Our increased understanding of the complex regulatory relationship between immune and metabolic cell types has engendered interest in exploiting this relationship to address the mounting threat of metabolic disease. Undeniably, the most effective manipulation of this relationship is accomplished by lifestyle modification. Dietary replacement of saturated fats and refined sugars by unsaturated fats and complex carbohydrates, as seen in Mediterranean diets for example, replaces a pro-inflammatory stimulus with an anti-inflammatory one, as outlined above, and is, unsurprisingly, associated with improvements in inflammation and insulin resistance (91
). Normalization of caloric intake is similarly associated with improvement in insulin resistance, largely through decreased adiposity. Exercise also operates through weight reduction, though it additionally promotes anti-inflammatory tone and suppresses chronic inflammation independent of weight loss (94
Despite the relative simplicity and undeniable efficacy of lifestyle interventions, persistent public disinterest in this approach has refocused attention on pharmacologic adjuncts. Unfortunately, the redundant and positively reinforcing quagmire that is metabolic syndrome—not to mention our desire for high-calorie food and lots of it—has largely thwarted initial efforts. These efforts can be divided into four main categories: 1) intake inhibition (e.g. appetite suppressants, malabsorptive agents, bariatric surgery), 2) output augmentation (e.g. stimulants), 3) immunosuppression, and 4) immunomodulation. The first two categories are solely based on thermodynamic arguments and as such will not be discussed here. Instead we will focus on the two latter approaches, both of which exploit the relationship between immune function and metabolism.
Not surprisingly, the first therapies targeting the immune component of obesity and metabolic syndrome were designed to broadly inhibit immune function. Our rudimentary early understanding of inflammation’s role in insulin resistance suggested that removing immune influences over metabolic tissues would prevent their detrimental influence. Without knowledge of the pathophysiologic mechanisms of metabolic disease, Williamson and Lond first demonstrated more than a century ago that high-dose salicylate treatment reduced the severity of glycosuria in diabetic patients (96
). Fifty years later, Reid and colleagues further demonstrated that aspirin treatment improved oral glucose tolerance test results in diabetic patients (97
). The modern interpretation of these experiments is that the salicylates operate through direct inhibition of IKKβ, a known mediator of inflammatory insulin resistance (98
). While the adverse effects of the salicylate doses required for meaningful pharmacological effect prevent their clinical adoption, targeted biologics have revived interest in this approach. Systemic TNFα blockade with biologics such as infliximab and entanercept have shown promising results in animal models; however, results have been disappointing in early prospective trials in diabetic patients and mixed in retrospective studies of patients taking the drugs for inflammatory conditions such as psoriasis and rheumatoid arthritis (101
). These mixed results may be the result of a failure of these interventions to adequately neutralize inflammation in the liver and adipose tissue microenvironments. Alternatively, their failure may be understood in the context of our discussion above regarding the complexity of macrophage function in metabolic syndrome—metabolic health is not defined solely by the absence of systemic inflammation. Inhibition of pathologic inflammation alone may not be sufficient to replace the positive trophic influences lost with the alternatively activated macrophage pool.
Therapies directed at biasing the immune system rather than inhibiting it, also known as immunomodulation, represent a more nuanced approach, integrating the needs to both blunt pathologic classical activation and promote positive alternative activation. Though not as developed as traditional anti-inflammatory approaches, immunomodulatory therapies have demonstrated promise. Although unrecognized at the time, the first large-scale use of an immunomodulatory agent occurred with the introduction of the statins. Originally targeted at lowering cholesterol levels (103
), statins have subsequently been shown to possess potent anti-inflammatory properties stemming from their unique ability to bias the immune response towards alternative activation via interference in isoprenoid biosynthesis (104
). Indeed, statin treatment of isolated dendritic cells in vitro leads to the cell autonomous upregulation of alternative markers, whereas treatment of uncommitted CD4+ helper T cells promotes Th2 maturation and the capacity to further alternatively bias uncommitted monocytes (106
). While their cholesterol-lowering properties are certainly important, their immunomodulatory capacity is thought to underlie much of the statins’ cardioprotective properties (108
). Indeed, statins have been shown to be effective in ameliorating inflammatory diseases as varied as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and graft-versus-host-disease (104
). Observational studies have even described a chemopreventative effect for statins in the development of inflammatory-driven colorectal malignancies similar to that of non-steroidal anti-inflammatory drugs (111
). Importantly, in contrast to the well-described adverse effects of current anti-inflammatory biologics, there is no evidence of any significant immunocompromise associated with their use. While most studies have focused on their cardioprotective effects, numerous studies have described mixed effects on insulin sensitivity despite reproducible improvements in inflammatory markers. Importantly, analysis of these reports demonstrates that certain statins (e.g. pravastatin, rosuvastation, fluvastatin) reproducibly improve insulin sensitivity independent of lipid lowering in obese subjects with and without diabetes (112
), while others (e.g. simvastatin) consistently fail to do so despite similarly improvements in inflammatory markers (112
). Interestingly, pravastatin therapy had no effect in lean, insulin sensitive patients, a population where previous studies have shown the alternative macrophage phenotype to be dominant (118
). When taken together, these findings suggest that statins may exert their effects at least partly through the promotion of tissue macrophage alternative activation.
Another unintended foray into immunomodulatory therapy has been described in the murky field of nutrition and supplements. It has been long-appreciated that diets rich in unsaturated fatty acids are correlated with reduced chronic inflammation and its sequelae (91
), and recent studies discussed above (i.e. TLR4 ligation by saturated fatty acids and PPARδ ligation by unsaturated) have lent mechanistic validity to them. Large numbers of both cross-sectional and prospective studies have examined this question and while the results are somewhat mixed, the data generally support the conclusion that unsaturated fatty acids, especially n-3 polyunsaturated fatty acids, improve global insulin sensitivity, tend to decrease adiposity, and significantly lower levels of serum inflammatory markers (91
). These data, when taken together with the mechanistic data discussed above, suggest that the long-appreciated dietary wisdom serves, at least in part, an immunomodulatory function by promoting alternative immune responses.
While immunomodulation may exert its efficacy through macrophage deviation as a final common pathway, Dosch et al recently capitalized on the ability of T lymphocytes to direct macrophage function through a novel lymphocyte-directed approach (71
). Recent studies have described a transition in the white adipose tissue-associated T lymphocyte population from protective Th2-biased helper cells to pathogenic Th1-biased helper and cytotoxic cells during the development of diet-induced obesity (71
). This shift parallels the alternative-to-classical transition in macrophage activation, and together they describe a shift in the tissue microenvironment from anti-inflammatory to inflammatory with all of its attendant metabolic sequelae (). Dosch and colleagues astutely recognized that eradication of adipose tissue-related lymphocytes from insulin resistant animals would reset the lymphocyte population and potentially redistribute the Th1/Th2 bias (71
). Indeed, treatment with an anti-CD3 antibody erases the Th1-skewed T cell repertoire, and subsequent repopulation restores the T cell balance to something approximating that seen in lean animals. Furthermore, the reintroduction of regulatory and Th2 T cells re-directs the inflammatory macrophage profile to the alternative phenotype and results in dramatically decreases tissue inflammatory markers and results in sustained normalization of insulin sensitivity (71
The evidence is clear that diet-induced insulin resistance is largely a disorder of deranged macrophage activation; however, efforts focused solely on inhibiting or correcting that derangement have fallen short of expectations. This is perhaps because once established, the metabolic derangements are self-sustaining and rely less upon continued inflammatory instigation, or alternatively, that these derangements provide their own inflammatory stimulation independent of immune function (e.g. high levels of saturated fatty acids can perpetuate insulin resistance in muscle and adipose tissue directly without intermediary leukocyte amplification). Regardless, it is likely that for any therapy to be effective in reversing established insulin resistance, it must target not only the driving mechanism of immune deviation but also the effector mechanisms of deranged skeletal muscle, liver, and adipose tissue metabolism. It is exactly this approach that is suggested by the discussion above: metabolic and immune functions not only communicate but also share certain transcriptional regulators, e.g. the PPARs, which are natural pharmacologic targets. Indeed, studies of synthetic PPARδ agonists have demonstrated great potential for use in metabolic syndrome: PPARδ activation not only promotes alternative macrophage activation and suppresses tissue inflammation (62
), but also directly increases oxidative lipid catabolism in skeletal and cardiac muscle, adipose tissue, and liver; improves serum lipid profiles and global insulin sensitivity; and promotes weight loss in obesity (125
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. There are three PPARs (α, δ, and γ) in mice and humans, which control nearly all aspects of fatty acid metabolism. Rate-limiting enzymes involved in transport, synthesis, storage, mobilization, activation or oxidation of fatty acids are all regulated by PPARs. In a tissue- and stimulus-dependent manner, PPARs regulate distinct programs of fatty acid metabolism. PPARα regulates β- and ω-oxidation of fatty acids in the liver, whereas PPARδ regulates their oxidation in other peripheral tissues, including white adipose tissue, skeletal muscle and heart. In contrast, PPARγ is essential for long-term storage of fatty acids as triglycerides in adipocytes. However, in macrophages, PPARγ is required for β-oxidation of fatty acids in response to IL-4.
PPARs regulate expression of their target genes through association with corepressor and coactivator proteins. Ligand binding results in a conformation change in the receptor, resulting in release of corepressor and recruitment of coactivator proteins. Endogenous ligands for PPARs include native and modified fatty acids, prostaglandins, leukotrienes and phospholipids. Fibric acids and thiazolidinediones are synthetic activators of PPARα and γ, and are currently used clinically to treat hypertriglyceridemia and type 2 diabetes mellitus, respectively.
Additionally, synthetic PPARγ ligands have been in clinical use for decades as insulin-sensitizing agents (126
). These drugs were originally thought to operate through direct insulin sensitization of adipocytes (127
); however, recent studies utilizing myeloid-specific deletion of PPARγ have demonstrated that the macrophage is an important site of action where they inhibit inflammation as well as promote the elaboration of insulin-sensitizing signals (67