You are what you eat!

Matarese G, Carrieri PB, Montella S, De Rosa V, La Cava A.

Abstract

Clinical and experimental data, together with epidemiological studies, have suggested that the pathogenesis of multiple sclerosis (MS) might involve factors that link the immune system with metabolic status. Moreover, recent research has shown that leptin, the adipocyte-derived hormone that controls food intake and metabolism, can promote experimental autoimmune encephalomyelitis, an animal model of MS. In patients with MS, the association of leptin with disease activity has been dissected at the molecular level, providing new mechanistic explanations for the role of this hormone in MS. Here, we review the intricate relationship between leptin and other metabolic modulators within a framework that incorporates the latest advances linking the CNS, immune tolerance and metabolic status. We also consider the translational implications of these new findings for improved management of MS.

Eur J Neurol. 2010 Feb;17(2):332-4. doi: 10.1111/j.1468-1331.2009.02701.x. Epub 2009 Jun 15.

Matarese G, Procaccini C, De Rosa V.

Abstract

Over the last few years, a series of molecules known to play a function in metabolism has also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production (i.e., genetic leptin deficiency, anorexia nervosa, malnutrition) are associated with increased susceptibility to infections. Conversely, immune-mediated disorders such as autoimmune disorders are associated with increased secretion of leptin and production of proinflammatory, pathogenic cytokines. Leptin could represent the "missing link" among immune response, metabolic function, and nutritional status. Indeed, more recently, leptin-deficient mice have been shown to be resistant to a series of experimentally induced autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Finally, leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signaling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3(+)CD4(+) T cells. These data suggest that leptin can be considered as a link among immune tolerance, metabolic state, and autoimmunity and that strategies aimed at interfering with the leptin axis could represent innovative, therapeutic tools for autoimmune disorders.

Neurosci Bull. 2006 Mar;22(2):115-7.

Leptin enhances the release of cytokines by peripheral blood mononuclear cells from acute multiple sclerosis patients.

Chen ZL, Wang DM, Duan JF, Wen SQ, Tang YF, Li ZX.

Abstract

Objective To explore the effect of leptin on cytokine production by PBMCs obtained from MS patients either in acute (relapse) or in stable (nonrelapse) phase of disease. 

Methods PBMCs were collected from 25 untreated acute MS patients, 11 stable MS patients and 20 healthy controls. PBMCs were cultured either with RPMI-1640 alone or with leptin (1.25 nmol/ml), phytohemagglutinin (PHA) (100 mug/ml), and leptin + PHA. 72 h later the supernate of the culture medium were collected and stored at -70 degrees C. The pro-inflammatory cytokine (IFN-gamma) concentration were determined using an enzyme-linked immunosorbent assay ( ELISA), and the anti-inflammatory cytokine (IL-4) concentration were investigated by radioimmunity methods. 

Results Our data showed that leptin induced IFN-gamma production by PBMCs of patients in an acute phase of disease but not in a stable phase or in healthy controls. Moreover, we found that PHA induced IL-4 production by PBMCs of patients in an acute phase of disease, but leptin inhibited this ability of PHA. 

Conclusion Leptin can affect on pro- and anti-inflammatory cytokine production by PBMCs collected from MS patients, may be this connected with leptin increase the susceptiveness of MS.

Figure: Main mechanisms involved in promoting autoimmunity in obesity. 1) Both adipocytes (fat cells) and immune cells massively infiltrating body fat secrete high levels of adipokines, responsible for a pro-inflammatory state as well as dysregulation of Th17/Treg balance (pro-inflammatory cells/regulatory cell balance); 2) AIM induces fat breakdown, producing saturated fatty acids. These act on fat tissue by promoting pro-inflammatory M1-macrophage infiltration. Also saturated fatty acids activate NLRP3-inflammasome, secreting IL1B and IL-18 involved in the generation of autoimmune diseases. AIM also forms immune complexes with natural autoreactive IgM (antibody) associated with self antigens, promoting retention on dendritic cells. Presentation of these self antigens by dendritic to B-cells leads to the production of IgG autoantibodies; 3) obesity promotes Th17 profile; 4) fatty food causes an alteration in gut microbes, leading to a change in the modulation of extra intestinal immune responses and deregulation of the Th17/Treg balance; 5) obese patients have a higher prevalence of vitamin D deficiency, which increase Th17 cells, B cells and secretion of antibodies as well as reducing Treg cells.

The negative connotations of obesity is so ingrained in our current society that, I predict, it will be the bastion of prejudice and unconscious racism in tomorrow's society. We may even purchase certain items of foods from supermarkets under the scrutiny of the label 'obesity kills', as we currently do so with tobacco.

Although the cause of MS remains undetermined, we know there's a role for environmental factors. Childhood and adolescent obesity increases the risk of MS with an odds ratio of 2 in women>men, and this is a critical period of susceptibility to factors promoting autoimmunity and may explain the greater female-to-male risk in MS. Obesity as you can see from the above figure predisposes to the induction of Th17, which we know exacerbates MS. 

But the most exciting field of investigation in this area has been the role of adipokines, in particular that of Leptin in the induction and progression of MS. Leptin is released primarily by fat cells and influences energy balance and satiety (essentially tells the brain when we've eaten enough!). An increase in Leptin levels observed in obese subjects, has also been seen in PwMS, although findings are conflicting (see below). The leptin deficient ob/ob mouse demonstrates that leptin is needed for EAE (mouse model of MS) development, and replacement of Leptin converted it from disease resistance to susceptibility by shifting from a Th2 (good) to a Th1 (mostly bad) immune response. Conversely, neutralization of Leptin reduced EAE onset, severity and mortality by promoting Th2 and Treg (regulatory T cell) profile. Studies in PwMS have been variable with some not showing a difference in MS and healthy subjects, while others demonstrate raised levels in those with no prior treatment, and even female RRMSers. Clearly it will be difficult to control for such a study, how would you pick the healthy controls? As a junior doctor, I remember participating in a study on Leptin and being booted off when my BMI crept past 20!