Inflammation, metabolism and adipokines: toward a unified theory

Let food be thy medicine and medicine be thy food. Hippocrates Malnutrition and consequent metabolic abnormalities have been recognized as a cause of poor immunity since time immemorial. Famines led to epidemics and a healthy diet was offered as a treatment for many diseases such as tuberculosis. Over the last century, our concept about malnutrition has expanded to include both under- and overnutrition. Overnutrition is associated with a myriad of diseases, the most well recognized among them being metabolic syndrome. The link between overnutrition and inflammation was established more recently. The important paper by Viser et al.1 in 1999 proposed that obesity is a state of low-grade inflammation. This study reported higher C-reactive protein (CRP) levels in obese individuals and established a correlation between CRP levels and body mass index (BMI). Subsequently, it was acknowledged that the inflammation linked to obesity, meta-inflammation, was one of the etiological factors for type 2 diabetes mellitus and insulin resistance. By virtue of their chronic persistent inflammation, autoimmune diseases proved to be robust disease models to study the effect of sustained inflammation on metabolism. The flurry of studies that followed firmly established that patients with autoimmune rheumatic diseases were more likely to have insulin resistance and associated metabolic abnormalities. The association between inflammation and metabolism is reciprocal with metabolic syndrome potentially influencing disease susceptibility, disease activity and treatment responsiveness in autoimmune rheumatic diseases. A recent meta-analysis which included 13 studies involving 400 609 participants and 13 562 rheumatoid arthritis (RA) patients showed that the relative risk (RR) for RA in obesity was 1.21 (95% CI: 1.02–1.44).2 Indeed the risk of RA increased by 13% (RR: 1.13; 95% CI: 1.01–1.26) for every 5 kg/m2 increase in BMI. A subgroup analyses showed that this association was for women and for seronegative RA. Another retrospective cohort study from Minnesota showed that obesity contributed to about 52% of new cases of RA between 1985–2007.3 Higher Disease Activity Score (DAS) and Health Assessment Questionnaire (HAQ) score, lower radiologic scores and lower therapeutic response have been noticed in obese RA patients.4 Interestingly, one study demonstrated a reduction in disease activity in RA patients undergoing bariatric surgery.5 Paradoxically, weight loss in a known RA patient was found to be a risk factor for mortality.6 Similar data is also emerging in spondyloarthritis. Obese individuals are more likely to develop psoriasis and obese psoriatics have a higher chance of developing psoriatic arthritis (PsA) with fewer chances of attaining a low disease activity state.7 In systemic lupus erythematosus (SLE), while BMI does not seem to influence the disease activity, damage accrual and atherosclerosis is higher in obese patients.8 The vital link between inflammation and metabolic syndrome is mediated by substances secreted from adipose tissue known as adipokines. These have pleotropic effects and their levels are altered in obesity. The list of adipokines has been ever expanding, but the more explored ones are leptin, adiponectin, resistin and visfatin. Among them, leptin is the one most studied in the context of inflammation. Structurally leptin resembles long chain cytokine family members such as interleukin (IL)-2 and IL-12.9 The full length leptin receptor isoform shows sequence homology to members of the class I cytokine receptor superfamily. The downstream signaling of this receptor is through the Janus-activated kinase/signal transducers and activators of transcription (JAK STAT) signal transduction pathway which it shares with a number of pro-inflammatory cytokines. The metabolic function of leptin is inducing satiety by acting at the hypothalamic level. Leptin levels are influenced by the caloric intake, amount of energy stored in the adipocytes, pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and hormones, including sex hormones. The levels of leptin are higher in females in comparison with males even after adjusting for BMI, a fact that has to be interpreted in the context of increased incidence of autoimmune diseases in females. In the innate immune system, leptin activates macrophages and natural killer (NK) cells and causes chemotaxis of neutrophils.9 In the adaptive immune system, it increases T cell survival, drives differentiation of naïve T cells toward the Th1 pathway, reduces T-reg and Th2 cell differentiation, and induces prostaglandin and reactive oxygen species (ROS) production. Congenital deficiency of leptin in both humans and mice were associated with reduced circulating CD-4 T cells, impaired T cell proliferation and cytokine release. Studies in autoimmune diseases have shown that leptin deficiency abrogates disease onset in experimental models of RA, SLE and multiple sclerosis (MS). Levels of leptin are elevated in patients with RA, MS and Sjögren's syndrome. Even in patients with normal weight, baseline leptin levels were found to predict higher disease activity and response to treatment.10 Elevated leptin levels are a risk factor for insulin resistance and cardiovascular disease (CVD) in RA11 In the synovium, leptin has been proposed to have a bone protective effect which might explain the lesser degree of radiologic erosions seen in obese RA patients.12 Adiponectin is a hormone secreted from adipocytes which has anti-inflammatory, anti-atherogenic and anti-diabetic actions.13 Structurally they resemble the complement component C1q. Adiponectin is an insulin sensitizer and its levels are reduced in obesity. It medicates macrophage activation through the adipokine receptors Adipo R1 and Adipo R2. The effect of this signaling is dependent on the state of polarization of macrophages. In M1 macrophages, it stimulates the release of pro-inflammatory mediators as TNF-α, IL-6 and IL-12. In M2 macrophages, it induces expression of IL-10, an anti-inflammatory cytokine. Adiponectin was also found to enhance the expression of scavenger receptors in macrophages. It enhances apoptotic clearance by binding to apoptotic cells by virtue of their structural similarity to C1q.14 In patients with active early RA, adipokine levels were found to be elevated following treatment with methotrexate and low-dose glucocorticoid.15 Different isoforms of adiponectin exist, but the low molecular weight form appears to be the one closely associated with disease activity.16 The leptin/adiponectin ratio is an independent risk factor for insulin resistance and CVD in RA,11 and adiponectin, but not the other adipokines, correlates with radiographic damage.12, 17 A pro-inflammatory role for adiponectin has also been proposed with in vivo studies showing increased prostaglandin E2 and matrix metalloproteinase (MMP) levels following stimulation of synovial fibroblasts with adiponectin.18 In PsA, levels of adiponectin were higher in patients with PsA and correlated with joint counts and use of anti-TNF therapy.19 Resistin and visfatin are other obesity-related hormones with effects on inflammation.14 Increased levels of resistin are associated with insulin resistance and increased production of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and IL-12. In RA patients, levels of resistin but not leptin or adiponectin correlated with inflammatory parameters.11 Another study found higher levels of resistin in RA patients but not in SLE.20 Visfatin has an insulinomimetic action. It increases IL-1β, TNF-α and IL-6 production. Higher levels of visfatin are seen in RA patients and a short-term reduction in visfatin levels is a marker for response in early RA.21 Higher visfatin levels are seen in ankylosing spondylitis and juvenile idiopathic arthritis (JIA),22, 23 and associate with methotrexate resistance in patients with JIA.23 In this edition, IJRD highlights the role of adipokines in various inflammatory joint diseases. Yaşar Bilge et al.24 explores the relation between adiponectin levels and change in disease state following treatment with methotrexate and low-dose prednisolone. Their study found that the levels of adiponectin increase following treatment with methotrexate in combination with low-dose prednisolone. Although the adiponectin levels tend to negatively correlate with insulin resistance at the end of 3 months of therapy, the difference was not statistically significant. This is one of the few studies that have longitudinally assessed the changes in adiponectin levels with change in disease activity and treatment. The data is not entirely conclusive and requires further exploration. Reactive oxygen damage has been one of the proposed pathologies in scleroderma. Winsz-Szczotka et al. connected the link between adipokines, free radical generation and stage of disease.25 They demonstrated that the levels of adiponectin and leptin are both reduced in scleroderma, more so in advanced disease. Total lipid peroxide, a marker for oxidative damage was higher in scleroderma patients and their levels showed positive correlation with leptin but a negative correlation with adiponectin confirming their pro- and antioxidant effects, respectively. Loghman et al.26 studied levels of urinary adiponectin in patients with SLE as a marker for nephritis and their results suggest that urinary adiponectin could be a good marker for prediction of lupus nephritis. Dikbas et al.27 showed that being a disease with close links to metabolic syndrome, psoriatic patients do indeed have higher levels of adipokines, namely adiponectin, visfatin and resistin, but they failed to show a correlation with disease activity in PsA. In conclusion, inflammation seems to be the singular driving force for a wide variety of biological processes in health and disease. The whole of physical science has been in the search for the ‘theory of everything’, that can link all the physical laws. As the link between inflammation and homeostasis is slowly unraveling, medical science may be heading toward that unified theory based on the pivotal role of inflammation. None. The authors declare no competing interests. All authors significantly participated and were involved in the conception and design, drafting the manuscript or revising it critically for intellectual content, and all authors approved the final version of the paper before submission.