inflammation and lipid signal.pdf

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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).

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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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