans.
All together, these findings indicate that decreasing
SCD1 expression in mice may protect against obesity and
can attenuate insulin resistance. In man, however, evidence
is less convincing. If anything, increased, rather than
decreased, levels of SCD1 mRNA levels are negatively
associated with MS-related diseases such as insulin resistance. Thus, for humans, an unequivocal conclusion is
currently not possible as the number of studies is too limited.
Therefore, more data from human studies are needed before
SCDs can be considered as a promising target to counter
obesity and the MS.

Acknowledgements
This work was, in part, supported by Diabetes Fonds
Nederland (Grant 2006.11.005).

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