Cell Metabolism

Review

The Inflammasome Puts Obesity in the Danger Zone

Rinke Stienstra,1,2,3 Cees J. Tack,1 Thirumala-Devi Kanneganti,4 Leo A.B. Joosten,1,2 and Mihai G. Netea1,2,*
1Department of Medicine
2Nijmegen Institute for Infection, Inflammation and Immunity (N4I)
Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands
3Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen 6703 HD, The Netherlands
4Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA

*Correspondence: m.netea@aig.umcn.nl
DOI 10.1016/j.cmet.2011.10.011

Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the
cytokine interleukin-1b (IL-1b) has emerged as a prominent instigator of the proinflammatory response in
obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms respon-
sible for IL-1b activation in adipose tissue, liver, and macrophages and demonstrated a central role of the
processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome.
These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to
insulin resistance and type 2 diabetes.

Introduction promoting activation of inflammasome-dependent caspase-1,

Accumulating evidence links inflammation to metabolic changes
associated with obesity and type 2 diabetes (Donath and Shoe-
lson, 2011). While several studies suggest that expanding
adipose tissue is an important first step in driving the enhanced
state of inflammation, the underlying molecular mechanisms
modulating this process are less clear. A wide variety of immune
cells, including macrophages, monocytes, T cells, and b cells,
have been shown to infiltrate the adipose tissue and affect its
homeostasis by releasing inflammatory cytokines (Anderson
et al., 2010). Adipocytes themselves are also capable of
releasing inflammatory mediators and contribute to the inflam-
matory response (McGillicuddy et al., 2011; Stienstra et al.,
2010; Meijer et al., 2011). In addition to adipose tissue, inflamma-
tion in liver and pancreatic islets is also evident in obese individ-
uals and participates in the pathogenesis of type 2 diabetes (Gre-
gor and Hotamisligil, 2011). One of the proinflammatory
cytokines mediating obesity-induced inflammation is interleukin
(IL)-1b, which is processed by caspase-1, a cysteine protease
regulated by a protein complex called the inflammasome.
Although growing evidence points to a crucial role for IL-1b in
mediating the development of insulin resistance, it should be
stressed that the inflammatory response driving the develop-
ment of insulin resistance probably is comprised of a combina-
tion of proinflammatory cytokines that jointly effectuate type 2
diabetes progression. For example, involvement of TNFa in
obesity-associated insulin resistance has been frequently re-
ported. Since biological processes are often multifactorial,
involvement of other cytokines like TNFa is plausible.
Although detrimental effects of IL-1b on b cell function have
been well documented, the proinflammatory effects of IL-1b that
mediate the development of tissue dysfunction and peripheral
insulin resistance have only recently received more interest. While
several lines of evidence have shown involvement of IL-1b in the
development of obesity-associated insulin resistance peripherally,
the quantitative contribution remains to be defined in more detail.
In the present review we will discuss recently identified meta-
bolic triggers that may function as potential danger signals,
and highlight new findings regarding the mechanisms involved
in the processing of IL-1b during the progression of obesity
and insulin resistance. In light of the growing interest to block
low-grade inflammation in obese and insulin-resistant subjects,
this review will particularly focus on the potential of the inflamma-
some as a therapeutic target in the treatment of obesity-induced
insulin resistance.
Pathogenic Role of IL-1b in the Development of Obesity,
Insulin Resistance, and Diabetes
IL-1b elicits potent proinflammatory actions through its binding
to the IL-1 receptor that in turn recruits the IL-1 receptor acces-
sory protein. This receptor complex signals through the myeloid
differentiation factor 88 (MyD88) adaptor protein that spurs on
IL-1 receptor-activated kinases (IRAK1 to 4). This leads to activa-
tion of several protein kinases, including mitogen-activated
protein kinase 8 (JNK), mitogen-activated protein kinase 1
(ERK), p38 MAPK, and inhibitor of kappaB kinase (IKK), that
initiate the transcription factors nuclear factor kB (NF-kB) and
activator protein 1 (AP1) to stimulate inflammatory gene expres-
sion (Dinarello, 2011) (see Figure 1). The proinflammatory actions
of IL-1b are recognized as an important contributor to the devel-
opment of both type 1 and type 2 diabetes (Donath and Shoe-
lson, 2011; Mandrup-Poulsen et al., 2010). While IL-1b has toxic
effects on pancreatic b cells in the process of autoimmune dia-
betes (Mandrup-Poulsen et al., 1986), the cytokine also appears
to be involved in b cell deterioration related to glucotoxicity in
type 2 diabetes (Donath et al., 2003), with both processes
leading to defective insulin production. By activation of Fas-trig-
gered apoptosis, which involves the transcription factor NF-kB,
IL-1b mediates b cell dysfunction. More peripherally, IL-1b
directly inhibits insulin signaling pathways by reducing tyrosine
phosphorylation of insulin receptor substrate 1 (IRS1) and nega-
tive regulation of IRS1 gene expression levels, thus inducing
a state of insulin resistance (Jager et al., 2007). In animal studies,
the lack of IL-1b or its receptor protects against the development
of adipose tissue inflammation and insulin resistance upon

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Cell Metabolism

Review

Figure 1. IL-1b Signaling Pathway: Overview of the Intracellular Signaling Pathways Activated by Binding of IL-1b to the IL-1 Receptor
Upon activation of the IL-1 receptor complex, IL-1b induces recruitment of the myeloid differentiation primary response gene 88 (MyD88), which in turn promotes
activation of the interleukin-1 receptor kinase (IRAK) cascade. Via tumor necrosis factor-associated factor 6 (TRAF6) and the c-Jun N terminus (JNK), p38
mitogen-activated protein (p38 MAPK), and the inhibitor of nuclear factor b (IKK) kinases, the IkB cofactor is degraded, which subsequently promotes the nuclear
translocation of NF-kB and AP-1. Both transcription factors have the capacity to induce proinflammatory gene expression of various cytokines and chemokines
that modulate the inflammatory response.

high-fat diet feeding (Wen et al., 2011; McGillicuddy et al., 2011).
This protective effect may partially be mediated by the absence
of IL-1b-controlled chemokine synthesis (Dinarello, 2011), which
governs the influx of various immune cells into adipose tissue,
thus promoting inflammation.
In line with the proposed pathogenic role of IL-1b, increased
circulating levels of this cytokine accompanied by elevated
levels of IL-6 positively correlate with the development of type
2 diabetes in humans (Spranger et al., 2003). Conversely,
blockade of excessive IL-1 signaling in subjects with type 2 dia-
betes improves glycemic control and b cell function while
reducing markers of systemic inflammation (Larsen et al.,
2007). Although clinical studies have revealed that inhibition of
IL-1 signaling improves glucose tolerance, data pointing to an
improvement of insulin sensitivity upon anti-IL-1 treatment are
scarce. However, clinical studies using salsalate, an unspecific
anti-inflammatory agent, have demonstrated a significant
improvement in insulin sensitivity (Goldfine et al., 2008). It should
be noted that highly targeted anticytokine treatment ap-
proaches, such as treatment with the anti-TNF antibody (inflixi-
mab), have been found to be successful in improving insulin
sensitivity in patients diagnosed with rheumatoid arthritis (Gon-
zalez-Gay et al., 2010; Huvers et al., 2007).
Until recently, the triggers and molecular switches controlling
IL-1b production during the development of obesity and insulin
resistance have remained largely unknown. In as much as
IL-1b elicits a vigorous inflammatory response, activation must
be tightly controlled and requires processing from an inactive
procytokine into the biologically active form by proteolytic
enzymes. Processing of cytokines of the IL-1 family, such as
IL-1b and IL-18, is mainly mediated by the cysteine protease
caspase-1, which in turn is activated by a protein platform
termed the inflammasome.
The Inflammasome
The inflammasome is an important part of our innate immune
system that responds to danger signals that are sensed by
a number of different intracellular NOD-like receptors (NLRs).
Different inflammasomes have been identified, including NLR
family pyrin domain-containing 1 (NLRP1), NLR family pyrin
domain-containing 3 (NLRP3), NLR family pyrin domain-con-
taining 6 (NLRP6), AIM2 (absent in melanoma 2), and IPAF

Cell Metabolism 15, January 4, 2012 ª2012 Elsevier Inc. 11


(IL-1b-converting enzyme protease-activating factor), which
each have the ability to respond to a wide variety of microbial
products or endogenous danger signals (Dunne, 2011). Hitherto,
NLRP3 is the most extensively studied inflammasome that, upon
its activation, forms a complex with its adaptor molecule PYD
and CARD domain containing protein (ASC) and thereby facili-
tates caspase-1-dependent processing of pro-IL-1b into its
active form. Normally, this proinflammatory response provides
protection for the host by inducing an acute phase response
(Dinarello, 2011).
Recent studies have identified the inflammasome as an impor-
tant contributor to the development of insulin resistance by
mediation of processing and release of IL-1b in various tissues
and cell types during the development of obesity. In addition to
IL-1b, caspase-1 is also able to process and activate IL-18 and
IL-33 (Arend et al., 2008). In contrast to IL-1b, IL-18 ameliorates
development of obesity and insulin resistance (Netea et al.,
2006). Interestingly, caspase-1 deficient mice lacking both
IL-1b and IL-18 are characterized by an improvement in insulin
resistance (Stienstra et al., 2010), suggesting that the insulin-
desensitizing effects of IL-1b override IL-18 action. The fact
that expression and circulating levels of IL-18 are easily detect-
able in healthy subjects, as compared to IL-1b, suggests that this
cytokine executes different functions, among which are the
opposing effects on insulin resistance.
NLRP3-Mediated Caspase-1 Activity in the Driver’s Seat
Several lines of evidence suggest that activation of inflamma-
some-mediated caspase-1 is one of the culprits behind the
enhanced inflammatory state characteristic of obesity and has
center stage in the pathogenesis of type 2 diabetes by acting
at two different levels.
First, caspase-1 appears to instigate defective insulin secre-
tion by promoting pancreatic dysfunction. Pancreatic b cells it-
self are capable of producing IL-1b (Böni-Schnetzler et al.,
2008; Maedler et al., 2002) through mechanisms involving the
NLRP3 inflammasome (Zhou et al., 2010). Additionally,
enhanced macrophages’ infiltration of the pancreas observed
in human type 2 diabetic patients and high-fat diet (HFD)-fed
mice (Ehses et al., 2007) may further potentiate IL-1b production.
The IL-1b-driven inflammation of the islets is proposed as the
central mediator of glucose-, lipid-, and amyloid-induced b cell
failure leading to defective insulin secretion (Masters et al.,
2011; Mandrup-Poulsen, 2010) and ultimately b cell death, two
processes distinctive for the pathogenesis of type 2 diabetes.
Second, activation of caspase-1 can alter the function of
peripheral tissues, including adipose tissue and liver, both criti-
cally involved in maintaining glucose homeostasis. Adipose
tissue of animals fed a high-fat diet to induce obesity and insulin
resistance is characterized by enhanced gene expression and
increased protein levels of caspase-1 (Stienstra et al., 2010; Van-
danmagsar et al., 2011). Similarly, feeding mice a methionine-
choline-deficient diet, which promotes the development of
nonalcoholic steatohepatitis (NASH), has been shown to
promote NLRP3-dependent caspase-1 activation within hepato-
cytes (Csak et al., 2011). The elevated activity of caspase-1 leads
to increased processing of IL-1b and promotes a proinflamma-
tory environment that drives tissue dysfunction. Indeed, the
absence of caspase-1 provides protection for the host against
12 Cell Metabolism 15, January 4, 2012 ª2012 Elsevier Inc.
Cell Metabolism
Review
the deleterious effects of high-fat diet feeding. For example,
caspase-1 / mice have a decreased influx of macrophages
into adipose tissue upon high-fat diet feeding (Stienstra
et al., 2011). Similarly, ASC / (Stienstra et al., 2011) and
NLRP3 / animals (Vandanmagsar et al., 2011) were protected
against the development of hepatosteatosis instigated by high-
fat diet feeding. Importantly, HFD-fed mice lacking caspase-1
were characterized by a robust improvement in insulin sensitivity
and were rescued from the development of obesity as compared
to wild-type mice (Stienstra et al., 2011). Notably, part of the
protective effects of the absence of caspase-1 may be accom-
plished by the reduction in weight gain as compared to the
wild-type animals fed the high-fat diet. A similar protection
against insulin resistance was observed in HFD-fed animals
lacking ASC or NLRP3 (Wen et al., 2011). However, different
phenotypical responses were observed between the various in-
flammasome knockout models upon high-fat diet feeding.
Whereas the absence of NLRP3 only provided protection against
high-fat diet-induced insulin resistance and fatty liver disease
after prolonged exposure to the diet for up to 9 months in one
model (Vandanmagsar et al., 2011), shorter periods of high-fat
diet feeding also appear to activate NLRP3 (Wen et al., 2011).
The absence of caspase-1 and ASC conferred protection
against the development of insulin resistance after 12 or
16 weeks of diet intervention. These results imply that NLRP3
activation may require secondary danger signals that are only
apparent after prolonged high-fat diet feeding and may include
lipotoxic metabolites like sphingolipids. Hypothetically, differ-
ences in the composition of the diets that were used to induce
obesity may have altered the supply of NLRP3 danger signals.
Alternatively, other inflammasomes next to NLRP3 may also be
involved in the development of obesity-induced insulin resis-
tance. Furthermore, differences in expression levels between
distinct adipose tissue cell populations may explain any pheno-
typical variance. While caspase-1 is highly expressed in both
adipocytes and nonadipoycte cells, the inflammasome
members NLRP3 and ASC are predominantly expressed in non-
adipocyte cells that are part of the adipose tissue. Although the
lower expression levels do not rule out any function of ASC and
NLRP3 in adipocytes, it appears that crosstalk between both cell
types determines the secretion levels of IL-1b by adipose tissue.
However, it should be emphasized that isolated adipocytes do
have the potential to produce IL-1b (Koenen et al., 2011b).
Hence, caspase-1 activation in adipocytes may rely on non-
NLRP3 inflammasome members or is controlled independently
of the inflammasome.
Additionally, important tissue-specific effects of various in-
flammasomes have recently been described, such as the regula-
tion of IL-18 production in intestinal epithelial cells by the NLRP6
inflammasome (Elinav et al., 2011). This opens up the intriguing
and yet unexplored possibility of specific inflammasome compo-
nents present in adipocytes, hepatocytes, macrophages, or
pancreatic b cells that may differentially affect the development
of insulin resistance. Alternatively, differential regulation of
similar inflammasome subtypes may also occur and mediate
tissue-specific effects.
There is supportive evidence for the involvement of the in-
flammasome in obesity-induced inflammation in humans. For
example, caspase-1 activity levels are more pronounced in the
Cell Metabolism
Review
visceral fat depot, which is a strong determinant of insulin resis-
tance, as compared to subcutaneous adipose tissue of mildly
obese subjects (Koenen et al., 2011b). In liver, expression levels
of NLRP3, caspase-1, and ASC are elevated in patients suffering
from NASH compared to healthy controls (Csak et al., 2011).
Conversely, substantial weight loss in obese subjects with type
2 diabetes was shown to reduce expression levels of IL-1b and
NLRP3 in adipose tissue and positively correlated with changes
in fasting plasma glucose levels (Vandanmagsar et al., 2011).
Overall, these results argue that activation of IL-1b by the in-
flammasome plays a central role in the pathogenesis of
obesity-induced insulin resistance. Since activation of cas-
pase-1 leading to the cleavage and secretion of IL-1b is under
tight control of the inflammasome, specific danger signals
should exist that arise during the development of obesity and
that are sensed by intracellular NLRs. Indeed, several studies
have identified metabolic danger signals that can efficiently acti-
vate the inflammasome, leading to caspase-1-driven cleavage of
IL-1b in a variety of cell types, both from nonmyeloid and myeloid
origin (Vandanmagsar et al., 2011; Wen et al., 2011; Csak et al.,
2011; Zhou et al., 2010; Masters et al., 2010).
Potential Metabolic Danger Signals that Activate IL-1b
Recent studies have revealed that activation of IL-1b requires
two signals (Gong et al., 2010; Joosten et al., 2010; Hornung
et al., 2009). Whereas the first signal ‘‘primes’’ the cell and acts
as an inducer of IL-1b and NLR mRNA transcription, the second
signal induces conformational changes in the inflammasome
that instigates caspase-1 activation. Classically, the first signal
is provided by invading pathogens driving IL-1b mRNA transcrip-
tion through pattern recognition receptors such as toll-like
receptors (TLRs) (Lamkanfi et al., 2008). The second signal is
of a more heterogeneous nature, as it can be represented by
microbial components such as microbial DNA (Muruve et al.,
2008), cell-wall components, and toxins (Ali et al., 2011), but
also by endogenous ligands such as adenosine triphosphate
(ATP) or uric acid (Mariathasan et al., 2006). The precise unifying
mechanism through which all these ligands induce caspase-1
activation is not known, although a rapid K+ efflux from cells
seems to be a common denominator that triggers activation of
the inflammasome (Lamkanfi et al., 2008). Notably, not all cell
types need sequential hits to induce IL-1b production. For
example, monocytes only require the first signal to induce in-
flammasome-dependent IL-1b release, due to the constitutive
activation of caspase-1 in this cell type (Netea et al., 2009).
Moreover, IL-1b can also be processed by caspase-1-indepen-
dent cleavage through neutrophil-derived serine proteases
(Joosten et al., 2009), yet no information is available concerning
the mechanism that controls this process.
Very recently, fatty acids, glucose, uric acid, and islet amyloid
polypeptide (IAPP) have been put forward as metabolic danger
signals that possess the capacity to activate the inflammasome
and stimulate IL-1b production (Figure 2). Below we will discuss
where exactly these signals might act to promote IL-1b release.
Fatty Acids
Elevated circulating levels of free fatty acids are one of the hall-
marks of type 2 diabetes (Krebs and Roden, 2005). Interestingly,
it has been suggested that saturated fatty acids bind and acti-
vate members of the TLR-family in vitro (Lee et al., 2001). For
example, palmitate acts as a ligand for TLR4 and induces IL-6
mRNA expression through activation of the transcription factor
NF-kB (Shi et al., 2006). Moreover, treatment of human THP-1
cells with palmitate has been shown to induce IL-1b mRNA
expression (Håversen et al., 2009) although some doubt has
been cast on whether saturated fatty acids can induce TLR
signaling (Erridge and Samani, 2009). However, elevated levels
of palmitate may provide the first signal needed for IL-1b produc-
tion though induction of IL-1b gene transcription, although it
has to be kept in mind that levels of all fatty acids are elevated
in type 2 diabetes and may alter the effect of palmitate on
IL-1b production.
In addition, recent work demonstrates that palmitate also has
the potential to directly activate the NLRP3-inflammasome in
macrophages and thus provide the second signal needed for
IL-1b release (Wen et al., 2011). Via detailed mechanistic
in vitro studies, it was shown that palmitate negatively affects
the activation of AMP-activated protein kinase (AMPK), an
energy-sensing kinase that regulates multiple biochemical path-
ways in all eukaryotes, including lipid and glucose metabolism
and apoptosis (Steinberg and Kemp, 2009). The reduction in
AMPK phosphorylation leads to defective autophagy, a process
known to regulate the clearance of dysfunctional mitochondria.
The authors propose that the subsequent intracellular accumula-
tion of mitochondrial-derived reactive oxygen species (ROS)
represents the trigger activating the inflammasome. Indeed,
ROS have long been proposed to activate the inflammasome,
although some controversy exists. For example, cells isolated
from patients diagnosed with chronic granulomatous disease
(CGD) have defective NADPH activity and thus cannot generate
NADPH-dependent ROS (van de Veerdonk et al., 2010; Meissner
et al., 2010). Upon stimulation, monocytes from CGD patients
produced similar or even increased amounts of IL-1b as
compared to cells from unaffected subjects, indicating
NADPH-independent activation of the inflammasome. In this
respect, enhanced production of ROS by mitochondria, a hall-
mark of insufficient mitochondrial function that is strongly asso-
ciated with type 2 diabetes (Jin and Patti, 2009), may be an alter-
native source driving NLRP3 inflammasome activation
(Tschopp, 2011).
Other pathways that mediate palmitate-induced inflamma-
some activation can also be envisaged. Exposure of cells to
palmitate induces intracellular accumulation of ceramide, which
is produced by a ubiquitous biosynthetic pathway initiated by the
condensation of palmitoyl-coenzyme A (CoA) and serine.
Prevention of de novo ceramide synthesis limited the develop-
ment of insulin resistance evoked by treatment of cells with satu-
rated fatty acids (Chavez et al., 2003). Given the fact that ceram-
ide has recently been identified as a potent activator of the
inflammasome in macrophages (Vandanmagsar et al., 2011),
palmitate may fuel ceramide biosynthesis, thereby providing
a continuous supply of danger signals for NLRP3 inflammasome
activation.
The palmitate-driven activation of the inflammasome is not
limited to macrophages, as nonmyeloid cell types including
hepatocytes have recently been shown to be a target of palmi-
tate-driven activation of the NLRP3-inflammasome as well.
Though palmitic acid has been nominated as the meta-
bolic activator that links obesity-induced insulin resistance to
Cell Metabolism 15, January 4, 2012 ª2012 Elsevier Inc. 13
 Cell Metabolism

Review

Figure 2. Activation of the Inflammasome

An overview of the metabolic triggers that have been shown to provide the first signal (induction of transcription) or the second signal (inflammasome activation)
leading to the production and release of IL-1b. The first signal that is aimed at inducing IL-1b transcription and subsequent production of pro-IL-1b can be
provided by glucose, palmitate, uric acid, or LPS. In order to facilitate processing of pro-IL-1b into its active form, a second signal is essential to facilitate in-
flammasome activation and caspase-1-dependent cleavage of pro-IL-1b. NLRP3-dependent activation of caspase-1 can be triggered by palmitate, ceramide,
glucose, uric acid, reactive oxygen species (ROS), or amyloid. Promotion of this cascade occurs in a variety of tissues, including the pancreas, liver, and adipose
tissue and may subsequently contribute to tissue dysfunction and the development of insulin resistance.

activation of innate immunity, this may not imply that all fatty acids
cause activation of the inflammasome. Since unsaturated fatty
acids have anti-inflammatory effects (Browning, 2003) and lack
the ability to activate TLR4 or evoke ceramide synthesis (Chavez
et al., 2003), one would predict that highly unsaturated species
prevent inflammasome activation. Accordingly, it is important to
characterize the inflammasome-activating potential of various
fatty acids differing in length and degree of unsaturation.
A potential confounder in most of the experiments pinpointing
ceramide or palmitate as activators of the inflammasome (and
other metabolic danger signals) may be the fact that cells were
primed with LPS (Wen et al., 2011; Vandanmagsar et al.,
2011). Notably, both palmitate and ceramide did not induce in-
flammasome activation and subsequent cleavage and secretion
of IL-1b without prior exposure of macrophages to LPS. Since it
has been reported that serum endotoxin levels are elevated in
obese animals due to a disruption in intestinal integrity (Cani
et al., 2008), LPS may serve as a first signal in obese individuals.
However, other priming signals may exist in vivo that synergize
with ceramide or palmitate to induce both proIL-1b transcription
and inflammasome activation, and these include other fatty
acids, glucose, or adipocytokines.
Glucose
It has been known for almost a decade that high glucose levels
promote IL-1b mRNA transcription (Shanmugam et al., 2003).
Glucose has been shown to activate PKC-alpha and, via phos-
phorylation of p38 MAPK and ERK1/2, lead to NF-kB activation
and subsequent IL-1b transcription in monocytes (Dasu et al.,
2007), hence priming cells for inflammasome activation.
Additional pathways may also participate in high glucose-
mediated activation of IL-1b release by providing the second
signal that is required to activate the inflammasome. Indeed,
glucose has been identified as a direct stimulator of caspase-1
activity (Vincent and Mohr, 2007). Recent evidence has sug-
gested that the NLRP3 inflammasome is activated in response
to high levels of glucose (Zhou et al., 2010). The mechanism of
action involves thioredoxin-interacting protein (TXNIP), a protein
that acts as an endogenous inhibitor of the ROS scavenging
protein thioredoxin (Minn et al., 2005; Parikh et al., 2007). Inter-
estingly, TXNIP levels are elevated in subjects with type 2 dia-
betes mellitus (Parikh et al., 2007), and its expression is robustly
induced by glucose (Stoltzman et al., 2008). Zhou et al. (2010)
have shown that, upon activation, TXNIP is able to directly
interact with NLRP3 in a ROS-dependent manner, leading to

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Cell Metabolism
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activation of caspase-1 and processing of IL-1b in pancreatic
islets. However, these observations could not be reproduced
in bone-marrow-derived macrophages lacking TXNIP and
exposed to high glucose levels (Masters et al., 2010). Neverthe-
less, treatment of the cells with 2-deoxy-D-glucose, which
blocks metabolic processing, prevents IL-1b processing and
release, implying that adequate glucose metabolism is indis-
pensable for inflammasome function (Masters et al., 2010).
It is reasonable to expect that the effects of high levels of
glucose on caspase-1-mediated IL-1b production differ among
various cell types. Indeed, although adipose tissue ex vivo
responds to high levels of glucose by inducing TXNIP and
producing higher levels of IL-1b, TXNIP ablation in adipocytes
did not affect caspase-1 activity levels (Koenen et al., 2011a).
However, knockdown of TXNIP did reduce IL-1b mRNA levels
within adipocytes, indicating that TXNIP regulates IL-1b gene
expression levels during the presence of high levels of glucose.
As TXNIP itself has the capacity to induce chromatin modifica-
tion (Perrone et al., 2009), it is conceivable that TXNIP may regu-
late IL-1b promoter availability.
In summary, high glucose levels may provide the priming
signal for transcription of IL-1b by activation of TXNIP, which
subsequently facilitates enhanced IL-1b expression levels. Addi-
tionally, high concentrations of glucose also promote the gener-
ation of ROS that is sufficient as second signal that promotes in-
flammasome activation and subsequently induces release of
bioactive IL-1b.
Uric Acid
Hyperuricemia often occurs in obese individuals and frequently
precedes the development of type 2 diabetes. It has been thought
that high levels of uric acid are a result of hyperinsulinemia, since
insulin normally reduces the renal secretion of uric acid. Interest-
ingly, lowering of circulating levels of uric acid improved insulin
sensitivity in fructose-fed rats (Nakagawa et al., 2006).
It has been suggested that uric acid drives inflammatory and
oxidative changes in adipocytes. Uric acid directly affects the
inflammatory status of the adipose tissue by regulating MCP-1
levels in adipocytes (Baldwin et al., 2011), thereby promoting
infiltration of macrophages (Ito et al., 2008). Interestingly, crys-
tals of monosodium urate, frequently observed in patients diag-
nosed with gout, have been uncovered as a robust inducer of the
NLRP3 inflammasome in macrophages (Martinon et al.,
2006).Can uric acid also drive obesity-induced inflammation by
activating the inflammasome?
Interestingly, uric acid is indispensable for normal adipogene-
sis, as animals that lack xanthine oxidoreductase (XOR), an
enzyme that generates uric acid from xanthine, exhibit a
decrease in adipose content and are characterized by a reduc-
tion in PPARg activity as compared to wild-type mice. More
importantly, uric acid levels within adipose tissue are enhanced
in obese animals as compared to lean mice, and this is accom-
panied by elevated transcription levels of XOR (Cheung et al.,
2007). Thus, it may be hypothesized that uric acid can directly
promote the inflammasome or modulate IL-1b mRNA transcrip-
tion. In theory, adipocyte death, which has been suggested to be
the driving force of adipose tissue inflammation by attracting
macrophages (Cinti et al., 2005), may also activate the inflamma-
some, since dying cells are known to release uric acid to alert the
immune system (Shi et al., 2003).
Although more work is needed, uric acid is an important candi-
date that may modulate inflammasome activation during the
development of obesity and insulin resistance.
Islet Amyloid Polypeptide
Islet amyloid polypeptide (IAPP), also known as amylin, is a regu-
latory peptide of 37 amino acids that is produced by pancreatic
b cells and inhibits insulin and glucagon secretion. The ability of
amylin to form protein aggregates that cluster in pancreatic islets
as amyloid deposits is believed to be of critical importance for
the loss of b cell mass and type 2 diabetes progression (Wester-
mark et al., 2011). Recent evidence has uncovered that IAPP has
the ability to energize the NLRP3 inflammasome, subsequently
promoting IL-1b production by the pancreas (Masters et al.,
2010). In contrast to glucose and palmitate, IAPP lacks the ability
to drive IL-1b mRNA expression, yet robustly promotes NLRP3-
mediated caspase-1 activation, partly by a disturbance in the
phagocytic machinery causing oxidative stress.
Interestingly, expression of IAPP by the pancreatic b cell line
MIN6 cells is activated by palmitate (Westermark et al., 2011),
suggesting that fatty acids may boost pancreatic IL-1b produc-
tion in type 2 diabetes.
Additional lines of evidence suggest that IAPP may also have
extrapancreatic sites of action, since expression of the peptide
has been detected in the gastrointestinal tract and sensory
neurons (Westermark et al., 2011). Moreover, inasmuch as circu-
lating levels of IAPP are elevated upon high-fat diet feeding of
animals (Westermark et al., 2011), it is plausible to expect that
IAAP-dependent activation of the inflammasome also occurs at
extrapancreatic sites.
Altogether, these data suggest that IAPP functions as a second
signal promoting NLRP3 activation and subsequent caspase-1-
dependent cleavage of IL-1b.
Therapeutic Interventions
Given the wealth of data that have implicated activation of the in-
flammasome in the pathogenesis of obesity-induced insulin
resistance, inhibition of IL-1b and caspase-1 may represent an
attractive therapeutic target. So far, only a few studies have
been conducted aimed at limiting IL-1b action, either by using
receptor antagonists or by neutralizing IL-1b. Blockade of
IL-1R-mediated signaling by the recombinant IL-1 receptor
antagonist (IL-1Ra) Anakinra was effective in improving glycemic
control in patients with type 2 diabetes (Larsen et al., 2007).
However, no improvement in insulin sensitivity levels as deter-
mined by euglycemic clamp was observed. In addition, no
changes in muscle gene expression or serum adipokine levels
were seen. Additionally, treatment with Anakinra had no direct
beneficial effect on insulin sensitivity in nondiabetic insulin-resis-
tant subjects (van Asseldonk et al., 2011). Although these obser-
vations suggest that IL-1 blockade in human subjects does not
reverse insulin resistance, only a limited number of studies
have been conducted so far. Additionally, Anakinra has a short
half-life and requires daily injections that often cause side effects
at the site of the subcutaneous injection, limiting its therapeutic
potential. Inhibition of IL-1 may be of more benefit in reversing
hyperglycemia-associated insulin resistance. It should be also
underlined that one cannot exclude the possibility that effects
on hepatic insulin resistance explain the effects observed in
the study of Larsen et al. (2007).
Cell Metabolism 15, January 4, 2012 ª2012 Elsevier Inc. 15

More recently, the development of IL-1b-neutralizing anti-
bodies that have successfully ameliorated insulin resistance
(Donath et al.,2008; Sloan-Lancaster et al.,2011; Rissanen
et al.,2011) has been reported. These preparations have a longer
half-life and require fewer injections and may therefore bear
superior therapeutic potential. Nevertheless, it must be empha-
sized that, to date, no clinical studies using anti-IL-1b therapies
have reported any improvement in insulin sensitivity levels.
A second potential approach would be direct inhibition of cas-
pase-1. Specific caspase-1 inhibitors have potent beneficial
effects in animal models of insulin resistance and type 2 diabetes
(Stienstra et al., 2010), and such pharmacological agents may
prove useful in humans as well. However, at this moment, no
caspase-1 inhibitors are available for human use. Interestingly,
Glyburide, a frequently used sulfonylurea drug for the treatment
of type 2 diabetes, has been shown to inhibit the NLRP3 inflam-
masome (Lamkanfi et al., 2009; Masters et al., 2010), and one
may hypothesize that at least part of its effects may be due to
its anti-inflammatory action.
However, one has to keep in mind that caspase-1 cleaves
alternative substrates including caspase-7 (Lamkanfi et al.,
2008), which may mediate its deleterious effects during the
development of obesity and insulin resistance. Therefore, thera-
pies aimed at specifically blocking caspase-1 may prove to be
more successful in attenuating type 2 diabetes, as compared
to strategies aimed solely at blockage of IL-1b.
Summary
Inflammation is one of the key events that underlie the develop-
ment of obesity-induced insulin resistance. Although different
roads may lead to its activation, the contribution of IL-1b to
the development of insulin resistance at the level of the b cell,
as well as peripherally, in obese individuals is now well estab-
lished. Active IL-1b is produced by cleavage of pro-IL-1b by
caspase-1, which is part of the inflammasome protein complex.
Although most studies performed to date provide indirect and
associative evidence, growing evidence indicates that the in-
flammasome can be activated by fatty acids, high glucose
levels, uric acid, and IAPP, linking metabolic danger signals to
activation of IL-1b synthesis. The described correlations and
associations, however, do not necessarily prove causative rela-
tionships.
Inhibition of the IL-1R signaling or IL-1b production by the
NLRP3-mediated activation of caspase-1 may ward off loss of
pancreatic b cell function, yet may also prevent the development
of insulin resistance in liver, muscle, and adipose tissue.
Although clinical evidence is currently lacking, inhibition of the
IL-1R signaling or IL-1b production by the NLRP3-mediated acti-
vation of caspase-1 may avert the development of insulin resis-
tance and represents an attractive therapeutic target to limit
pathological complications associated with obesity, insulin
resistance, and type 2 diabetes.
ACKNOWLEDGMENTS
The authors would like to thank Sander Kersten for his valuable comments.
R.S. was supported by a Ruby Grant of the Dutch Diabetes Research Founda-
tion. M.G.N. was supported by a Vici Grant from the Netherlands Organization
for Scientific Research (NWO).
16 Cell Metabolism 15, January 4, 2012 ª2012 Elsevier Inc.
Cell Metabolism
Review
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