Leptin in intestinal inflammation: good and bad gut feelings

Leptin, a molecule that is critical in the regulation of energy balance, body weight, and reproductive function, is a strong regulator of T cell function.¹ This is one of many examples of redundancy and of the overlapping roles of molecules within the neuroendocrine and immune systems.² Leptin is part of the helical cytokine family along with interleukin (IL-) 6, IL-12, and IL-15, its receptor (ObR) belonging to the group of class I cytokine receptors, which includes gp-130, the common signal transducing component for the IL-6 related family of cytokines.¹ Leptin is expressed particularly in adipose tissue and to a lesser extent in other tissues such as muscle, stomach, and placenta.¹ More recently, leptin has also been shown to be expressed in activated inflammatory T helper 1 lymphocytes during experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.³ In keeping with these findings, the ObR has been found not only on the hypothalamus and adipose tissue but also on immune cells such as T lymphocytes and monocytes.^1,4 Addition of this hormone to T cells in culture can alter both their growth rate and pattern of production of cytokines—proteins that influence or mediate immune functions.^4,5 Indeed, leptin enhances the activity of T cells that produce proinflammatory cytokines and that orchestrate many organ specific autoimmune diseases.^4,5

In the current issue of Gut, Siegmund and colleagues⁶ describe the potent effects of leptin on T cell mediated intestinal autoimmunity and further define the role of leptin and its receptor in the development of such diseases [see page 965]. The authors elegantly demonstrate that T cells from naturally leptin receptor deficient (db/db) obese mice display a reduced capacity to induce, on passive transfer, a T cell mediated model of colitis in T cell deficient mice (scid mice). In this model, it is possible to study the function of leptin receptor deficient T cells in a normal microenvironment where insulin, glucocorticoids, and other factors are not altered as they are in db/db obese mice. Leptin and its receptor were expressed on transferred wild-type (WT) T cells and infiltrating lymphocytes. Transfer of T cells from db/db mice induced delayed disease compared with transfer of WT cells. Histological examination of the colon, early after induction of disease, revealed marked inflammation in mice injected with WT cells whereas no inflammation was observed in mice receiving db/db cells. The delayed disease could not be attributed to the effect of increased levels of glucocorticoids in db/db donor mice as treatment with glucocorticoids of WT donor lymphocytes did not change their pathogenic capacity. Lamina propria infiltrating lymphocytes (LPL) from WT and db/db mice showed no difference in terms of differentiation, expression of homing receptors, or activation markers. Interestingly, the most evident difference was an increased rate of apoptosis of LPL derived from db/db mice and reduced production of inflammatory cytokines and chemokines. Finally, the nuclear receptor peroxisome proliferator activated receptor γ (PPARγ), known to inhibit expression of inflammatory cytokines, including leptin, was highly expressed in colonic cells of mice that had received db/db cells.^6,7

Recent reports have shown that leptin secreted by the gastric mucosa is not fully degraded by proteolysis and can reach the intestine in an active form able to control the expression of sodium/glucose and peptide transporters on intestinal epithelial cells.^8,9 Therefore, it may be speculated that leptin displays a dual nature: as a growth factor for the intestine, involved in the absorption of carbohydrates and proteins on the one hand, and as a mediator of the intestinal inflammation induced by T lymphocytes on the other.^6,8–10 In addition, leptin deficient ob/ob mice are resistant to a variety of experimental models of inflammation/autoimmunity.^11–13 In particular, they are resistant to intestinal inflammation induced by administration of dextran sulphate sodium or trinitrobenzene sulphonic acid.¹⁰ In these models, resistance to colitis in the absence of leptin was associated with reduced cytokine secretion and increased apoptosis of LPL. The report by Siegmund et al further reinforces the role of leptin and particularly its receptor in intestinal autoimmunity.⁶ It is well known that there are some confounding factors in animal models of leptin deficiency such as ob/ob and db/db mice where massive obesity, insulin resistance, hyperglycaemia, and high levels of glucocorticoids could account for the altered immune response.^1,5 In the present report, the model utilised elegantly rules out the possible influence on T cell pathogenicity of other factors, such as hyperglycaemia, hyperinsulinaemia, and hypercorticosteronaemia, that characterise db/db mice.

Antagonists of the ObR may well be considered as possible agents able to alter the progression of intestinal inflammation. Recently, mesenteric adipose tissue from patients with Crohn’s disease and ulcerative colitis showed high levels of expression of leptin mRNA.¹⁴ It is well known that food deprivation in the context of intestinal inflammation can improve disease symptoms and reduce the number of relapses.¹⁵ Many controlled trials in humans have shown that fasting and dietary change can ameliorate symptoms of patients with intestinal bowel disease, rheumatoid arthritis, and multiple sclerosis.^3,15–18 In view of the results of Siegmund et al, we must also consider whether fasting and changes in diet might change leptin levels, thus altering the function of T cells. The implication of this work is that the leptin/ObR axis drives the activity of proinflammatory, self-reactive T cells and that reduction in leptin secretion and/or in the ObR signalling machinery can change the pattern of cytokines generated and the disease inducing potential of intestinal T cells. The idea that leptin could also have a significant role in intestinal inflammation is strengthened by studies of the genes expressed in patients with intestinal bowel disease: leptin and related genes are overexpressed in both intestinal mucosa and mesenteric adipose tissue.¹⁴ Once again, we witness the remarkable choreography of molecules related to body weight and energy metabolism and the parallel roles of these same molecules in the finely tuned immune response.¹⁹ In the context of the whole animal, however, there is still much to understand about the potential interactions between fat, metabolism, and the immune response. Increasing experimental evidence is revealing the importance of molecules, including leptin, at the interface between the immune system and metabolic regulation. In a broader context, the work by Siegmund et al illustrates how the state of immunity is influenced by the presence of leptin whose serum levels correlate with nutritional status. Leptin enhances the transport of nutrients across the intestinal barrier and supports an immune response poised to repulse pathogens.^5,8,9 But it may also represent a key substrate for the seed of autoimmunity to take root. Therefore, manipulation of the leptin/ObR axis may provide a novel means of downregulating T cell mediated autoimmune responses.