Background Research has found a link between obesity or being overweight and the likelihood of getting autoimmune disorders. This relationship can be described immunologically, where T lymphocyte overstimulation is influenced by energy and nutrient sensing mechanisms. Adipose tissue is an organ with immunological action that can influence systemic immune responses by producing adipocytokines.
Immune cells, on the other hand, can impact adipocyte metabolism and homeostasis by secreting anti- and pro-inflammatory cytokines. This suggested that metabolic overload caused by obesity could have an effect on immunometabolism, possibly altering vulnerability to autoimmune disorders.
Obesity and vulnerability to type 1 diabetes
Obesity has been found as a risk factor for autoimmune diseases such as type 1 diabetes (T1D) and multiple sclerosis (MS). (MS). Studies on young obese people have revealed a 1.6- to 1.9-fold increase in the risk of getting MS during adolescence and young adulthood. This association with obesity, however, was not found at the onset of MS.
This association was also confirmed in people who possess the human leukocyte antigen (HLA)-DRB1*15:01 susceptibility allele, which is responsible for presenting myelin self-antigens to autoreactive T cells. Similarly, an elevated body mass index (BMI) at birth is associated with an increased susceptibility to T1D in children. The findings point to a virtually linear relationship between birth weight and the prevalence of T1D.
Rapamycin’s mechanistic target and body obesity (mTOR)
Body adiposity has been shown to trigger the hyperactivity of intracellular energy- and nutrient-sensing pathways like mTOR, resulting in metabolic overload in peripheral tissues. Immune cells that are accountable for both effector and regulatory immune responses are included. It has been noted that the adipocytokine leptin, in conjunction with increased amounts of circulating nutrients, can enhance inflammatory immune responses in MS patients who are obese and have not gotten prior treatment.
Overexpression of nutrients and leptin causes continuous mTOR activation in T cells, resulting in irregular T cell receptor signaling. (TCRs). Excessive mTOR activation within T cells mimics a powerful, above-normal TCR stimulus that prevents forkhead-box P3 (FOXP3) gene transcription. This gene’s expression is required for the formation and maintenance of anti-inflammatory CD4+CD25+FOXP3+ regulatory T cells. (Tregs). Obesity has been shown to impair anti-inflammatory thymic Treg transcription and peripheral differentiation from CD4+CD25 conventional T (Tconv) cell precursors owing to leptin overproduction.
mTOR function and normal BMI
Physiological nutrients and fluctuations in leptin caused by daily fasting and feeding periods drive mTOR activity oscillations. These oscillations, however, are lost in instances of obesity due to excessive food consumption. As a result, it can be deduced that in people with normal BMI and physiological feeding and fasting cycles, sustenance and maintenance of self-tolerance are associated with fluctuations in mTOR activity within Tregs. Treg expansion and functionality appear to be critical for suppressing pathogenic TH1 and TH17 cells and avoiding autoimmunity.
Insulin, leptin, and insulin-like growth factor 1 (IGF-1) are nutrition and metabolism-related growth factors that activate mTOR signaling in immune cells. This activation has an effect on both systemic and intracellular immunometabolism, influencing autoimmunity and inflammation. Tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-6, IL-17, interferon-g (IFN-g), and leptin have all been discovered to be secreted by adipose tissue. This secretion has been related to a higher risk of autoimmunity and peripheral tissue damage.
The interaction of fat tissue and the immune system
In both structure and function, the immune system and adipose tissue communicate and engage with one another. Adipose tissue usually surrounds both primary and secondary lymphoid organs. Adipose tissue’s proximity to T cells, B cells, Tregs, dendritic cells, and macrophages promotes their migration to the adipose tissue. Adipocytes can also show immune-like behaviors.
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Obesity-related changes in the quantity and efficacy of Treg cells may have an influence on susceptibility to infections and malignancies. The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been related to the generation of autoantibodies and is more severe in obese people. Furthermore, people with a greater BMI have better responses to cancer immunotherapy than people with a lower BMI.
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Conclusion
According to this perspective, molecules that interact with leptin derived from adipocytes can influence immune function, and this modulation can differ based on metabolic status. The molecular analysis of the impact of individual nutrients on immunological self-tolerance, as well as the specific time frame during which Caloric Restriction (CR) can serve as a viable therapeutic approach for autoimmunity associated with obesity, are areas that require further investigation.
