Multiple sclerosis (MS) is a neurodegenerative disorder that causes inflammation in the central nerve system (CNS), which leads to neuropathy [19, 20]. According to epidemiological studies, its prevalence is closely associated with nutrition, and it commonly occurs in people with high levels of fatty acid and Vitamin D deficiency [21]. This study evaluated serum levels of Leptin, Orexin-A, and TGF-β in 25 MS patients and investigated the relationship between these factors and BMI.
We found low levels of TGF_B and Orexin-A and high levels of Leptin in MS patients compared to healthy controls, and the stories had changed significantly. Also, significant differences were observed in the levels of triglycerides and cholesterol between test groups. But the relationship between BMI and serum levels of Orexin A, TGF_B, and Leptin was not statistically significant.
An increase in BMI is an MS risk factor, and MS is more common in people who are genetically predisposed to high BMI [22]. The mechanism of BMI increase in MS has not yet been well studied. But some studies have reported a direct relationship between BMI and disability in RRMS patients. One study reported that women who experienced higher BMIs in adulthood were more likely to develop MS at an earlier age. This could be prevented by choosing a proper lifestyle and dietary habits [23]. Several studies over the past decade have shown that early obesity in childhood and adulthood are significant risk factors for MS [24]. With the onset of MS, obesity can worsen the disease and impair the response to the treatment (s). Therefore, obesity causes sensitivity to MS and acts as an essential risk factor for the disease [14].
High levels of pro-inflammatory cytokines and leptin and low anti-inflammatory cytokines were observed in obese MS patients [25]. Generally, MS patients under a therapy regimen show lower leptin levels in serum and CSF, whereas leptin levels during the acute phase of MS are usually high [21, 26]. Reducing leptin levels leads to amelioration of experimental autoimmune encephalomyelitis (EAE), an experimental animal model for human MS. Also, the onset of disease was delayed, and the clinical symptoms improved [27].
Nowadays, we know more about leptin's role in the immune system [26–28]. Leptin directly acts on the leptin receptor (LepR) on CD4+ T cells and induces metabolic and functional changes in T cells. Leptin-resistant CD4+ T-cells can not regulate cytokine production properly [29]. This receptor-mediated problem is the basis of some autoimmune diseases such as MS.
Leptin induces anorexia during acute inflammatory responses [30]. Various studies have shown that nutritional intake is significantly lower in MS patients than in healthy controls [31]. A significant increase in leptin levels can explain the reduction in nutrient intake. On the other hand, Orexin-A is essential for eating behavior. Orexin-A increases appetite while decreasing metabolism [32, 33]. Our results showed significant changes in both Orexin-A and leptin concentration in MS patients compared to healthy controls following these reports. Orexin-A secretion is increased during physical activity [34]. Some diseases affecting the CNS, such as MS, can reduce the secretion of this neuropeptide.
Unfortunately, the importance of nutritional status is often underestimated by patients and therapists. Probably, an imbalance in Orexin-A and leptin levels affects the eating behaviors of patients. On the other hand, there is dietary advice available for MS patients, which is contradictory and not investigated [35].
Interestingly, we could not find any association between BMI values in the patient and control groups. This finding was also reported by some other studies [31, 36]. What is the explanation for this contradictory finding? Although there was enough appetite and suitable hormonal levels, high leptin level and low Orexin-A level, the BMI did not change in the patients group compared to the control group. Studies have shown leptin resistance when people have a diet rich in fat [37, 38]. As we have shown in Table 2, MS patients had significantly higher triglycerides and cholesterol levels than healthy participants, which may induce leptin resistance in patients. Also, MS is a nervous system disorder that may disrupt many nervous system-associated processes, such as vagal nerve functions, appetite, metabolism, and obesity. In addition, MS can affect many cytokines and inflammatory mediators [39, 40]. Orexins also have neuroprotective and immune-regulating (i.e. anti-inflammatory) properties. Studies show that orexins may have therapeutic potential in several pathologies with a single immune component, including multiple sclerosis, Alzheimer's disease, obesity, septic shock, and cancer [41]. We suggest more investigations into dietary-dependent neuropathy in MS patients and more in-depth examinations of the role of BMI in MS patients.
TGF-β, a cytokine produced by monocytes, smooth muscle cells, and endothelial cells, is involved in tissue development, extracellular matrix production, and immune system regulation via blocking inflammatory responses and promoting regulatory T cells. Furthermore, TGF-β plays a pivotal role in obesity and some significant disorders [42, 43]. Mice lacking TGF-β receptors developed the inflammatory disease. Also, the inability of T cells to produce TGF-β led to the development of autoimmune disorders [44]. Also, according to a study, the imbalance in IL-10 and TGF levels leads to obesity via inefficient regulation of the inflammatory cytokines [45].
TGF-β ameliorates EAE in mice. It seems that TGF-β is associated with an increase in specific cytokines such as interleukin 2 (IL2), IL6 and IL12 [46]. Regulating the TGF-β level can be utilized as a therapeutic approach. A study demonstrated that TGF-β is low in MS patients, associated with increased IL2 and IL6 [47]. In one study, a significant reduction in TGF-β expression was observed in patients with RRMS, consistent with our research [48]. In one study done in 2011, TGF-β signalling protected mice from obesity and diabetes. These results suggest that TGF-β signalling regulates glucose tolerance and energy homeostasis and suggest that modulating TGF-β activity may be an effective treatment strategy for obesity [49]. TGF-β is a central regulator in many pathophysiological processes in MS. We demonstrated there was no significant association between BMI and TGF-β in MS patients.