Proper regulation and management of energy, substrate diversity and quantity, as well as macromolecular synthesis and breakdown processes, are fundamental to cellular and organismal survival and are paramount to health. Cellular and multicellular organization are defended by the immune response, a robust and critical system through which self is distinguished from non-self, pathogenic signals are recognized and eliminated, and tissue homeostasis is safeguarded. Many layers of evolutionarily conserved interactions occur between immune response and metabolism. Proper maintenance of this delicate balance is crucial for health and has important implications for many pathological states such as obesity, diabetes, and other chronic non-communicable diseases.
The overwhelming frequency of metabolic diseases such as obesity and diabetes may be related to organismal design and the evolutionary constraints within which natural selection has acted throughout history. Some of the initial thoughts and considerations of this relationship have been described previously1. However, it is worth stressing that, in general, selective pressures in evolution do not favour the development of countermeasures against excess nutrients and energy, but rather select for phenotypes that ensure survival in the face of deficiencies. For example, while there seems to be no need to defend against obesity, a strong rationale can be envisioned to defend against starvation. The same argument could be made regarding sugar concentrations in body fluids; while hyperglycaemia is not an immediate threat to survival, hypoglycaemia is. Hence, organisms harbour strong and redundant pathways to seek food, favour energy efficiency and storage, produce glucose and prevent hypoglycaemia. While these features provide selective advantage in the context of supply limitations, with the removal of these selective pressures, they have now become a prominent liability expressed in the form of obesity and related metabolic diseases such as diabetes (Fig. 1).
So how do the interface of metabolism and immunity relate to this transformation? The evolutionary advantages of a strong defence system are obvious in protecting against pathogens, and as a strong immune response is dependent on energy sources, one can also argue that the integration of these systems and their cooperation in responding to fluctuations in the energy and nutrient environment would be highly advantageous. From this perspective, an intriguing way to think about this paradigm would be to envision immune mediators, such as cytokines, as metabolic hormones. In fact, this aspect of immunometabolism is extremely well-conserved among organisms and will be the main topic of discussion in this work. Infection-related metabolic alterations, as well as the metabolic and energetic programming of the immune response, are also critical components of immunometabolism that were recently reviewed elsewhere2 and will not be covered here.
I would also like to emphasize here the duration and scale of responses as key determinants of outcomes. In the setting of infection, a successful immune response is strong but often short-lived, resulting in elimination of the pathogen followed by termination of the response, and the organism lives. If the result is a failure, the organism dies. In this evolutionary framework, there is no host survival advantage to chronic inflammation or to a low-grade response incapable of pathogen elimination. These constraints that govern the outcomes of immune responses are described in a recent review by R. Medzhitov3. It has also been well-established that inflammation is essential for repair, remodelling, and even renewal of tissues, including those with critical metabolic function. These responses also need to be temporally and spatially regulated to maintain homeostasis, including metabolic homeostasis, otherwise they will be uniformly damaging when sustained. Hence, broad, potent or permanent interferences targeting immune resolution or activation may have unintended and adverse consequences for tissue health, and if these tissues and related functions are critical for metabolic homeostasis, for the metabolic health of the organism as well. Finally, it is discernible that such an ancient and critical response will present layers of specificity as well as redundancy, hence its experimental or therapeutic management requires thorough consideration beyond the targeting of individual components.
These considerations aside, the immunological aspect of metabolic regulation in a multicellular organism could be framed in its most fundamental form by examining a highly conserved relationship between a potent and pleiotropic immune mediator (tumour necrosis factor, TNF), a pathogen sensing system (the Toll-like receptors, TLRs), and a powerful metabolic hormone (insulin). While this paradigm emerged from the observations made in obese and diabetic rodent models and examination of metabolic consequences in genetic or other interventions that target TNF and subsequently TLRs, it is highly conserved throughout evolution. Importantly, this entire cascade and the central signalling nodes and mediators have now been demonstrated in Drosophila4. Hence, unequivocal evidence links TNF to insulin action and production as a mechanism of evolutionary adaptation that is captured during the more recent maladaptive state of chronic nutrient and energy surplus exemplified by obesity (the same is also applicable to TLRs). Using this simple and highly preserved framework, it is possible to incorporate many layers of complexity with numerous mediators, hormones, and signalling systems to explore immunometabolism (Fig. 2).
Immunometabolic integration in invertebrates
The strong link between nutrient sensing and immune signalling is rooted in their common evolutionary origin. In Drosophila, for example, the fat body carries out liver, adipose, and immune functions1,4. The fat body is capable of sensing both infectious and metabolic disturbances, and studies of Drosophila have helped to illuminate highly conserved immunometabolic pathways discovered in mammals. Indeed, the fat body is the major producer of Eiger, the Drosophila orthologue of TNF5. Activation of Wengen (a TNF receptor) or TLR signalling results in inhibition of insulin action through JNK and MyD88 pathways converging on GSK3 and Foxo as targets6,7. Studies in humans and mammalian models have demonstrated that JNK kinase activity has an important upstream role in integrating inflammatory and metabolic function, and this is conserved in Drosophila, where JNK signalling regulates the expression of the lipocalin Nlaz, an orthologue of RBP4, antagonizing expression of Drosophila insulin-like peptide (Dilp) and insulin/IGF signalling6,8. As in mammals, exposure to dietary stress (overfeeding or a high-sugar diet) results in resistance to Dilp action in the fat body downstream of JNK activity9,10.
A very recent study provided a final and critical missing piece of evidence that demonstrates the highly evolutionarily conserved activity of TNF that is also central to metabolic disease, that is, diabetes in the fruit fly. Eiger (TNF), produced by fat cells, acts through Grindelwald (the second putative Drosophila TNF receptor) to control body size during substrate deprivation. Most importantly, reduction of Grindelwald in the fat body prevents the development of hyperglycaemia in the setting of a high sugar diet4. Taken together, these data reinforce a general model in which TNF and other immune mediators act as adipose-derived hormones (adipokines) that work to couple nutritional status to adaptive responses, and the misapplication of this system in the setting of chronic nutrient excess is a key underlying mechanism in the pathogenesis of metabolic disease, from flies to humans (Fig. 2). Similar lines of evidence are also emerging from work in other model organisms such as Caenorhabditis elegans and Danio rerio, demonstrating a high degree of evolutionary conservation and providing powerful platforms for mechanistic and interventional studies.
Components of immunometabolic interactions
Initial support for our understanding of the connection between obesity and metabolic disease came from the findings that macrophages secrete a molecule (TNF) that induces insulin resistance in adipocytes11, and that obesity was associated with increased expression of inflammatory mediators in adipose tissue and that this inflammation interfered with glucose metabolism12,13. Numerous interventional studies have since validated this postulate (complete references available at http://www.metaflammation.org). The demonstration of macrophage infiltration into the adipose tissue of obese mice was another important milestone14,15. Although immune cell infiltration into adipose tissue had been observed almost forty years earlier16,17, the potential contribution of these cells, or inflammation in general, to metabolic health or dysfunction was unappreciated at the time. The later studies were the basis for investigations into the possibility that adipose tissue macrophages act as direct modulators of metabolism, and led to work that showed that, in obesity, free fatty acid exposure promotes the polarization of adipose tissue resident macrophages towards a pro-inflammatory (M1-polarized) phenotype which can block insulin action18,19,20. Recent work has begun to unravel the molecular mechanisms that underlie these events, including the identification of epigenomic alterations that determine macrophage sensitivity to metabolically driven inflammatory (metaflammatory) signals21, and the discovery of additional macrophage-secreted products that attenuate insulin signalling22. Although I am unable to cover the topic in detail in this manuscript, it is important to note that subsequent work has demonstrated that many other immune cell types including dendritic cells, mast cells, eosinophils and lymphoid cells also contribute to metabolic tissue homeostasis and to the control of glucose metabolism. Furthermore, certain macrophage populations, as well as other resident immune cells, are also critical in tissue homeostasis and turnover of stromal constituents such as adipocytes, and hence the nature, amount, and activation state of these immune cells in the tissue environment is critical in determining their impact on systemic metabolism.
The inflammasome, a protein complex that enables maturation of the pro-inflammatory cytokines IL-1β and IL-18 by caspase-1-mediated cleavage, is an integral part of innate immunity. The role of the inflammasome in metabolic disease is firmly supported by a multitude of studies, which demonstrate that mice deficient in various inflammasome components as well as IL-1β or its receptor IL-1R1 are protected from diet-induced insulin resistance23,24. Treating rodent diabetic models with an inhibitor of IL-1 signalling or an antibody targeting IL-1β has also been shown to have metabolic benefits, including improved insulin sensitivity and improved β cell survival25. Finally, this pathway plays an important role in human diabetes25,26.
A danger signal that is released by the inflammasome is HMGB1, which is a ligand for the receptor for advanced glycation end products (RAGE). Neutralization of HMGB1 or deletion of its receptor results in reduced inflammation and weight gain and improved glucose tolerance in mouse models27,28. Notably, studies of inflammasome-driven release of HMGB1 demonstrated that the double-stranded-RNA-sensing kinase PKR is a critical mediator of inflammasome activity and metabolic regulation29. While one study observed that PKR is dispensable for inflammasome activation30, work from many other groups has since provided ample evidence linking PKR to inflammasome activity which in fact is responsive to cellular metabolic status31,32,33,34. Lastly, recent studies illustrated a remarkable possibility of activating PKR through endogenous double-stranded RNA signals in response to metabolic stress35, and it is possible that other endogenous ligands can also engage PKR in this manner. Since small nucleolar RNA production is also required for lipotoxicity36, PKR may directly sense endogenous messages related to the metabolic milieu and integrate them with innate immune responses to regulate systemic homeostasis. This postulate is consistent with the finding that there is a marked reduction in stress- and nutrient-induced JNK activation in the absence of PKR, resulting in protection against high-fat-diet-induced obesity, insulin resistance and diabetes in multiple studies (reviewed in ref. 37), although one study has not observed these effects38. On the other hand, PKR activity has been linked to pancreatic β cell failure and lipid-induced muscle insulin resistance in numerous other studies39,40,41.
Newly identified role for the adaptive immune system
Many recent studies have demonstrated that in addition to alterations to the innate immune system, obesity is also associated with increased activation of adaptive immunity. For example, there are shifts in the influx of T cells in the adipose tissue in obesity; increases in CD4+ and CD8+ T cells have been documented in obese humans and mice42. Conversely, regulatory T (Treg) cells in adipose tissue are positively associated with insulin sensitivity43,44, and induction or adoptive transfer of Treg cells improves glucose homeostasis in obese mice45. In line with this, mice deficient in adipose tissue Treg cells are also protected against age-related insulin resistance46. Notably, the beneficial effect of Treg cells requires expression of PPARγ, an important metabolic mediator, and genetic deletion of PPARγ in Treg cells is sufficient to prevent anti-diabetic actions of PPARγ agonists, providing yet another layer of evidence into the immunometabolic nature of type 2 diabetes47. B cells also accumulate in the adipose tissue of obese mice48, and in this setting they produce a more inflammatory repertoire of cytokines49. By contrast, the number of tolerance-promoting regulatory B cells in adipose tissue is decreased in models of obesity50, as are the number of anti-inflammatory type 1 natural killer T (NKT) cells51 and iNKT cells52. Most intriguingly, obesity triggers abnormal B cell function, which is reflected in the production of autoantibodies and pathological immunoglobulins48. While the relative contribution of the adaptive immune system activation to the pathologies of systemic glucose homeostasis in obesity remains incompletely understood, there are exciting potential opportunities in this area with translational possibilities.
Pleiotropism of hormones, cytokines and signalling networks
Altered production of many pro- or anti-inflammatory cytokines, adipokines and lipid mediators, as well as signalling through a plethora of immune receptors and intracellular mediators, has been observed in obesity and experimentally linked to metabolic pathology. These are too numerous to list here but a comprehensive compilation is presented in Supplementary Fig. 1 (extended version available at http://www.metaflammation.org). The signalling kinases are also numerous and include PKC, p38, ERK, JNK, IKK, JAK, AMPK, mTOR and PKR. The overwhelming majority of these signalling networks converge on metabolic hormone action, most critically on insulin and glucagon, but also several others. Careful studies have revealed that the actions of many classical inflammatory molecules are context-dependent and may vary on the basis of duration and dose of exposure as well as the production and target sites. Therefore, association studies and analysis of global single-gene-deletion models in mice may often not tell the whole (or even the accurate) story. One of the best examples of a molecule with such complex roles is IL-6, the circulating levels of which have been shown by many to be increased in the setting of obesity and to correlate with diabetes risk and metabolic syndrome. In line with this finding, IL-6 induces insulin resistance in various tissues and cell types, but acutely enhances insulin signalling in muscle. Accordingly, in some in vivo studies, blocking IL-6 action with a neutralizing antibody improves insulin sensitivity in obese mice, while other groups have shown that IL-6 interference does not alter insulin sensitivity, and the descriptions of Il6−/− mice are also greatly variable with both beneficial and detrimental effects (references available at http://www.metaflammation.org).
Analogous intricacies also exist in the studies of the effects of inflammatory signalling networks on metabolism. Although a large body of evidence supports a detrimental role on glucose metabolism for pathological IκB kinase (IKK) activation in multiple tissues, other approaches that promote or interfere with IKK activity have produced conflicting results. For example, blocking IKK action in the adipose tissue of mice, which was designed as a strategy to block the inflammatory response, in fact results in massive adipose tissue inflammation and metabolic deterioration related to the role of IKK activity in the resolution of inflammation53. IKK activation can also impinge upon endoplasmic reticulum (ER) function and the unfolded protein response (UPR)54. Importantly, beneficial metabolic effects of salicylates have been reported in mouse models of, and in humans with, metabolic disease, although the degree to which these effects are mediated through IKK signalling in humans and the impact on insulin action versus improved insulin secretion remains to be explored55,56. Similarly, while many independent studies in mice and humans support the conclusion that p38 activation is detrimental for metabolism, occasional reports suggest that it may have beneficial effects57,58. Conversely, the role of pathological JNK activation in obesity is an important benchmark in experimental studies evaluating immunometabolic phenotypes, and its detrimental impact on glucose homeostasis has been consistently and convincingly documented in many studies59,60. Numerous studies have also addressed the target cell types and tissues involved in this biology and the underlying mechanisms continue to be explored by many groups61,62. Regrettably it is not possible to examine these studies in detail here, but these differential findings underscore the limitations that may be encountered in efforts to study immunometabolic biology and to therapeutically target classical inflammatory pathways with an all-or-none or linear framework, wherein single molecules have context-dependent and pleiotropic functions, positive and negative, on both local and systemic inflammation and the metabolic outcomes. This is characteristic of not just immune mediators, but even metabolic hormones that modulate systemic glucose metabolism such as glucagon.
Metabolic inflammation was first described in adipose tissue, it presents the highest complexity at this site, and has been examined in detail with thousands of studies. However, it is critical to emphasize that adipose tissue is neither the sole site of metaflammation nor could it be assumed to be the only player in metabolic homeostasis or related pathologies. Obesity-related influx of immune cells occurs in many other tissues such as the hypothalamus, liver, muscle, pancreatic islets and the gut (Fig. 1). The immunometabolic program within each organ also includes stromal components and metabolic cells, such as adipocytes, hepatocytes and β cells. These cells not only control the energy and substrate fluxes into the immune effectors but also themselves produce many cytokines, chemotactic molecules and lipid mediators. Hence, the systemic impact of metabolic inflammation as well as the bidirectional interactions between immune and stromal components are critical considerations in determining physiological and pathological outcomes. Some examples are provided in other sections of this text.
Organelle dynamics and function in immunometabolism
A key question in understanding immunometabolic biology is whether mechanisms can be identified that integrate nutrient and immune responses and provide a broad framework for metabolic failure in the face of energy and nutrient excess. In the past ten years, work from many labs has shown that one of the key components of metabolic health involves organelle homeostasis, particularly in the ER. Fluctuations in nutrient supply and metabolic demand impair ER function and activate the UPR. Notably, elements of the UPR converge on many inflammatory pathways including JNK and IKK, the activation of which block insulin action as well as secretion and impair glucose homeostasis63,64. Furthermore, the link between UPR activation and inflammation was shown to be dependent on the pattern recognition receptors NOD1 and NOD2 (ref. 65), and the ER is a critical site for inflammasome activation66. ER function may more generally be an important factor in determining immune cell fate and function, including eosinophil differentiation, immunoglobulin production from B cells and IL-6 expression in macrophages67. Taken together, these findings strongly indicate that by modulating the state of the ER, metabolic stress can have a profound and direct impact on immune system function, and the ER may serve as key site where the information on the nutrient and energy status of the cell can be relayed to inflammatory pathways. Notably, it is also now clear that inflammation itself may impair ER function. In genetically obese mice, the increased production of nitric oxide leads to post-translational modifications of the UPR component IRE1, which impairs its ability to cleave XBP1 mRNA and initiate a pro-resolution program68. In general, proper activation of XBP1 is important for metabolic homeostasis in the liver, however it has been reported that lack of XBP1 in the liver can also be protective against insulin resistance69. Hence, the metabolic biology mediated by this branch of the UPR also exhibits a great deal of variation on the basis of the experimental system used, and it is likely that neither constitutive activation nor complete inhibition would result in successful long-term management of metabolism. These issues notwithstanding, it is clear that a chronic inflammatory environment is not conducive to maintaining a healthy equilibrium in the ER.
In most cells, organelle homeostasis does not occur in isolation, and the ER is not the only organelle exhibiting dysfunction in obesity. There is growing body of compelling evidence that obesity induces a state of mitochondrial dysfunction70. Many recent studies have provided insight into the mechanisms involved, and offered further support that mitochondrial dysfunction may be one of the critical events in the development of obesity-induced metabolic pathologies. In rodents, a high-fat diet leads to uncoupled respiration and oxidative stress in the liver, which contributes to pathologies in glucose metabolism71. In macrophages, increased ROS production promotes pro-inflammatory polarization and can lead to insulin resistance in vivo72,73. There is also evidence of reduced mitochondrial function in type 2 diabetic patients in adipose tissue74 and skeletal muscle75, although how alterations in mitochondrial function relate to glucose metabolism and insulin action is an area of active debate and exploration, which will not be covered in detail here. Notably, we now know that at least in liver, dysfunction of the ER and mitochondria are linked phenomena, as obesity induces abnormal connections and communication between these organelles, resulting in excess mitochondrial calcium accumulation, oxidative stress and dysfunction76. Relatedly, the ER-resident E3 ubiquitin ligase synoviolin controls the turnover of PGC-1β, thereby modulating mitochondrial respiration and energy expenditure, with consequences for body weight and metabolic regulation77. Furthermore, altered calcium signalling may be a generalized dysfunction that contributes to obesity-induced metabolic decline in many tissues and cell types (reviewed in ref. 78).
Nutrients and metabolites as fuel and signalling molecules
The concept that nutrients, particularly circulating lipids, have a role in determining insulin sensitivity dates from at least as early as the 1960s, when it was recognized that lipids and fatty acids reduced insulin-induced glucose uptake in isolated heart muscle79. This effect was subsequently shown systemically in animal models including rats and in humans80. Since then, it has become clear from studies in humans and animal models that lipid-induced insulin resistance and impaired glucose metabolism may also involve other mechanisms, including the activation of inflammatory pathways81,82,83,84. For example, the innate immune component TLR4 has been identified as a receptor for saturated and polyunsaturated fatty acids19,85,86, and although this sensing may occur indirectly, mice with loss of function of TLR4 are protected from the effects of diets high in saturated fat87,88. Deletion of the TLR adaptor molecule MyD88 in the central nervous system also protects mice from diet-induced insulin resistance89. Taken together, ample evidence supports the involvement of TLR signalling in metabolic control in multiple experimental models7,88.
Notably, other critical mechanisms may contribute to the role of lipid-induced insulin resistance independent of TLR signalling. For example, mice fed a high-fat diet exhibit changes in their serum, muscle and adipose tissue lipid profiles indicative of mitochondrial dysfunction, and incubating macrophages with these lipids drives expression of proinflammatory cytokines90,91. Furthermore, many cytokines also induce the production of ceramides, which themselves may have potent metabolic effects, as has been reviewed elsewhere92. Another line of evidence indicates that lipid-induced insulin resistance in skeletal muscle is associated with accumulation of fatty acyl-CoA and DAG, leading to activation of PKCθ, which blocks insulin action through IRS-1 serine phosphorylation and other mechanisms84,93. Similar results have also been observed in human studies94. However, the full extent of this pathway’s ability to mediate diet-induced insulin resistance is unclear, in part because animal models used to investigate the role of PKCθ in the development of insulin resistance have given rise to complex results95,96. Fatty-acid-induced activation of PKC as well as JNK in macrophages has also been linked to the production of inflammatory cytokines and promotion of muscle insulin resistance97. The interactions between direct mechanistic targets of these pathways, and how they are linked to metabolic pathologies is being explored, however it is clear that the DAG–PKC and the ceramide pathways are extremely promising avenues for further research with important implications for human metabolic disease. More research is necessary to fully understand whether these pathways are indeed separate from or an integrated part of the immunometabolic systems described here. As many lines of evidence demonstrate activity of signalling molecules such as PKC or JNK in both metabolic and immune responses, a model integrating these systems (see ref. 37) is likely to be most accurate (Fig. 3, references available at http://www.metaflammation.org). While it is not possible to cover the topic in further depth, it is important to note that there are also many lipids that play anti-inflammatory roles and produce metabolic benefits that have been identified98.
Immunometabolic links in human studies
Studies of human subjects have long provided clues of the link between inflammatory signalling and metabolic disease. Indeed, as early as 1884 it was noted that patients with meningitis exhibit a transient diabetic syndrome, and a careful review of cases suggested that the frequency of diabetes was so high that a meningitis diagnosis might be missed and patients treated exclusively for their hyperglycaemia99. Since then, ample studies in human subjects have continued to underscore the potential role of immunity in diabetes in genetic, clinical, epidemiological and population studies (For some examples and references, see http://www.metaflammation.org).
Immune genes and metabolic phenotypes in GWAS
Some of the initial loci identified in genome-wide association studies (GWAS) linked to type 2 diabetes are implicated in the regulation of insulin secretion and insulin processing100,101, leading to the suggestion that relative susceptibility to β cell failure may be the dominant genetic contribution to diabetes risk102,103. Some have even suggested the initial scarcity of hits identified in established immune pathways may impugn the biological link between inflammation and diabetes susceptibility. While this may be the case, the volume of genetic evidence should not be interpreted as supporting or refuting the translatability to humans, and indeed careful examination reveals many immunological components genetically linked to metabolic phenotypes in humans. For example, fasting insulin and glucose levels were linked to PTPRJ, which is a regulator of T cell signalling104, and variants in ST6GAL1, which has a role in antigen production, have been linked to type 2 diabetes susceptibility105. A large-scale GWAS identified multiple loci with known roles in immunity as being susceptibility loci for type 2 diabetes, including MAEA, which has a role in macrophage maturation, CMIP, which is involved in T cell signalling, and WWOX, an oxidoreductase that mediates TNF-mediated apoptosis106. Similar links exist for JNK, GPR120, and others107,108. Most recently, two large-scale studies published in 2015 combined GWAS with ‘metabochip’ analysis to identify many immunological loci that are linked to metabolic traits109,110. In this work, waist–hip ratio is linked to MAP3K1, a part of the JNK pathway, MACROD1, a regulator of NFκB activation, NFE2L3 (also known as NRF3) which coordinates cellular stress responses, and the inflammasome component NLRP3 (ref. 110). In addition, this approach linked variants of IFNGR1, TLR4 and NLRC3 to body mass index109. However, since human genetic variability is estimated to contribute to a fraction of the heritability of complex traits, and many of the direct genetic hits are still being investigated for their causal impact on phenotypic outcomes, it is prudent to interpret both positive and negative results with caution. Integrated approaches including the analysis of chromatin states and global gene expression or metabolomic profiles in mouse models and in humans have also provided additional examples of the contribution of inflammation to metabolic phenotypes111,112. Taken together, these findings not only provide multiple layers of genetic support for the immunometabolic component of diabetes and obesity but also clearly demonstrate the broad similarities between model organisms and humans in this biology.
Emerging data from human trials
As we progress in our understanding of the molecular mechanisms that underlie the connections between obesity and metabolic disease, the ultimate goal is the development of successful translational approaches to treat patients or prevent disease. Biologics targeting classical inflammatory molecules including IL-1, IL-6 and TNF are already currently in clinical use for the treatment of rheumatoid arthritis, Crohn’s disease and other chronic inflammatory diseases, and assessment of these patients provides some insight into whether these approaches might have metabolic benefit in these populations. However, the results of these studies have been variable; for example in the case of TNF, while some have concluded that anti-TNF therapy reduces risk of diabetes or improves insulin sensitivity, others have not replicated these findings. The same is also true in small proof-of-principle studies in obese patients. However, large retrospective and meta-analysis studies have concluded that anti-TNF therapy improved insulin sensitivity or hyperglycaemia and importantly, reduced lifetime risk of diabetes113,114. Multiple studies have provided highly promising evidence that antagonizing IL-1 signalling improves insulin secretion and, in some patients, enhances insulin sensitivity26. A detailed analysis of the pros and cons of these trials was recently reported115. The limited success of these approaches targeting individual cytokines so far should not be considered endorsements or indictments of the proposed immune mechanisms; indeed successful immunological interventions have been extremely challenging even in diseases such as type 1 diabetes, where the immune mechanisms driving the pathology are well-established, and in others (such as Crohn’s and rheumatoid arthritis), anti-cytokine treatments only benefit a small fraction of the patients116. Overall, it is clear that TNF or IL-1 blockade have benefits, but better patient selection and precision is needed to realize the full translational potential of these approaches.
In addition to these well-established immunomodulatory strategies, which perhaps represent the ‘low-hanging fruit’ to be used for additional indications, the use of other anti-inflammatory molecules such as resolvins, ω-3 fatty acids, palmitoleate, or fatty acid-hydroxyl fatty acids provide extremely promising prospects for translational opportunities through lipid mediators or metabolism with encouraging leads98. There is also an exciting prospect related to erythropoietin (EPO), which has potent anti-inflammatory and tissue-protective effects, acting as a direct and indirect antagonist of TNF117. These actions of EPO are independent of its haematopoietic effects, and are signalled through an atypical heteromeric low-affinity receptor. Recently, a selective peptide agonist of this form of the receptor called ARA290 has been shown to be effective against obesity-induced inflammation and insulin resistance in mice118, and proof-of-principle studies in humans showed promising improvements in glucose control and dyslipidemia119. There is now a larger clinical trial planned to test the EPO receptor antagonist ARA290 (NCT01933529). Finally, it is important to note that essentially all existing anti-diabetic remedies, including metformin, thiozolidinediones, DPP4 inhibitors, incretin agonists, and even lifestyle interventions including exercise and caloric restriction, all exhibit anti-inflammatory activity120,121,122. Notably, statins reportedly exert pro-inflammatory action, such as stimulation of inflammasome activity, which may underlie the perplexing increase in diabetes risk identified in some studies with statin use123,124. While each one of these approaches presents pros and cons, especially in the complex multifactorial metabolic disease space, they all point to critical and causal involvement of abnormal immune response in metabolic pathologies. I am hopeful that there will be more refined and better stratified clinical studies116 and many additional approaches to clarify further the immune-metabolic basis of obesity and diabetes and its effective translation to human diseases (Box 1).
Challenges, caveats, and reflections
In this author’s opinion, the challenges remaining in this field can be identified in few distinct areas. How does metabolic inflammation start and at what point does it become detrimental? What are the unknown mechanisms that guard metabolic organs from nutritional, metabolic, or immune challenges to maintain homeostasis? What are the appropriate model systems and paths to translation to prevent or treat human disease? The current status of some of these issues is discussed throughout the text. Regarding the initiation of metaflammation, there are several interesting and emerging concepts, one of which is that dying adipocytes release toxic cargo including cell-free DNA, which engages immune effectors and initiates inflammatory responses125. A second compelling hypothesis is related to hypoxia, which is a ubiquitous feature of adipose tissue in obesity in experimental models and humans126. A third emerging concept is obesity-induced genotoxicity and related stress responses, particularly in the adipose tissue127. However, it is unclear whether these mechanisms occur in isolation, in a sequence or together, or whether they have relevance to other tissues where metabolic inflammation occurs, such as liver and pancreas. In particular, the inflammatory responses in the brain to metabolic stress have been observed both in mice and humans, with important metabolic consequences, but little is known about the mechanisms that trigger them128. Perhaps a promising avenue in this regard is the involvement of toxic lipids or metabolites and the targeting of inflammatory signalling networks, which may also include the production of endogenous RNA species. Finally, failure of organelles structurally and/or functionally may serve as a critical event in metabolic homeostasis, as well as in the initiation or propagation of metaflammation37,63. These are all exciting developments that have the potential to provide insight into new aspects of metabolism and the origin of the immunometabolic aetiology of obesity and diabetes.
Specific to inflammation, it is important to remember that intact inflammatory pathways are critical for the health of tissues and proper homeostasis, including the health of adipose tissue expansion in response to caloric excess129. An active immune system is required for acute responses and organismal maintenance, and thus integrity of the tissue function as well as metabolic homeostasis cannot be sustained without the immune response. Hence, general disruption of inflammatory pathways may not only compromise the ability to combat invaders but also result in tissue damage and even induce systemic inflammation through the disruption of repair and remodelling or by creating dysbiosis130,131. A thoughtful consideration of the implications of manipulating immune responses to treat chronic diseases is therefore warranted.
There is also tremendous redundancy in the pathways that support inflammation as well as its resolution, and this certainly is also the case in immunometabolic regulation (Supplementary Fig. 1, extended version available at http://www.metaflammation.org). This poses an important and unresolved question regarding how we design and interpret immunometabolic changes in genetic models, especially in inbred mouse strains. Just as a clinical study with a single subject may be informative but cannot be definitive or generalizable, genetic interventions in inbred strains have limitations in determining the efficacy or translatability of putative targets. Finally, in humans there is also tremendous inter-individual variability in the magnitude of the immune response, even exhibiting strong seasonal fluctuations132,133,134. Given these difficulties, and the need for therapeutic approaches that do not permanently interfere with entire branches of the immune system and are free of undesirable outcomes, translating our experimental insights into successful clinical interventions will require nuanced thinking, combinatorial approaches, and new experimental paradigms. A very promising approach is the use of outbred or even wild strains, such as in collaborative and diversity cross studies, and integrating genetic variation with other environmental modifiers to establish links with complex metabolic phenotypes and facilitate successful translation to human disease135,136.
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I am grateful to all members of the Hotamisligil laboratory for helpful discussions, and especially G. Parlakgül for the initial preparation of figures, and K. Claiborn for discussions and invaluable editorial assistance. Work in the Hotamisligil laboratory is supported by grants from the National Institutes of Health (DK052539, HL125753, AI116901), the JDRF (2SRA-2016-147-Q-R), and sponsored research agreements from Union Chemique Belge and Servier.
The author declares no competing financial interests.
Reviewer Information Nature thanks M. Febbraio and R. Kahn for their contribution to the peer review of this work.
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Hotamisligil, G. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017). https://doi.org/10.1038/nature21363
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