at the intersection of metabolism and inflammation that contribute to diabetes. the obesity-linked inflammatory diseases diabetes, fatty liver dis …
Review
Inflammation, stress, and diabetes
Kathryn E Wellen and Gökhan S Hotamisligil
Department of Genetics Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
Over the last decade, an abundance of evidence has emerged demonstrating a close link between metabolism and immunity It is now clear that obesity is associated with a state of chronic low-level inflammation In this article, we discuss the molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes We also consider mechanisms through which the inflammatory response may be initiated and discuss the reasons for the inflammatory response in obesity We put forth for consideration some hypotheses regarding important unanswered questions in the field and suggest a model for the integration of inflammatory and metabolic pathways in metabolic disease
Inflammation, stress, and diabetes Survival of multicellular organisms depends on the ability to fight infection and heal damage and the ability to store energy for times of low nutrient availability or high energy need Metabolic and immune
systems are therefore among the most basic requirements across the animal kingdom, and many nutrient and pathogen-sensing systems have been highly conserved from organisms such as Caenorhabditis elegans and Drosophila to mammals Perhaps not surprisingly, metabolic and immune pathways have also evolved to be closely linked and interdependent Many hormones, cytokines, signaling proteins, transcription factors, and bioactive lipids can function in both metabolic and immune roles In addition to using some of the same cellular machinery, metabolic and immune systems also regulate each other The normal inflammatory response relies upon metabolic support, and energy redistribution, particularly the mobilization of stored lipid, plays an important role in fighting infection during the acute-phase response 1 The basic inflammatory response thus favors a catabolic state and suppresses anabolic pathways, such as the highly conserved and powerful insulin signaling pathway The integration of metabolism and immunity, which under normal conditions is beneficial for the maintenance of good health, can become deleterious under conditions of metabolic challenge, as exemplified by the
immunosuppression characteristic of malnourished or starving individuals 13 Famine has been a prominent hazard to human health throughout history, and for thousands of years the link between infection and poor nutrition has been well recognized Today this threat is as widespread as ever, and there are approximately 1 billion undernourished individuals worldwide 3 In the past century, however, the pendulum has also swung in the opposite direction, and now as many if not more people are overweight or obese 4 With the advent of this chronic metabolic overload, a new set of problems and complications at the intersection of metabolism and immunity has emerged, including the obesity-linked inflammatory diseases diabetes, fatty liver disease, airway inflammation, and atherosclerosis 5 There is now a wealth of evidence indicating close ties between metabolic and immune systems Among the many reasons to
Nonstandard abbreviations used: AP-1, activator protein1; DAG, diacylglycerol; FABP, fatty acidbinding protein; IB, inhibitor of NF-B; IKK, inhibitor of NF-B kinase; IRS, insulin receptor substrate; JIP1, JNK-interacting protein1; LXR, liver X receptor; TLR, Toll-like receptor; TZD,
thiazolidinedione Conflict of interest: The authors have declared that no conflict of interest exists Citation for this article: J Clin Invest 115:11111119 2005 doi:101172/JCI200525102
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maintain a healthy weight is the emerging paradigm that metabolic imbalance leads to immune imbalance, with starvation and immunosuppression on one end of the spectrum and obesity and inflammatory diseases on the other end Figure 1 In this article, we will discuss the molecular and cellular links between metabolism and inflammation, particularly in the context of obesity and diabetes Common inflammatory mediators, stress responses, and signaling pathways will be highlighted Finally, we will consider the origin of and the reasons for the inflammatory response in obesity Obesity is characterized by inflammation Factors at the crossroads of inflammation and metabolic disease A little more than a decade ago, the first molecular link between inflammation and obesity — TNF- — was identified when it was discovered that this inflammatory cytokine is overexpressed in the adipose tissues of rodent models of obesity 6, 7 As is the case in mice, TNF- is overproduced in
the adipose as well as muscle tissues of obese humans 810 Administration of recombinant TNF- to cultured cells or to whole animals impairs insulin action, and obese mice lacking functional TNF- or TNF receptors have improved insulin sensitivity compared with wild-type counterparts 6, 11 Thus, particularly in experimental models, it is clear that overproduction of TNF- in adipose tissue is an important feature of obesity and contributes significantly to insulin resistance It rapidly became clear, however, that obesity is characterized by a broad inflammatory response and that many inflammatory mediators exhibit patterns of expression and/or impact insulin action in a manner similar to that of TNF- during obesity, in animals ranging from mice and cats to humans 1214 Transcriptional profiling studies have revealed that inflammatory and stress-response genes are among the most abundantly regulated gene sets in adipose tissue of obese animals 1517 A list of many of these genes, which have been identified through a variety of approaches, is provided in Table 1 In addition to inflammatory cytokines regulating metabolic homeostasis, molecules that are typical of adipocytes, with
well-established metabolic functions, can regulate the immune response Leptin is one such hormone that plays important roles in both adaptive and innate immunity, and both mice and humans lacking leptin function exhibit impaired immunity 1820 Indeed, reduced leptin levels may be responsible, at least in part, for immunosuppression associated with starvation, as leptin administration has been shown to reverse the immunosuppression of mice starved for 48 hours 21 Adiponectin, resistin, and visfatin are
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Figure 1
Metabolism and immunity are closely linked Both overnutrition and undernutrition have implications for immune function Starvation and malnutrition can suppress immune function and increase susceptibility to infections Obesity is associated with a state of aberrant immune activity and increasing risk for associated inflammatory diseases, including atherosclerosis, diabetes, airway inflammation, and fatty liver disease Thus, optimal nutritional and metabolic homeostasis is an important part of appropriate immune function and good health
also examples of molecules with immunological activity that are produced in
adipocytes 2226 Finally, lipids themselves also participate in the coordinate regulation of inflammation and metabolism Elevated plasma lipid levels are characteristic of obesity, infection, and other inflammatory states Hyperlipidemia in obesity is responsible in part for inducing peripheral tissue insulin resistance and dyslipidemia and contributes to the development of atherosclerosis It is interesting to note that metabolic changes characteristic of the acute-phase response are also proatherogenic; thus, altered lipid metabolism that is beneficial in the short term in fighting against infection is harmful if maintained chronically 1 The critical importance of bioactive lipids is also evident in their regulation of lipid-targeted signaling pathways through fatty acidbinding proteins FABPs and nuclear receptors see Regulation of inflammatory pathways, below Macrophages and the link between inflammation and metabolism The high level of coordination of inflammatory and metabolic pathways is highlighted by the overlapping biology and function of macrophages and adipocytes in obesity Figure 2 Gene expression is highly similar; macrophages express many, if not the majority of
adipocyte gene products such as the adipocyte/macrophage FABP aP2 also known as FABP4 and PPAR, while adipocytes can express many macrophage proteins such as TNF-, IL-6, and MMPs 6, 2729 Functional capability of these 2 cell types also overlaps Macrophages can take up and store lipid to become atherosclerotic foam cells Preadipocytes under some conditions can exhibit phagocytic and antimicrobial properties and appear to even be able to differentiate into macrophages in the right environment, which suggests a potential immune role for preadipocytes 30, 31 Furthermore, macrophages and adipocytes colocalize in adipose tissue in obesity The recent finding that obesity is characterized by macrophage accumulation in white adipose tissue has added another dimension to our understanding of the development of adipose tissue inflammation in obesity 16, 17 Macrophages in adipose tissue are likely to contribute to the production of inflammatory mediators either alone or in concert with adipocytes, which suggests a potentially important influence of
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macrophages in promoting insulin resistance However, no direct evidence has been offered to establish
this connection thus far In terms of the immune response, integration between macrophages and adipocytes makes sense, given that both cell types participate in the innate immune response: macrophages in their role as immune cells by killing pathogens and secreting inflammatory cytokines and chemokines; and adipocytes by releasing lipids that may modulate the inflammatory state or participate in neutralization of pathogens While it is not yet known whether macrophages are drawn to adipose tissue in other inflammatory conditions, it is conceivable that macrophage accumulation in adipose tissue is a feature not only of obesity, but of other inflammatory states as well Inflammatory pathways to insulin resistance As discussed above, it is now apparent that obesity is associated with a state of chronic, low-grade inflammation, particularly in white adipose tissue How do inflammatory cytokines and/or fatty acids mediate insulin resistance? How do the stresses of obesity manifest inside of cells? In recent years, much has been learned about the intracellular signaling pathways activated by inflammatory and stress responses and how these pathways intersect with and inhibit insulin signaling
Insulin affects cells through binding to its receptor on the surface of insulin-responsive cells The stimulated insulin receptor phosphorylates itself and several substrates, including members of the insulin receptor substrate IRS family, thus initiating downstream signaling events 32, 33 The inhibition of signaling downstream of the insulin receptor is a primary mechanism through which inflammatory signaling leads to insulin resistance Exposure of cells to TNF- or elevated levels of free fatty acids stimulates inhibitory phosphorylation of serine residues of IRS-1 3436 This phosphorylation reduces both tyrosine phosphorylation of IRS-1 in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby inhibits downstream signaling and insulin action 35, 37, 38 Recently it has become clear that inflammatory signaling pathways can also become activated by metabolic stresses originating
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Table 1 Factors that mediate the intersection of metabolism and immunity
Factors TNF- IL-6 Metabolic regulation in obesity S1, S2A in obesity S6, S7 Effects Mouse model LOF S4, GOF S5 LOF S10, GOF S11 LOF
S12
Promotes insulin resistance S1, S3 Promotes insulin resistance; central anti-obesity action S8S11 Leptin in obesity S12 Multiple effects on immune function; suppresses appetite; promotes FA oxidation S12S14 Adiponectin in obesity S15 Antiinflammatory; promotes insulin sensitivity; stimulates FA oxidation S15, S16 Visfatin in obesity S20 Early B cell growth factor; insulin mimetic S20, S21 Resistin Variable in obesity S22, S23 Induced in endotoxemia/inflammation; promotes insulin resistance; regulates fasting blood glucose level S23S26 IL-1 by hyperglycemia S28 Proinflammatory; regulates insulin secretion; involved in central leptin action S29, S30 IL-1R in obesity S31 Antiinflammatory; opposes leptin action S29 IL-8 in obesity S32 Proatherogenic S33, S34 IL-10 in obesity; in metabolic syndrome S35 Antiinflammatory; promotes insulin sensitivity S36 IL-18 in obesity S37, S38 Proatherogenic S39, S40 MCP-1 in obesity S41 Proatherogenic; promotes insulin resistance S34, S41, S42 MIF in obesity S43 Inhibits macrophage migration M-CSF Monocyte/macrophage differentiation; stimulates adipose growth S44 TGF- in obesity S45, S46 Inhibits adipocyte differentiation and adipose
tissue development; regulates atherosclerosis S47S49 Soluble TNFR in obesity S52S54 Proinflammatory C-reactive protein in obesity S55, S56 Proinflammatory; atherogenic; risk factor for diabetes S55, S57S59 Haptoglobin in obesity S60 Proinflammatory
LOF S17, GOF S18, S19
LOF S20 LOF S24, GOF S25, S27
LOF S30
LOF S33
LOF S40 GOF S39 LOF S42
GOF S44 LOF S50, S51, GOF S49
GOF S57
, increase; , decrease; FA, fatty acid; GOF, gain-of-function; IL-1R, IL-1 receptor ; LOF, loss-of-function; MCP-1, monocyte chemotactic protein-1; MIF, macrophage migration inhibitory factor; TNFR, TNF receptor ASee Supplemental References; supplemental material available online with this article; doi:101172/JCI200525102DS1
from inside the cell as well as by extracellular signaling molecules It has been demonstrated that obesity overloads the functional capacity of the ER and that this ER stress leads to the activation of inflammatory signaling pathways and thus contributes to insulin resistance 3941 Additionally, increased glucose metabolism can lead to a rise in mitochondrial production of ROS ROS production is elevated in obesity, which causes enhanced activation of inflammatory pathways 42, 43
Several serine/threonine kinases are activated by inflammatory or stressful stimuli and contribute to inhibition of insulin signaling, including JNK, inhibitor of NF-B kinase IKK, and PKC- 44 Again, the activation of these kinases in obesity highlights the overlap of metabolic and immune pathways; these are the same kinases, particularly IKK and JNK, that are activated in the innate immune response by Toll-like receptor TLR signaling in response to LPS, peptidoglycan, double-stranded RNA, and other microbial products 45 Hence it is likely that components of TLR signaling pathways will also exhibit strong metabolic activities JNK The 3 members of the JNK group of serine/threonine kinases, JNK-1, -2, and -3, belong to the MAPK family and
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regulate multiple activities in development and cell function, in large part through their ability to control transcription by phosphorylating activator protein1 AP-1 proteins, including c-Jun and JunB 46 JNK has recently emerged as a central metabolic regulator, playing an important role in the development of insulin resistance in obesity 47 In response to stimuli such as ER stress, cytokines, and fatty acids,
JNK is activated, whereupon it associates with and phosphorylates IRS-1 on Ser307, impairing insulin action 36, 39, 48 In obesity, JNK activity is elevated in liver, muscle, and fat tissues, and loss of JNK1 prevents the development of insulin resistance and diabetes in both genetic and dietary mouse models of obesity 47 Modulation of hepatic JNK1 in adult animals also produces systemic effects on glucose metabolism, which underscores the importance of this pathway in the liver 49 The contribution of the JNK pathway in adipose, muscle, or other tissues to systemic insulin resistance is currently unclear In addition, a mutation in JNK-interacting protein1 JIP1, a protein that binds JNK and regulates its activity, has been identified in diabetic humans 50 The phenotype of the JIP1 loss-of-function model is very
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to lipid infusion, high-fat diet, or genetic obesity 59, 60 Moreover, inhibition of IKK in human diabetics by high-dose aspirin treatment also improves insulin signaling, although at this dose, it is not clear whether other kinases are also affected 61 Recent studies have also begun to tease out the importance of IKK
in individual tissues or cell types to the development of insulin resistance Activation of IKK in liver and myeloid cells appears to contribute to obesity-induced insulin resistance, though this pathway may not be as important in muscle 6264 Other pathways In addition to serine/ threonine kinase cascades, other pathways contribute to inflammation-induced insulin resistance For example, at least 3 members of the SOCS family, SOCS1, -3, and -6, have been implicated in cytokineFigure 2 Lipids and inflammatory mediators: integration of metabolic and immune responses in adipocytes mediated inhibition of insulin signaling and macrophages through shared mechanisms Under normal conditions, adipocytes store 6567 These molecules appear to inhibit lipids and regulate metabolic homeostasis, and macrophages function in the inflammatory insulin signaling either by interfering with response, although each cell type has the capacity to perform both functions In obesity, adi- IRS-1 and IRS-2 tyrosine phosphorylation pose tissue becomes inflamed, both via infiltration of adipose tissue by macrophages and as a or by targeting IRS-1 and IRS-2 for proresult of adipocytes themselves becoming producers
of inflammatory cytokines Inflammation of teosomal degradation 65, 68 SOCS3 has adipose tissue is a crucial step in the development of peripheral insulin resistance In addition, in proatherosclerotic conditions such as obesity and dyslipidemia, macrophages accumulate lipid also been demonstrated to regulate central to become foam cells Adipocytes and macrophages share common features such as expres- leptin action, and both whole body reducsion of cytokines, FABPs, nuclear hormone receptors, and many other factors As evidenced by tion in SOCS3 expression SOCS3/ and genetic loss-of-function models, adipocyte/macrophage FABPs modulate both lipid accumula- neural SOCS3 disruption result in resistion in adipocytes and cholesterol accumulation in macrophages, as well as the development tance to high-fat dietinduced obesity and of insulin resistance and atherosclerosis PPAR and LXR pathways oppose inflammation and insulin resistance 69, 70 promote cholesterol efflux from macrophages and lipid storage in adipocytes Inflammatory cytokine stimulation can also lead to induction of iNOS Overproduction of nitric oxide also appears to similar to that of JNK1 deficiency in mice, with reduced JNK
contribute to impairment of both muscle cell insulin action and activity and increased insulin sensitivity 51 Interestingly, the cell function in obesity 71, 72 Deletion of iNOS prevents JNK2 isoform plays a significant nonredundant role in athero- impairment of insulin signaling in muscle caused by a high-fat sclerosis 52, though apparently not in type 2 diabetes Recent diet 72 Thus, induction of SOCS proteins and iNOS represtudies in mice demonstrate that JNK inhibition in established sent 2 additional and potentially important mechanisms that diabetes or atherosclerosis might be a viable therapeutic avenue contribute to cytokine-mediated insulin resistance It is likely for these diseases in humans 52, 53 that additional mechanisms linking inflammation with insulin PKC and IKK Two other inflammatory kinases that play a large resistance remain to be uncovered role in counteracting insulin action, particularly in response to lipid metabolites, are IKK and PKC- Lipid infusion has been Regulation of inflammatory pathways demonstrated to lead to a rise in levels of intracellular fatty acid Lipids and lipid targets The role of lipids in metabolic disease is commetabolites, such as
diacylglycerol DAG and fatty acyl CoAs plex As discussed above, hyperlipidemia leads to increased uptake This rise is correlated with activation of PKC- and increased of fatty acids by muscle cells and production of fatty acid metabSer307 phosphorylation of IRS-1 54 PKC- may impair insu- olites that stimulate inflammatory cascades and inhibit insulin lin action by activation of another serine/threonine kinase, signaling 54 On the other hand, intracellular lipids can also IKK, or JNK 55 Other PKC isoforms have also been reported be antiinflammatory Ligands of the liver X receptor LXR and to be activated by lipids and may also participate in inhibition PPAR families of nuclear hormone receptors are oxysterols and fatty acids, respectively, and activation of these transcription facof insulin signaling 56 IKK can impact on insulin signaling through at least 2 path- tors inhibits inflammatory gene expression in macrophages and ways First, it can directly phosphorylate IRS-1 on serine resi- adipocytes, in large part through suppression of NF-B 7379 dues 34, 57 Second, it can phosphorylate inhibitor of NF-B LXR function is also regulated by innate immune pathways IB, thus activating NF-B,
a transcription factor that, among Signaling from TLRs inhibits LXR activity in macrophages, causother targets, stimulates production of multiple inflammatory ing enhanced cholesterol accumulation and accounting, at least mediators, including TNF- and IL-6 58 Mice heterozygous in part, for the proatherogenic effects of infection 80 Indeed, for IKK are partially protected against insulin resistance due lack of MyD88, a critical mediator of TLR signaling, reduces
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Figure 3
Nutrient and pathogen sensing or response systems have important overlapping features, and their modulation by obesity or infection can lead to overlapping physiological outcomes For example, the chronic inflammation of obesity leads to elevated plasma lipid levels and the development of insulin resistance, eventually resulting in fatty liver disease, atherosclerosis, and diabetes Infection typically leads to a more transient and robust inflammatory response and short-term hyperlipidemia that aids in the resolution of the infection In some circumstances of chronic infection, however, insulin resistance, diabetes, and
atherosclerosis can result
atherosclerosis in apoE/ mice 81 Interestingly, despite the inhibitory effects of TLR signaling on LXR cholesterol metabolism, LXR appears to be necessary for the complete response of macrophages to infection In the absence of LXR, macrophages undergo accelerated apoptosis and are thus unable to appropriately respond to infection 82 Unliganded PPAR also seems to have proinflammatory functions, mediated at least in part through its association with the transcriptional repressor B cell lymphoma 6 BCL-6 83 The activity of these lipid ligands is influenced by cytosolic FABPs Animals lacking the adipocyte/macrophage FABPs ap2 and mal1 are strongly protected against type 2 diabetes and atherosclerosis, a phenotype reminiscent of that of thiazolidinedione-treated TZD-treated mice and humans 27, 84, 85 One mechanism for this phenotype is potentially related to the availability of endogenous ligands for these receptors that stimulate storage of lipids in adipocytes and suppress inflammatory pathways in macrophages 86 In general, it appears that location in the body, the composition of the surrounding cellular environment, and coupling to target signaling pathways
are critical for determining whether lipids promote or suppress inflammation and insulin resistance Accumulation of cholesterol in macrophages promotes atherosclerosis and of lipid in muscle and liver promotes insulin resistance, while, as seen in TZDtreated and FABP-deficient mice, if lipids are forced to remain in adipose tissue, insulin resistance in the context of obesity can be reduced 85 Thus, lipids and their targets clearly play both metabolic and inflammatory roles; however, the functions that they assume are dependent on multiple factors Pharmacological manipulation of inflammation In corroboration of genetic evidence in mice that loss of inflammatory mediators or signaling molecules prevents insulin resistance 11, 47, 59, pharmacological targeting of inflammatory pathways also improves insulin action Effective treatment has been demonstrated both with inhibitors of inflammatory kinases and with agonists of relevant transcription factors As discussed above, salicylates promote insulin signaling by inhibiting inflammatory kinase cascades within the cell Through inhibition of IKK and possibly other kinases, salicylates are able to improve glucose metabolism in both obese
mice and diabetic humans 53, 55, 74 Targeting of JNK using a synthetic inhibitor and/or an inhibitory peptide has been demonstrated to improve insulin
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action in obese mice and reduce atherosclerosis in the apoE-deficient rodent model 52, 53 These results directly demonstrate the therapeutic potential of JNK inhibitors in diabetes Synthetic ligands have been produced to all 3 PPAR isoforms as well as LXR-, though only PPAR and PPAR ligands have been approved for clinical treatment 87, 88 TZDs, high-affinity ligands of PPAR, which are given clinically as insulin-sensitizing agents, likely improve insulin action through multiple mechanisms, including both activating lipid metabolism and reducing production of inflammatory mediators such as TNF- 85, 8993 Synthetic PPAR ligands, fibrates, are used to treat hyperlipidemia These drugs appear to work predominantly through stimulation of fatty acid oxidation, though they also have antiinflammatory actions that contribute to their effects 87, 94 LXR ligands have been demonstrated to improve glucose metabolism in experimental animals 88, and it remains to be seen whether suppression of inflammation
contributes to this action In targeting inflammation to treat insulin resistance and diabetes, it is possible that seeking inhibitors for individual inflammatory mediators may not be a maximally effective strategy, as other redundant components may be sufficient to continue to propagate inflammatory pathways For example, targeting individual inflammatory cytokines may not be highly effective, whereas targeting the inflammatory kinases JNK and IKK generates a robust antidiabetic action because these factors integrate signals from multiple inflammatory mediators On the other hand, if a more central process or mediator can be identified, this may provide an even more attractive target The ER stress pathway could potentially be one such central process, in that this pathway is able to activate both JNK and IKK; thus, inhibiting the ER stress response through addition of chaperones or other mechanisms could potentially disable both of these arms of the inflammatory response and rescue insulin action 39 It has recently been demonstrated that mice in which the chaperone ORP150 is transgenically or adenovirally overexpressed exhibited reduced ER stress and improved insulin tolerance
compared with controls, whereas reduction of the expression of this molecule in liver results in increased ER stress and insulin resistance 40, 41 Origin of inflammation in obesity While we are now aware of many of the inflammatory factors that mediate insulin resistance and have some understanding of the intracellular pathways involved, there is still much that remains
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Figure 4
Model of overlapping metabolic and inflamm 
atory signaling and sensing pathways in adipocytes or macrophages Inflammatory pathways can be initiated by extracellular mediators such as cytokines and lipids or by intracellular stresses such as ER stress or excess ROS production by mitochondria Signals from all of these mediators converge on inflammatory signaling pathways, including the kinases JNK and IKK These pathways lead to the production of additional inflammatory mediators through transcriptional regulation as well as to the direct inhibition of insulin signaling Other pathways such as those mediated through the SOCS proteins and iNOS are also involved in inflammation-mediated inhibition of insulin action Opposing the inflammatory pathways are
transcription factors from the PPAR and LXR families, which promote nutrient transport and metabolism and antagonize inflammatory activity More proximal regulation is provided by FABPs, which likely sequester ligands of these transcription factors, thus promoting a more inflammatory environment The absence of FABPs is antiinflammatory The cell must strike a balance between metabolism and inflammation In conditions of overnutrition, this becomes a particular challenge, as the very processes required for response to nutrients and nutrient utilization, such as mitochondrial oxidative metabolism and increasing protein synthesis in the ER, can induce the inflammatory response IR, insulin receptor
poorly understood Crucial questions that are currently open regard the initiation of the inflammatory response Is inflammation the primary event linking obesity with insulin resistance, or does the inflammatory response begin only after the onset of resistance to insulin? How and why does the body initiate an inflammatory response to obesity? Does obesity per se induce an inflammatory response, or is inflammation initiated as a secondary event by hyperlipidemia or hyperglycemia? In reviewing
the facts, it is fairly clear that obesity promotes states of both chronic low-grade inflammation and insulin resistance However, even in the absence of obesity, infusion of animals with inflammatory cytokines or lipids can cause insulin resistance 54 Additionally, humans with some other chronic inflammatory conditions are at increased risk for diabetes; for example, about one-third of patients with chronic hepatitis C develop type 2 diabetes, and elevated TNF- levels are implicated in this link 95, 96 Rheumatoid arthritis also predisposes patients to diabetes and particularly cardiovascular disease, and some evidence indicates a link between inflammatory lung diseases and risk of cardiovascular disease and diabetes 9799 Finally, removal of inflammatory mediators or pathway components, such as TNF-, JNK, and IKK, protects against insulin resistance in obese mouse models, and
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treatment of humans with drugs that target these pathways, such as salicylates, improves insulin sensitivity 6, 11, 47, 59, 61 Thus, the available evidence strongly suggests that type 2 diabetes is an inflammatory disease and that inflammation is a primary cause of
obesity-linked insulin resistance, hyperglycemia, and hyperlipidemia rather than merely a consequence Figure 3 But how does the inflammatory response begin? Though this question cannot currently be answered, we can suggest some reasonable speculations based on the available data It seems likely that the inflammatory response is initiated in the adipocytes themselves, as they are the first cells affected by the development of obesity, or potentially in neighboring cells that may be affected by adipose growth How might expanding adipocytes trigger an inflammatory response? One mechanism that, based on newly emerging data, appears to be of central importance is the activation of inflammatory pathways by ER stress Obesity generates conditions that increase the demand on the ER 3941 This is particularly the case for adipose tissue, which undergoes severe changes in tissue architecture, increases in protein and lipid synthesis, and perturbations in intracellular nutrient and energy fluxes In both cultured cells and whole animals, ER stress leads to activation
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of JNK and thus contributes to insulin resistance 39 Interestingly, ER
stress also activates IKK and thus may represent a common mechanism for the activation of these 2 important signaling pathways 100 A second mechanism that may be relevant in the initiation of inflammation in obesity is oxidative stress Due to increased delivery of glucose to adipose tissue, endothelial cells in the fat pad may take up increasing amounts of glucose through their constitutive glucose transporters Increased glucose uptake by endothelial cells in hyperglycemic conditions causes excess production of ROS in mitochondria, which inflicts oxidative damage and activates inflammatory signaling cascades inside endothelial cells 101 Endothelial injury in the adipose tissue might attract inflammatory cells such as macrophages to this site and further exacerbate the local inflammation Hyperglycemia also stimulates ROS production in adipocytes, which leads to increased production of proinflammatory cytokines 42 Why inflammation? Perhaps one of the most difficult questions to answer is why obesity elicits an inflammatory response Why, if the ability to store excess energy has been preserved through the course of evolution, does the body react in a manner that is harmful to itself?
We hypothesize that this reaction is tied to the interdependency of metabolic and immune pathways Could obesity-induced inflammation simply be a side effect of this interaction that was never selected against since chronic obesity and its associated disorders have been so rare over time for people in their reproductive years? Perhaps the stresses of obesity are similar enough to the stresses of an infection that the body reacts to obesity as it would to an infection For example, in both infection and obesity, intracellular stress pathways such as the JNK and IKKNF-B pathways are activated Could these pathways be activated by similar mechanisms in both conditions? One mechanism that appears to be critical for initiation of this response in both situations is ER stress During viral infection, stress pathways are activated by an excess of viral proteins in the ER 102 Similarly, the demands of obesity also result in an overloaded ER and activation of these pathways 39 Another scenario might be related to the capturing of components of the insulin-signaling pathway by microorganisms Some pathogens activate host intracellular signaling cascades, including the PI3KAkt pathway, which is
also critical for insulin signaling 102 Perhaps in a situation in which this pathway becomes overstimulated by an increased need to take up glucose, the cell begins to interpret the signal as an indication of infection and responds by resisting the anabolic insulin signal and instead activating catabolic and inflammatory pathways On the other hand, perhaps the inflammatory response to obesity is not simply an undesirable byproduct, but rather a homeostatic mechanism to prevent the organism from reaching a point at which excess fat accumulation impairs mobility or otherwise diminishes fitness Lipid storage and accumulation of fat weight require anabolic processes, exemplified by insulin action, whereas inflammation stimulates catabolism, including lipolysis from adipocytes It is conceivable that mechanisms such as the activation of catabolism via inflammation and hence resistance to anabolic signals may be an attempt to keep body weight within acceptable bounds While there is no available experimental evidence that addresses the role of low-grade inflammation in such
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homeostasis, some support for this idea can be seen in findings that
experimentally induced local inflammation or insulin resistance in adipose tissue, such as that in adipose-specific insulin receptor knockout mice and adipose-specific TNF transgenic mice, is metabolically favorable, resulting in a lean phenotype and systemic insulin sensitivity 103, 104 Conclusions Our understanding of the characteristics of inflammation in obesity and the mechanisms by which this inflammation contributes to insulin resistance has been increasing rapidly over the last decade, such that we can now suggest a synthesized model Figure 4 While it is clear that inhibition of insulin receptor signaling pathways is a central mechanism through which inflammatory and stress responses mediate insulin resistance, it is likely that other relevant pathways, molecules, and alternative mechanisms involved in this interaction have yet to be uncovered Of particular interest is the role of alterations in mitochondrial function in diabetes While we did not cover this topic in this article, the reader is referred to an excellent recent review for more information 105 Another important question is whether genetic differences can predispose some individuals to inflammation-mediated
insulin resistance Several studies have reported associations between diabetes and polymorphisms in the promoters of TNF- and IL-6 106109 The most well-accepted polymorphism associated with type 2 diabetes is found in the gene encoding PPAR 110 As it is a transcription factor with some antiinflammatory activities, such as suppressing the production of TNF-, one could imagine how altered activity of PPAR could affect susceptibility to inflammation in obesity Similarly, genetic variations in the FABP, JNK, IKK, or ER stress pathways or any other loci that modulate the extent of inflammation and consequently insulin resistance could define the risk of individuals for developing metabolic complication of obesity Finally, in addition to diabetes and cardiovascular disease, inflammation is also known to be important for linking obesity to airway inflammation and asthma, fatty liver disease, and possibly cancer and other pathologies Understanding the mechanisms leading from obesity to inflammation will have important implications for the design of novel therapies to reduce the morbidity and mortality of obesity through the prevention of its associated chronic inflammatory disorders
Acknowledgments We are grateful to the members of the Hotamisligil laboratory for their contributions Research in the Hotamisligil laboratory has been supported by the NIH, the American Diabetes Association, and the Pew and Sandler Foundations We regret the omission of many important references by our colleagues in the field due to space limitations Note: References S1S60 are available online with this article; doi:101172/JCI200525102DS1 Address correspondence to: Gökhan S Hotamisligil, Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA Phone: 617 432-1950; Fax: 617 432-1941; E-mail: ghotamis@hsphharvardedu
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