In an increasingly overweight population, obesity is bringing with it a host of negative health implications including an increased risk of diabetes, cancer and autoimmune disorders. This disease burden has been linked to the number of effects obesity has on the immune system. Since the linking of TNF-alpha, a cytokine which is overexpressed in adipose tissue to insulin resistance,¹ a host of inflammatory mediators and more traditional hormones has been linked to immune cell activation and obesity. 

Many of the these mediators are derived from macrophages, which infiltrate adipose tissues in obesity and are scarce in adipose tissues from lean individuals.² It is now clear that levels of circulating and adipose tissue immune cells differ according to weight. As clinicians, we need to educate ourselves about these changes because the emerging evidence is that they not only cause the complications of obesity but contribute to a vicious cycle of weight gain. 

Key immune cells

While much of the work has focused on macrophages in obesity, our interest has recently turned to invariant natural killer T-cells (iNKT) that instruct macrophages on how to behave. These innate T-lymphocytes are small in number (0.5% of circulating T-cells) and recognise lipid antigens. Recent studies have shown that iNKT cells appear to be directly involved in regulation of weight and metabolism. 

This concept that the immune system itself might regulate metabolism and body weight has not been widely considered to date. Lynch et al showed that obese individuals have lower circulating iNKT cells compared to lean controls. Patients who underwent gastric bypass surgery had an increase in peripheral iNKT levels following weight loss after surgery. However, the surprising observation was that mice lacking iNKT cells showed a significant tendency to gain weight with associated elevated fasting glucose levels, impaired glucose tolerance and increased insulin resistance. Then following restoration of iNKT cells in these mice there was significant rapid weight loss and improved glucose metabolism compared to controls.³

In another important study, Nguyen et al demonstrated that macrophages also impact directly on weight and metabolism by inducing thermogenesis and lipolysis of white adipose tissue.⁴

Interleukin-4 (IL-4) is emerging as a key cytokine linking the immune system to metabolism. IL-4 is required to activate macrophages, and mice deficient in IL-4 signalling have been shown to lose less weight.⁴ IL-4 also appears to be key to the action of iNKT cells where it has been shown that activation of these cells by an IL-4 signalling pathway resulted in macrophage activation and improved glucose homeostasis.⁵

Role of hormones

The second major component to the story is the demonstration that iNKT cells and macrophages are regulated by a range of gut hormones, adipokines and hormones of the hypothalamic-pituitary axis. 

The presence of a range of receptors for hormones and neuropeptides on immune cells reminds us that this relationship between hormones and immune cells has long been known.⁶ Indeed the anti-inflammatory properties of corticosteroids have resulted in much therapeutic benefit but significant weight gain and high sugars, while thyroid hormone, growth hormone, prolactin and insulin-like growth factor all have an immunomodulatory role. 

Similarly the gut hormones cholecystokinin, ghrelin, glucagon-like-peptide-1 (GLP-1) and peptide YY – the primary role of which is classically seen as controlling appetite and energy homeostasis – have also been found to exert control over the immune system. Of particular note is GLP-1 – this incretin molecule that is released from intestinal cells in response to glucose ingestion is now being used to treat diabetes and obesity. 

We have recently shown that treating obese diabetes patients with psoriasis with GLP-1 analogues resulted in an unexpected improvement in psoriasis. This we proposed was thought to be due to an effect of GLP-1 on iNKT cells. We demonstrated a reduction in psoriatic plaque iNKT cell numbers and an increase in circulatory iNKT levels in response to treatment with GLP-1 and showed that it regulated iNKT cell function.⁷ Furthermore, GLP-1 has also been shown to activate and modulate macrophage function.⁸

GLP-1 therefore increases iNKT cell levels, which cause weight loss following adoptive transfer in mice and also activates macrophages, which have a role in thermogenesis and weight loss. We must consider the possibility that these effects on immune cells might be directly accountable for some of their impact on metabolism and weight. 

Furthermore, if IL-4 is indeed a significant part of the link between the immune system and weight, then any substance that affects IL-4 production (hormonal or otherwise) could impact on thermogenesis and ultimately on body weight. For example, it has been shown that smoking increases IL-4 production from immune cells.⁹ This may explain some component of the poorly understood effects of smoking on weight regulation. 

Conclusion

Taken together we must reconsider how we view mechanisms of weight gain. The simple equation of energy-in versus energy-out may no longer apply if hormones – and indeed other substances – are manipulating immune cells which are in turn having an effect on thermogenesis and weight. We need to learn much more about the relationship between hormones, immune cells and obesity, but it is clear that there is significant therapeutic potential in this now re-emerging field.  

References

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