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INFLAMMATION AND LIPID SIGNALING IN THE ETIOLOGY OF
INSULIN RESISTANCE
Christopher K. Glass, M.D.and Jerrold M. Olefsky, M.D.
Abstract
Inflammation and lipid signaling are intertwined modulators of homeostasis and immunity. In
addition to the extensively studied eicosanoids and inositol phospholipids, emerging studies
indicate that many other lipid species act to positively and negatively regulate inflammatory
responses. Conversely inflammatory signaling can significantly alter lipid metabolism in the liver,
adipose tissue, skeletal muscle and macrophage in the context of infection, diabetes and
atherosclerosis. Here, we review recent findings related to this interconnected network from theperspective of immunity and metabolic disease.
Introduction
Insulin resistance is a major metabolic abnormality in the great majority of patients with
Type 2 diabetes and the incidence of this disease has reached epidemic proportions around
the globe (Hupfeld et al., 2006; Kahn et al., 2006). Obesity is clearly the most common
cause of insulin resistance, and it is the parallel epidemic of obesity, which is driving the
rising incidence of Type 2 diabetes (Kahn et al., 2006). The etiology of insulin resistance
has been intensely studied (Qatanani and Lazar, 2007; Shulman, 2000), and it is now
recognized that chronic tissue inflammation is an important cause of obesity-induced insulinresistance (Attie and Scherer, 2009; Lumeng and Saltiel, 2011; Olefsky and Glass, 2010;
Shoelson et al., 2007). One of the initial lines of evidence for this relationship derived from
the unexpected observations that TNF, a cytokine associated with cachexia in cancer, was
elevated in obese adipose tissue in rodents and that inhibition of this cytokine improved
glucose tolerance and insulin sensitivity (Hotamisligil et al., 1993). Subsequently, studies
demonstrated that a key mechanism underlying obesity-induced inflammation is the
accumulation of increased numbers of tissue macrophages, particularly in obese adipose
tissue (Weisberg et al., 2003; Xu et al., 2003). These adipose tissue macrophages (ATMs)
can span the spectrum from the most pro-inflammatory, M1-like, cells to anti-inflammatory,
M2-like, macrophages (Lumeng et al., 2007a; Lumeng et al., 2007b; Nguyen et al., 2007).
The proinflammatory ATMs are often referred to as classically activated macrophages(CAMs) while the anti-inflammatory macrophages are referred to as alternatively activated
macrophages (AAMs).
2012 Elsevier Inc. All rights reserved.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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NIH Public AccessAuthor ManuscriptCell Metab. Author manuscript; available in PMC 2014 September 05.
Published in final edited form as:
Cell Metab. 2012 May 2; 15(5): 635645. doi:10.1016/j.cmet.2012.04.001.
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In obesity, the balance is tilted towards the M1-like macrophage polarization state (Lumeng
et al., 2007a), and these cells secrete a number of different cytokines, such as TNFa, IL-1b,
etc. In turn, these cytokines can act through paracrine mechanisms to directly inhibit insulin
action in insulin target cells (i.e. hepatocytes, myocytes, and adipocytes) (Feve and Bastard,
2009; Hotamisligil, 1999). It is also possible that these tissue cytokines leak into the
systemic circulation to cause insulin resistance through endocrine effects. Cytokine
signaling activates stress kinases such as S6K, IKK, JNK1, and PKC, whichphosphorylate IRS1 on inhibitory serine residues and results in impaired downstream
signaling (Hotamisligil, 2006; Schenk et al., 2008). Cytokines can also inhibit insulin action
through transcriptional mechanisms by decreasing the expression levels of key insulin
signaling molecules (Stephens and Pekala, 1992). Finally, cytokines can promote ceramide
biosynthesis, which directly inhibits Akt activation, as discussed below (Holland et al.,
2011).
While ATMs are considered to be the ultimate effector cell elaborating cytokines which
cause insulin resistance, their recruitment to adipose tissue and their activation state are
influenced by other immune cell types that populate obese adipose tissue, including T cells,
B cells, eosinophils, and mast cells (Feuerer et al., 2009; Kintscher et al., 2008; Liu et al.,2009; Nishimura et al., 2009; Winer et al., 2011; Wu et al., 2011). However, inflammation is
not the only mechanism of insulin resistance in obesity. For example, various abnormalities
of lipid metabolism have been described which can also impair insulin signaling (Itani et al.,
2002; Savage et al., 2007). These lipotoxic effects include the production of intracellular
lipid mediators, such as diacylglycerols (Samuel et al., 2010), as well as more direct effects
of circulating saturated fatty acids. However, chronic tissue inflammation and lipid
abnormalities are not completely separable processes, and these two systems are closely
intertwined, and each can amplify the other in the in vivo pathophysiologic setting. In this
review, we focus on the inter-connections between abnormal lipid signaling and pro-
inflammatory pathways in insulin resistant states.
Effects of Fatty Acids on Inflammation
Saturated Fatty Acids
Circulating FFAs are typically elevated in insulin resistant states, and dietary fat intake has
an important influence on the composition of these FFAs (Fielding et al., 1996). The
association between elevated FFA levels and insulin resistance is well known (Park et al.,
2007) and numerous studies have demonstrated that infusions of triglyceride emulsions plus
heparin to rapidly raise FFA levels, will cause a decrease in insulin sensitivity (Boden et al.,
1991; Roden et al., 1996; Staehr et al., 2003) . In addition to circulating FFAs, macrophages
and other immune cell types in adipose tissue are exposed to high local concentrations of
FFAs released from adipocytes by lipolysis. In this way, these cells exist within a lipid-rich
environment that could amplify the effects of SFAs within adipose tissue.
SFAs are pro-inflammatory lipid compounds, with many studies demonstrating that
treatment of various cell types with SFAs broadly activates inflammatory signaling in
macrophages, adipocytes, myocytes, hepatocytes, etc. (Hwang and Rhee, 1999; Nguyen et
al., 2007; Nguyen et al., 2005; Yu et al., 2002). This leads to stimulation of IKK/NFB and
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JNK1/AP1, as well as release of cytokines (Fig. 1). Several laboratories have independently
reported that pro-inflammatory effects of SFAs are mediated, at least in part, through
activation of Tlr4 and/or Tlr2 (Lee et al., 2001; Nguyen et al., 2007; Schaeffler et al., 2009;
Senn, 2006; Shi et al., 2006). Tlr2 and Tlr4 are members of the TLR family of receptors that
recognize pathogen-associated molecular patterns (PAMPs) as well as endogenously derived
indicators of tissue injury (Kumar et al., 2009). Tl4 ligands include lipopolysaccharide
(LPS), a component of the cell walls of gram-negative bacteria while Tlr2 ligands includethe lipoteichoic acid component of gram-positive bacteria (Kumar et al., 2009; Poltorak et
al., 1998), In the absence of Tlr4, SFA-mediated inflammatory signaling is abrogated in
adipocytes (Shi et al., 2006). Furthermore, Tlr4 KO mice are resistant to the effects of high
fat diets to cause decreased insulin sensitivity ((Saberi et al., 2009; Shi et al., 2006), Fig. 1).
As an additional aspect of Tlr4-mediated inflammation, it has been reported that obesity is
associated with gastrointestinal dysbiosis in which LPS derived from GI tract microflora
leaks into the systemic circulation (Brun et al., 2007; Creely et al., 2007).
It has been suggested that the reported effects of SFAs on widely used indicators of TLR4
activation in macrophages, such as TNF, are due to contamination of the serum or albumin
used in these experiments with endotoxin (Erridge and Samani, 2009). While this mayaccount for some of the effects reported in cultured macrophages, infusion of heparin/lipid
emulsions results in Tlr4-dependent inflammatory responses in adipose tissue (Shi et al.,
2006). Collectively, there is substantial evidence for functionally important relationships
between SFAs, TLR signaling and insulin resistance, but the molecular mechanisms remain
unclear. Structural considerations (Park et al., 2009) and direct binding assays (Schaeffler et
al., 2009) argue against the possibility that SFAs are direct ligands for Tlr4. There are
several ways in which SFAs could indirectly activate Tlr signaling. One possibility is
through interaction with SFA binding proteins that function as TLR co-receptors. A
precedent for this type of mechanism is provided by the ability of CD36, a fatty acid
transporter and oxidzed LDL receptor, to interact with Tlr2 and induce signaling in response
to oxidized LDL (Seimon et al., 2010; Stewart et al., 2010). SFAs have also been reported toinduce Tlr4-depedent gene expression by promoting dimerization of Tlr4, a necessary step
in receptor activation, within specialized lipid domains termed lipid rafts in macrophages
(Fig. 1) (Wong et al., 2009). This appears to be dependent on the ability of SFAs to
stimulate NADPH oxidase production of ROS. In independent studies, SFA treatment led to
membrane redistribution of c-Src so that it is now concentrated in lipid rafts, where it
becomes activated (Holzer et al., 2011). This then leads to stimulation of JNK1 and its
proinflammatory target genes (Fig. 1). It is possible that the dimerization of Tlr4, as well as
the redistribution of c-Src in lipid rafts upon SFA treatment are mechanistically related
events, providing a pathway for SFA-induced pro-inflammatory signaling. A third
possibility is that SFAs may stimulate the production or release of a tissue damage signal
that is sensed by Tlrs. There are a number of endogenously derived molecules that havebeen shown to exert these types of functions when released from necrotic or damaged cells,
such as high mobility group proteins (Park et al., 2004). In concert, substantial additional
work will be required to fully establish the molecular mechanisms linking SFAs to Tlr
signaling.
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SFAs can also stimulate stress and/or inflammatory pathways by TLR-independent
mechanisms. Treatment of macrophages with SFAs leads to an increase in ROS production
and this can activate a number of stress kinases. The ability of SFAs to increase ROS levels
may also drive stimulation of the NLRP3 (nucleotide binding domain, leucine-rich repeats
containing family, pyrin domain-containing 3) inflammasome (Wen et al., 2011). NLRP3
forms a complex with the adaptor protein ASC (apoptotic speck protein containing a caspase
recruitment domain) that regulates caspase 3-dependent cleavage of pro-IL1to releaseactive IL1 (Ting et al., 2008). Recent studies have demonstrated that SFA-induced ROS
can activate the NLRP3-ASC inflammasome complex, thereby, increasing release of IL1
(Wen et al., 2011). When applied to insulin target cells, IL-1can decrease insulin signaling,
providing another mechanism for SFA mediated inflammatory responses causing insulin
resistance. Indeed, NLRP3, ASC, and caspase 1 knockout mice are all protected from HFD-
induced inflammation and insulin resistance (Wen et al., 2011).
Finally, SFAs are precursors to other lipid products, such as DAGs, and intracellular levels
of DAGs can be increased in insulin resistant states (Kumashiro et al., 2011). This can lead
to PKC activation with decreased insulin signaling, and this concept has been the subject of
recent reviews (Samuel et al., 2010). Taken together, these mechanisms would explain animportant component of lipotoxicity in which SFAs promote the chronic tissue
inflammatory state which can cause insulin resistance.
In addition to stimulating inflammatory pathways, SFAs can lead to decreased insulin
sensitivity through other mechanisms. For example, SFAs are precursors for ceramide
biosynthesis, and ceramide can directly cause decreased insulin signaling, as discussed in
more detail below (Stratford et al., 2004; Summers, 2010; Ussher et al., 2010). Finally,
FetuinA is a glycoprotein primarily made in hepatocytes and secreted into the circulation. In
vitro studies have demonstrated that SFA treatment of hepatocytes leads to increased
FetuinA mRNA expression and secretion, and other studies have indicated that FetuinA can
directly inhibit the early steps of insulin signaling (Dasgupta et al., 2010).
Ceramide Metabolism
Lipid and inflammatory pathway signaling are closely intertwined processes which can
result in insulin resistance. One important crossroad between these two pathways, relevant
to the development of decreased insulin sensitivity involves ceramide biosynthesis. Many
papers have demonstrated strong associations between intracellular ceramide levels and the
development of insulin resistance (Holland et al., 2011; Stratford et al., 2004; Ussher et al.,
2010). For example, the saturated fatty acid palmitate is a preferential substrate leading to
the biosynthesis of ceramide, providing another potential mechanism for SFA-induced
insulin resistance (Ussher et al., 2010). Elevated intracellular ceramide levels can stimulate
the ability of phosphatase 2A to dephosphorylated Akt and this inhibits insulin signaling,providing a mechanism for ceramide-mediated insulin resistance (Stratford et al., 2004).
Recent studies have revealed a further role for ceramide at the nexus of inflammation and
lipid signaling. Thus, independent of their roles as precursors for ceramide biosynthesis,
SFA stimulation of the Tlr4 pathway causes an increase in expression of the enzymes
involved in ceramide biosynthesis (Holland et al., 2011). Other non-lipid Tlr4 agonists, such
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as LPS, have a similar effect. Interestingly, stimulation with TNFrecapitulated the
increased ceramide biosynthesis (Dbaibo et al., 2001; Holland et al., 2011), and these
authors showed that the effect of Tlr4 and TNFsignaling on ceramide biosynthesis was
IKKdependent, directly demonstrating how inflammatory pathway signaling inputs can
promote biosynthesis of a lipid moiety, i.e., ceramide, which directly inhibits insulin
signaling (Fig. 1).
Omega 3 Fatty Acids
While SFAs promote inflammation and insulin resistance, other classes of fatty acids can
have beneficial effects. For example, long chain polyunsaturated omega 3 FAs, such as
DHA and EPA, can exert anti-inflammatory effects, and this has been known for many years
(Calder, 2006; Lang et al., 2003; Polozova and Salem, 2007; Proudman et al., 2008; Weldon
et al., 2007).
However, the mechanisms for these effects have been poorly understood until recently.
There is a family of lipid sensing GPCRs, including GPR40, 41, 43, 84, and 120 (Itoh et al.,
2003; Tazoe et al., 2008; Wang et al., 2006), and recent reports have indicated that omega 3
FAs can stimulate GPR120 (Hirasawa et al., 2005; Oh et al., 2010).. With respect to
inflammation, omega-3 FAs are ligands for GPR120 and can exert robust and broad anti-
inflammatory effects in various macrophage types (Oh et al., 2010). For example, when
RAW267.4 cells or intraperitoneal macrophages are treated with Tlr4/2 agonists, or TNF,
potent stimulation of inflammatory pathways occurs. However, when macrophages are
pretreated with omega 3 FAs, these proinflammatory effects are inhibited (Lee et al., 2003)
and these anti-inflammatory effects are completely abrogated in the absence of GPR120 (Oh
et al., 2010). These studies show that omega 3 FAs are ligands for GPR120 and exert anti-
inflammatory effects by signaling through this receptor. In this sense, GPR120 emerges as a
receptor/sensor for this anti-inflammatory class of fatty acids.
The mechanisms for this effect are also of interest. TAK1 is a proximal kinase in theseproinflammatory pathways and in response to inflammatory signals, the adaptor protein
TAB1 associates with and activates TAK1, stimulating both the IKK/NFB and the
JNK/AP1 pathways. Activation of GPR120 by omega 3 FAs specifically inhibits TAK
phosphorylation and activation, providing a mechanism for the broad inhibition of Tlr and
TNF signaling (Oh et al., 2010). arrestins are a family of molecules which can serve as
adaptor or scaffold proteins for a number of different GPCRs (Luttrell and Lefkowitz, 2002).
Interestingly, omega 3 FA stimulation leads to direct association between GPR120 and
arrestin-2 and the anti-inflammatory effects of GPR120 are completely arrestin-2
dependent. The apparent mechanism for this is that DHA stimulation leads to GPR120/
arrestin-2 association with subsequent internalization of the complex. The internalized
arrestin-2 then associates with TAB1, stealing it from the TAK1 complex, leading toinactivation of TAK1 with inhibition of downstream inflammatory signaling to IKK/NFB
and JNK/AP1 ((Oh et al., 2010), and Figure 2).
These cellular mechanisms translate to the in vivo situation. Thus, omega 3 FA treatment of
WT obese mice led to marked in vivo anti-inflammatory and insulin sensitizing effects, but
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no such effects were observed in obese GPR120 KO animals. Taken together, it appears that
an important mechanism for the anti-inflammatory effects of omega 3 FAs operates through
the GPR120 signaling pathway in macrophages.
It is possible that additional mechanisms also exist which could participate in the anti-
inflammatory effects of omega 3 FAs. For example, these FAs can be metabolized to small
lipid mediators termed protectins/resolvins and studies have shown that addition of
protectins/resolvins to in vitro systems can produce anti-inflammatory effects (Serhan and
Chiang, 2008; Serhan et al., 2008) (Fig. 1). Furthermore, in vivo studies in mice also
indicate anti-inflammatory effects through the resolvin/protectin system. Finally, omega 3
FAs are metabolized through a variety of lipid biosynthetic pathways and can inhibit the
production of arachidonic acid and other pro-inflammatory eicosanoids.
Palmatoleate
Palmatoleate (C16:1N7) is a nutritional component of many food stuffs and can also be
produced by de novo lipogenesis. Circulating C16:1N7 levels are directly correlated with
insulin sensitivity in mice and that inhibition of C16:1N7 production can cause insulin
resistance (Cao et al., 2008). Based on this work, they suggest that C16:1N7 is a lipokine
secreted from adipocytes that can modulate glucose homeostasis in muscle and liver through
endocrine effects. When added to cells C16:1N7 can produce insulin-like effects and these
may relate to GPR120 in adipocytes. C16:1N7 is a GPR120 agonist and, in adipocytes, it
stimulates glucose transport through a Gq-dependent signaling pathway that leads to
GLUT4 translocation.
Effects of inflammation on lipid metabolism
While the impact of inflammation on gene expression has been studied in a variety of tissues
and cell types, much less is known regarding the influence of inflammation on the vast
repertoire of lipids that function as structural components of cell membranes, sources ofenergy, and signaling molecules. Notable exceptions are provided by the eicosanoids and
inositol phospholipids, which have been subjected to extensive analysis based on their roles
as essential signaling molecules in diverse aspects of development, homeostasis and
immunity. For example, prostaglandins represent a class of eiconsanoids that are generated
from arachidonic acid in membrane phospholipids through the sequential actions of
phospholipase A and cyclooxygenase enzymes. Both classes of enzymes are under direct
control by signaling pathways that respond to PAMPs and inflammatory cytokines, enabling
rapid and robust increases in prostaglandin generation. The resulting prostaglandin
metabolites have diverse biological roles, including amplification of inflammatory responses
that contribute to the cardinal signs of inflammation (redness, heat, pain, swelling). In the
case of the inositol phospholipids, extensive work over the past decade has revealed diverseroles of phosphatidylinositol 3-kinases, particularly PI3Kand PI3K, in responding to
inflammatory signals to orchestrate specific aspects of innate and adaptive immune
responses. These topics have been the focus of recent reviews (Dennis et al., 2011; Fung-
Leung, 2011; Ghigo et al., 2010; Ricciotti and FitzGerald, 2011).
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In contrast, knowledge of effects of inflammation on metabolism of most other classes of
lipids remains at a relatively rudimentary level. In this section, we discuss the impact of
inflammation on lipid metabolism from the perspective of the relationship between
inflammation and metabolic disease. We begin with a brief description of the effects of
innate immunity-driven inflammation on lipid metabolism at the whole body level, and then
consider effects at the organ and cellular level in the liver, adipose tissue, skeletal muscle
and macrophage. We conclude this section with a discussion of the intersection ofinflammatory signaling pathways with transcription factors that control cholesterol and fatty
acid biosynthesis.
Inflammation and lipid metabolism at the whole body level
At the whole body level, inflammation initiated by severe bacterial and viral infection can
result in marked changes in lipid and lipoprotein metabolism. For example, infection with
gram-negative organisms has long been known to induce marked hypertriglyceridemia and
elevated circulating free fatty acid levels (Gallin et al., 1969). Although these changes are
likely to reflect metabolic adaptations that enable the host to resist infection, there is also
evidence that high density lipoproteins (HDL) and triglyceride-rich lipoproteins themselves
function to bind and neutralize bacterial endotoxins (Harris et al., 2000). Experimental
studies using LPS to mimic infection indicate that increases in very low density lipoproteins
(VLDL) account for the majority of the rise in serum triglycerides, resulting from both
increased production and decreased catabolism (Feingold et al., 1992b). The hyperlipidemia
of sepsis was initially considered to be a consequence of catecholamine release, which
stimulate release of free fatty acids from adipose tissue that are taken up by the liver,
metabolized and released in VLDL particles (Nonogaki et al., 1994). In addition, TNF-
was found to suppress lipoprotein lipase synthesis, which could contribute to
hypertriglyceridemia by decreasing the rate of triglyceride clearance in the periphery (Figure
3) (Kawakami et al., 1987). Additional cell-autonomous mechanisms also contribute to
increased lipolysis, as discussed in further detail below.
In addition to the potential roles of SFAs as endogenous activators of TLR signaling, low
levels of endotoxin derived from bowel flora are present in the portal circulation, with levels
varying dependent on various factors, including diet (Amar et al., 2008; Backhed et al.,
2004). The concentration of LPS required to increase VLDL secretion is orders of
magnitude lower than that required to induce sepsis, raising the possibility that endogenous
endotoxins may contribute to low levels of TLR4 activation (Feingold et al., 1992b). A
recent study of TLR4/mice indicated a modestly exaggerated hypoglycemic response to
fasting and elevated levels of circulating and skeletal muscle triglycerides. No effect on
insulin sensitivity was observed, suggesting a role of TLR4 in glucose and lipid metabolism
independent of insulin during fasting.(Pang et al., 2010)
Toll like receptors, including TLR4, are most highly expressed in cells that play direct roles
in innate immune responses, such as macrophages, that are major sources of cytokines and
chemokines in the setting of infection and tissue injury. However, TLRs are also expressed
on a broad range of other cells types, including adipocytes, hepatocytes, and skeletal muscle
cells (e.g., (Lang et al., 2003; Matsumura et al., 2000; Shi et al., 2006)). The expression of
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TLRs in these cells may enable them to complement the functions of specialized immune
cells through, for example, the production of chemokines and cytokines. Recent studies
further suggest that TLR signaling within parenchymal cells of the liver, adipose tissue and
skeletal muscle serves to modulate diverse aspects of their specific roles in metabolism. As
noted above, inhibitory effects of LPS and cytokines such as TNFand IL1on insulin
signaling pathways are well established (reviewed in (Olefsky and Glass, 2010)). Inhibition
of insulin signaling can itself potentially impact on lipid metabolism, but there is substantialevidence that inflammatory signaling pathways affect many aspects of lipid metabolism
independently of their effects on insulin. For example, direct infusion of a relatively low
dose of TNFinto normal human subjects increased whole body lipolysis by 40% and a
corresponding increase of free fatty acids over a 4h time period (Plomgaard et al., 2008). No
changes in glucose homeostasis were observed in this acute treatment protocol.
Because TLR4 signaling stimulates expression of a broad range of cytokines that are linked
to insulin resistance, such as TNFand IL1, it will be of particular interest to tease apart
direct and indirect effects on lipid homeostasis in specific cell types in vivo. Bone marrow
reconstitution experiments, in which wild type bone marrow was replaced with TLR4-
deficient bone marrow, conferred protection against diet/obesity-induced insulin resistance,consistent with important roles in macrophages and other bone marrow-derived cells (Saberi
et al., 2009). However, these studies did not address the effects of hematopoietic deletion of
TLR4 signaling on lipid metabolism.
In addition to contributing to development of insulin resistance, TLRs have been shown to
contribute to the development of atherosclerosis (reviewed in (Coban et al., 2009; Curtiss
and Tobias, 2009; Olefsky and Glass, 2010)). In this context, TLR-driven inflammation is
thought to contribute to pathology by amplifying recruitment of macrophages and other
immune cells to atherosclerotic lesions and to influence processes that promote
modifications of LDL that increase its uptake by macrophages and smooth muscle cells,
such as oxidation (reviewed in (Rocha and Libby, 2009)). As discussed in further detail
below, studies in cell culture models suggest important effects of TLR4 signaling in
hepatocytes, skeletal muscle cells, and adipocytes. Development of a conditional allele of
TLR4 would be a valuable resource for investigation of direct and indirect effects of TLR4
engagement in tissues other than the hematopoietic system.
Inflammation and lipid metabolism in the liver
Early studies of the effects of LPS on lipoprotein metabolism demonstrated that low doses
of LPS stimulated hepatic de novo fatty acid synthesis and lipolysis, both of which provided
a source of fatty acids for the increase in hepatic triglyceride production (Figure 3)
(Feingold et al., 1992b). The molecular basis for this effect, which is observed within a few
hours of LPS treatment, has not been clearly established. Becaues LPS injection inducesnumerous cytokines, including TNFand IL1, effects in liver could be primary responses
to LPS or secondary responses to cytokines, or both. De novo fatty acid biosynthesis is
primarily regulated by sterol response element binding protein 1c (SREBP1c) (reviewed in
(Horton, 2002)). Liver X receptors induce expression of SREBP1c, as well as directly
regulate numerous genes involved in fatty acid biosynthesis and metabolism (Repa et al.,
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2000; Schultz et al., 2000). Increased production of fatty acids would therefore presumably
require activation of the SREBP pathway either at a transcriptional or post-transcriptional
level, but this has not been directly shown in an LPS model. A recent study of TNFin the
livers of fasting mice indicated that TNFinterferes with adaptation to fasting and activates
the insulin-Insig-SREBP signaling pathway (Fon Tacer et al., 2007). Significant alterations
were observed in lipid homeostasis, including reduction of HDL-cholesterol, an increase in
LDL-cholesterol, and elevated expression of cholesterogenic genes. This was accompaniedby an increase of pre-cholesterol metabolites and suppression of cholesterol elimination
through bile acids. At the transcriptional level, a shift in the expression of genes promoting
fatty oxidation toward those involved in fatty acid synthesis was observed. Consistent with
these studies, a different form of inflammatory stress induced by casein injection increased
hepatic cholesterol accumulation and enhanced sterol regulatory element binding protein 2
(SREBP2), low-density lipoprotein receptor (LDLr) and HMGCoA-reductase mRNA and
protein expression in livers of C57BL/6J mice and in HepG2 cells (Ma et al., 2008). In
addition, treatment of HepG2 cells with IL-6 or IL-1increased nuclear SREBP2, increased
HMGCoA reductase protein levels and partially inhibited the normal feedback inhibition of
the cholesterol biosynthetic pathway in response to cholesterol loading (Zhao et al., 2011).
LPS-induced changes in the liver sinusoidal endothelial cells predicted to reduce access ofhepatocytes to circulating lipoproteins has also been suggested to contribute to
hypertriglyceridemia (Cheluvappa et al., 2010). Hepatocyte overexpression of IB kinase
(IKK), the major kinase required for activation of NFB downstream of TLR, TNFand
IL1signaling was recently shown to result in increased VLDL synthesis (van Diepen et al.,
2011), indicating that specific activation of IKKwithin hepatocytes is sufficient to induce
hypertriglyceridemia.
Many questions remain regarding the impact of inflammation on lipid metabolism in the
liver. In particular, defining the mechanisms that connect inflammatory signaling pathways
to altered functions of the SREBPs is of particular interest, as these mechanisms might be
amenable to therapeutic interventions. In addition, there is a very limited understanding ofthe impact of inflammation on specific lipid species within broad lipid categories (fatty
acids, sterols, phospholipids, triglycerides, etc). Inflammatory responses have the potential
to reprogram lipid metabolic pathways so as to change membrane properties, signaling
events, energy utilization, and other basic cellular processes. The outcome of inflammatory
stimuli on lipid metabolism may also be influenced by the sterol and fatty acid composition
of the diet, for example the relative content of -3 and -6 fatty acids.
Inflammation and lipid metabolism in muscle
Recent studies in human skeletal muscle, rodent skeletal muscle, and skeletal muscle cell
cultures using both gain and loss of function approaches provided evidence that TLR4
signaling reduces fatty acid oxidation (Frisard et al., 2010; Pang et al., 2010) and that actions
in muscle may contribute to increased circulating triglycerides (Figure 3). Fasting animals
with a loss of TLR4 function exhibited increased oxidative capacity in skeletal muscle,
lower levels of triglycerides and non-esterified free fatty acids. Changes in substrate
metabolism under conditions of low (metabolic) LPS concentrations were suggested to be
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independent of skeletal muscle-derived pro-inflammatory cytokine production (Frisard et al.,
2010).
One important consequence of inflammatory signaling in muscle is an increase in
production of ceramide, which as discussed above, may be a key intermediate that links
inflammation to insulin resistance by blocking activation of Akt/PKB. Studies in c2c12
myoblasts indicated that the LPS or saturated fatty acid-induced ceramide production was
associated with IKK-dependent upregulation of genes driving ceramide biosynthesis.
Importantly, increased ceramide production was not required for TLR4-dependent induction
of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance
(Holland et al., 2011).
Interleukin (IL)-6 is an inflammatory cytokine that is chronically elevated in type 2 diabetes
but also during exercise. Acute (4h) infusion of physiological concentrations of IL4 into
healthy human subjects had no effects on glucose levels but increased systemic fatty acid
oxidation approximately twofold after 60 min, which remained elevated by 2h after the
infusion (Wolsk et al., 2010). The increase in oxidation was followed by an increase in
systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged, but
skeletal muscle unidirectional fatty acid and glycerol release was increased, indicative of an
increase in lipolysis. The increased lipolysis in muscle could account for the systemic
changes. These effects in muscle were correlated with activation of STAT3, a downstream
target of IL-6, whereas no changes in phosphorylated AMP-activated protein kinase or
acetyl-CoA carboxylase levels could be observed. Il-6 could thus contribute to some of the
observed changes in skeletal muscle lipid metabolism seen in the context of TLR4
activation, acting as an autocrine factor or as a paracrine/endocrine factor released by
immune cells such as macrophages.
As in the case of the liver, inflammation induces substantial changes in fatty acid
metabolism in skeletal muscle, but the mechanisms remain very poorly understood and the
impact on classes of lipids beyond fatty acids and ceramides have not been extensively
evaluated. The differential effects of LPS and IL-6 signaling underscore the complex nature
of the inflammatory response, which rather than being a single entity evolves as a highly
variable and context dependent process. IL-6 signaling exerts effects on gene expression by
controlling phosphorylation of STAT3. Intriguingly, STAT3 has been shown to directly
regulate the activities of the mitochondrial electron transport chain in liver and heart, which
could provide a connection between effects of IL-6 signaling and fatty acid oxidation in
skeletal muscle (Wegrzyn et al., 2009).
Inflammation and lipid metabolism in adipose tissue
LPS, TNFand IL1induce lipolysis in primary adipocytes and adipocyte cell lines,indicating a cell-autonomous effect that can act independently of catecholamine- induced
lipolysis (Figure 3) (Feingold et al., 1992a; Franchini et al., 2010; Kawakami et al., 1987;
Ryden et al., 2002; Zhang et al., 2002; Zu et al., 2008). Inhibitor studies suggest that TNF
increases lipolysis in adipocytes by activation of mitogen-activated protein kinase kinase
(MEK), extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK) and
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elevation of intracellular cAMP leading to activation of PKA, with some variations in
relative importance observed dependent on the specific cellular system used (Ryden et al.,
2002; Zhang et al., 2002). PKA activation directly affects lipolysis by phosphorylating the
lipid droplet associated protein perilipin (Granneman et al., 2007). This results in release of
CGI-58/Abhd5, which binds to and co-activates adipose triglyceride lipase (ATGL)
(Granneman et al., 2009). ATGL has recently been shown to be the major lipase responsible
for TNF-induced lipolysis in 3T3L1 adipocytes (Yang et al., 2011). These studies alsoprovided evidence that TNFsignaling profoundly suppresses the expression of G0S2, a
recently identified endogenous inhibitor of ATGL. Thus, TNFsignaling acts
simultaneously to stimulate activators and suppress inhibitors of ATGL activity. Given the
central importance of triglyceride hydrolysis in adipose tissue, liver and skeletal muscle in
overall fatty acid metabolism, it will be of great interest to explore the importance of these
regulatory pathways in each tissue in vivo. Intriguingly, salicylates block the lipolytic
response to TNF (Zu et al., 2008), an effect that may contribute to their insulin-sensitizing
activities.
The production of TNFand IL1could potentially account for the effects of LPS on
adipose tissue lipolysis , but the use of adrenergic or interleukin-1 receptor antagonists andTNF-neutralizing antibodies did not abolish increases in serum levels of FFA and
triglycerides in endotoxemic rats (Feingold et al., 1992b; Nonogaki et al., 1994). Notably,
neither adipocytokine secretion nor NFB activation is involved in endotoxin-induced
lipolysis (Zu et al., 2009). In contrast to catecholamines and TNF, endotoxin stimulates
lipolysis without elevating cAMP production and activating protein kinase A and protein
kinase C. Instead, endotoxin induces phosphorylation of Raf-1, MEK1/2, and ERK1/2.
Upon inhibition of ERK1/2 but not JNK and p38 MAPK, endotoxin-stimulated lipolysis
ceases. Endotoxin causes down-regulation and phosphorylation of perilipin, which would be
expected to result in activation of ATGL by CGI-58.
Intriguingly, recent studies have found that deletion of BLT1, a receptor for leukotriene B4
(LTB4), protects mice from high fat diet-induced insulin resistance (Spite et al., 2011).
BLT1-deficient mice exhibited a marked reduction in accumulation of classically activated
adipose tissue macrophages and a reduction in pro-inflammatory cytokines. Although LTB4
itself was not directly measured in these assays, these findings suggest that the pro-
inflammatory response of adipose tissue to a high fat diet results in LTB4 production from
arachidonic acid, which serves to recruit LTB4-positive monocytes into adipose tissue.
Pharmacological blockade of BLT1 might thus have insulin-sensitizing effects in the context
of obesity.
Interferon regulatory factor 4 (IRF4), which plays key roles in regulation of function of
immune cells, was recently shown to regulate the transcriptional response to nutrient
availability in adipocytes. Fasting induces IRF4 in an insulin- and FoxO1-dependent
manner. IRF4 is required for lipolysis, at least in part due to direct effects on the expression
of ATGL and hormone-sensitive lipase. Conversely, reduction of IRF4 enhances lipid
synthesis (Eguchi et al., 2011).
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The extent to which inflammation-driven lipolysis in adipose tissue contributes to insulin
resistance remains to be clearly established. The influence of free fatty acids on
inflammation, described above, and the proximity of adipose tissue macrophages to
lipolysis-generated FFAs suggests the possibility of a local positive feedback loop that
amplifies insulin resistance. It will therefore be of interest to evaluate the consequences of
inhibiting lipolysis on inflammation and insulin resistance in vivo.
Inflammation and lipid metabolism in the macrophage
Based on the key pathogenic roles of macrophages and TLRs in the development of
atherosclerosis (Moore and Tabas, 2011) and diabetes (Olefsky and Glass, 2010), the LIPID
MAPS consortium recently reported a comprehensive analysis of the effects of TLR4
signaling on the lipidome and transcriptome of RAW264.7 macrophages (Dennis et al.,
2010). These studies demonstrated immediate responses in fatty acid metabolism,
represented by increases in eicosanoid synthesis, and delayed responses characterized by
alterations in sphingolipid and sterol biosynthesis. TLR4 activation generated increases in
almost every category of sphingolipid analyzed, including free sphingoid bases and their
phosphates (e.g. sphingosine- 1-phosphate), ceramides, sphingomyelins, and
glycosphingolipids. It would not be surprising for inflammatory signaling to have similar
effects on the lipidomes of other metabolically important cell types, including adipocytes,
hepatocytes and skeletal muscle cells. Consistent with this, the impact of TLR4 signaling on
ceramide production in RAW264.7 cells and C2C12 skeletal muscle cells is similar (Holland
et al., 2011). Notably, lipid remodeling of glycerolipids, glycerophospholipids, and prenols
was also observed in activated RAW264.7 cells, indicating that TLR4 signaling leads to
alterations in a majority of mammalian lipid categories (Dennis et al., 2010). Thus, it is
likely that extension of these methods to primary cells and tissues would be highly
informative. Along these lines, a recent lipidomic analysis of adipose tissue macrophages
from ob/ob mice indicates that macrophage triglycerides accumulate during the transition
from insulin-sensitive to obese/insulin resistance. Treatment with a PPARagonist
prevented triglyceride accumulation in these cells (Prieur et al., 2011).
Signaling pathways that connect inflammation to lipid metabolism
The TLR, IL1and TNFsignaling pathways are best understood with respect to their roles
in initiation and amplification of innate immune responses through the activation of latent
transcription factors that include members of the NFB, AP-1, and IRF gene families. Much
less is known, however, with respect to the mechanisms by which inflammatory signaling
pathways affect lipid metabolism. Regulation of post-translational modifications, e.g.,
perilipin phosphorylation, is likely to play an important role. In addition, significant effects
of inflammatory signaling pathways on the expression and function of transcription factors
that regulate lipid homeostasis have been identified. For example, TLR4 activation is apotent suppressor of PPARexpression in the macrophage (Barish et al., 2005), and TLR3
and TLR4 inhibit LXR function by a mechanism that involves the TRIF adapter protein
(Castrillo et al., 2003). It will be of interest to explore whether inflammatory signaling
influences the expression or processing of the SREBP transcription factors that play central
roles in fatty acid and cholesterol biosynthesis. A large number of other transcription factors
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also influence lipid metabolism, including PPAR, PPAR, Forkhead transcription factors,
KLFs and others. The emergence of sensitive and quantitative methods to measure major
and minor lipid species by mass spectroscopy, coupled with genome-wide measurement of
gene expression, are likely to important new insights into the relationships between
inflammation, lipid metabolism and disease in the years ahead.
Conclusions
Striking progress has been made in the last few years in deconvoluting the complex
relationships between lipid metabolism and inflammation that contribute to metabolic
disease. In particular, new molecular mechanisms accounting for pro-inflammatory effects
of saturated FFAs and anti-inflammatory effects of -3 PUFAs have been discovered. In
addition, the production of ceramide in response to inflammatory signaling in skeletal
muscle and macrophages is emerging as an important mechanism contributing to insulin
resistance. At the level of the impact of inflammation on lipid metabolism, recent studies
have uncovered likely molecular mechanisms by which inflammatory mediators such as
LPS and TNFfunction to stimulate lipolysis in adipose tissue, through the indirect
regulation of ATGL. Studies extending the analysis of these mechanisms in vivo should be
productive lines of investigation for the future. Many aspects of the relationship between
inflammation and lipid metabolism remain poorly understood. In particular, mechanisms by
which inflammatory signaling regulates the functions of SREBPs, LXRs and PPARs remain
almost completely unknown, and are potential targets for therapeutic intervention. The
ability to investigate the extent to which inflammation reprograms lipid metabolism to alter
the production, catabolism and inter-conversion of specific lipid species has until recently
been significantly limited by technology. The recent development of improved
instrumentation and methodologies for analysis of diverse lipid species by mass
spectrometry is now enabling substantial efforts to understand how the lipidome is regulated
at a more global level. It will be of particular interest to bring the combination of lipidomics
and transcriptomics to the analysis of the impact of dietary interventions on lipid metabolismin key metabolic organs. Fatty acid composition of the diet can vary widely, from being
relatively high in saturated (animal-derived) FFAs such as palmitic acid that have direct pro-
inflammatory effects, to relatively high in -6 (e.g., corn oil-derived) FFAs such as linoleic
acid that can be further elongated, de-saturated and converted to pro-inflammatory
prostaglandins, to relatively high in -3 (e.g., fatty fish and certain seed oil-derived) FFAs
that exert anti-inflammatory effects. As there is now substantial interest in the agricultural
and food products industries to develop new food oils and food products with increased
levels of -3 PUFAs, the rationale, specific form and advisability of these efforts should rest
on a deeper knowledge of the relationship between lipid metabolism, inflammation and
disease.
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Figure 1. The effects of fatty acids on inflammation and insulin resistance
Saturated fatty acids (SFAs) stimulate inflammatory pathways through Tlr4 dependent and
independent mechanisms. SFAs are also precursors for ceramide biosynthesis, and
inflammatory pathway stimulation by SFAs, as well as cytokines, induces the enzymes
which produce ceramide, providing two mechanisms for increased ceramide content. Omega
3 FAs produce anti-inflammatory effects by stimulating GPR120 and production of
resolvins and protectins. Omega 6 FAs can be proinflammatory through their metabolism to
leukotrienes and prostaglandins.
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Figure 2.
(A) Tlr4 and TNF receptor signaling stimulates the TAK1/TAB1 complex which then
activates IKKand MKK4 to stimulate the downstream NFB and JNK1 inflammatorypathways. (B) Omega 3 FAs activate GPR120 causing it to associate with arrestin-2. The
GPR120arrestin-2 complex then undergoes endocytosis and the internalized arrestin-2
binds to TAB1, stealing it from the TAK1 complex, causing TAK1 inactivation with
inhibition of subsequent downstream proinflammatory signaling. Adapted from (Oh et al.,
2010).
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Figure 3.
Impact of inflammation on lipid metabolism. Inducers and amplifiers of inflammation
include ligands for pattern recognition receptors (e.g. LPS), cytokines (e.g., Il1) and
saturated fatty acids (SFAs). Each of these inflammatory stimuli influence lipid metabolism
in liver, skeletal muscle and adipose tissue by acting on both parenchymal cells and resident
immune cells. Although some effects are seen in all three organs (e.g., increased TG
hydrolysis), other effects may be organ-specific (e.g., increased fatty acid biosynthesis in
liver).
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