Is Nature Lost Weight Loss Motivation?

Written | Qi's clinical data from multiple immune diseases, including asthma, suggest that obese patients have more severe disease and are resistant to conventional therapy than normal-sized patients [1, 2], But the mechanism behind this phenomenon remains unclear
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Recent evidence suggests that obesity and metabolic diseases also affect the immune system, but the mechanisms and implications for immunotherapy remain largely unknown [3]
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On March 30, 2022, a number of teams including Alexander Marson's team from the University of California, San Francisco collaborated to publish an article titled Obesity alters pathology and treatment response in inflammatory disease in the journal Nature.
The research team used two specialties.
The model of atopic dermatitis found that obesity can transform the classical type 2 T helper cell (TH2) predominant associated with atopic dermatitis (AD) into a TH17 predominant inflammatory type.
PPARγ activity is reduced in murine TH2 cells, and treatment with small molecule agonists of PPARγ can limit the progression of TH17 pathology and enhance the therapeutic response to TH2-targeted biotherapeutics
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Taken together, these findings shed light on the impact of obesity on immune disease and suggest a precision medicine approach to obesity-induced immune dysregulation
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To explain the effect of obesity on immunotherapy, the researchers first induced AD mouse models of atopic dermatitis with the vitamin D3 analog MC903.
Compared with lean mice, obese mice had significantly increased inflammatory responses and exhibited more severe erythema and scaly
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In another model of AD induced with ovalbumin and papain, obese mice also showed more severe allergic airway responses, such as increased cellular infiltration across multiple immune subpopulations
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Flow cytometry showed that CD4+ T cells positive for TH17 cytokines IL-17A and IL-17F were significantly increased in obese mice compared with TH2 cytokines (Figure 1)
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Not only that, the degree of TH17 differentiation between lean and fat mice also showed significant differences, and most of the TH17 in fat mice were in the late stage of differentiation
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Interestingly, AD is a typical model of TH2-driven autoimmunity, a finding that suggests that obesity may shift TH2-directed inflammation toward aberrant TH17-dominated inflammation
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Figure 1.
Obesity transforms typical TH2-driven inflammation into more severe TH17-driven disease -17A and IL-17F positive cells showed a further upward trend
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So what factors lead to the above phenomenon? The nuclear hormone receptor (NHR) superfamily is a class of transcription factors sensitive to systematic changes in physiological and metabolic states, among which PPARγ stands out due to its high expression in TH2 and differential expression in TH17 and TH2
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To assess how obesity affects gene expression downstream of PPARγ in T cells, the researchers used CHIP-seq to determine the genome-wide binding site of PPARγ in TH2 cells.
The genes regulated by PPARγ in obese mice are in TH2 compared to lean mice.
Significantly lower, suggesting that PPARγ may play a role in maintaining the inflammatory dominance of TH2, and its deficiency may favor other TH cell responses
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To test this idea, the researchers generated T-cell-specific PPARγ-deficient mice.
When treated with MC903, PPARγ-TKO lean mice exhibited symptoms similar to wild-type AD fat mice.
Flow analysis showed that IL-17A and IL-17F positive cells increased
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As a PPARγ agonist, if administered to fat mice, will TZD promote TH2-selective responses and inhibit TH17? So the researchers used this drug to treat AD fat mice and PPARγ-TKO lean mice, which significantly reduced AD severity and TH17 subsets in the fat mice
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So if the drug can strengthen the TH2-dominated immune response in AD, can it restore the anti-IL-4/IL-13 efficacy? The researchers found that administration alone did not reduce AD ​​severity in obese mice, but improved anti-IL-4/IL-13 treatment
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Overall, this study explains how obesity alters the structure of the immune response and suggests a new strategy for precision immunotherapy to overcome the immune system alterations induced by a high-fat diet
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Link to the original text: https://doi.
org/10.
1038/s41586-022-04536-0 Publisher: Eleven References 1.
Hersoug, LG & Linneberg, A.
The link between the epidemics of obesity and allergic diseases: does obesity Induce decreased immune tolerance? Allergy 62, 1205–1213 (2007).
2.
Wenzel, SE Asthma phenotypes: the evolution from clinical to molecular approaches.
Nat.
Med.
18, 716–725 (2012).
3.
Buck, MD, Sowell, RT, Kaech, SM & Pearce, EL Metabolic instruction of immunity.
Cell 169, 570–586 (2017).
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