Nat commun: Obesity causes mucous membrane-related invaric T cells to promote inflammation and intestinal ecological disorders, which in turn contribute to metabolic dysfunction.

In an article published in Nature Communications, Professor Agn?s Lehuen of the University of Paris, France, found that MAIT cells promote inflammation of adipose tissue and back intestines, leading to damage to insulin and glucose metabolism.
MAIT cells in adipose tissue by inducing M1 macrophages to polarize in the way that mr1 depends, and in the intestines by inducing microbiome disorders and loss of intestinal integrity.
findings suggest that blocking MAIT cell activeization during obesity may be an effective strategy for reducing chronic inflammation, preventing malnutrition and improving metabolic parameters.
obesity is characterized by chronic low inflammation of the visceral adipose tissue (VAT), which is the main driver associated with the development of insulin resistance to type 2 diabetes (T2D).
VaT inflammation in obesity is the result of tissue accumulation that includes M1 macrophages, CD8 inflammatory immune cells, T cells, Th17 cells of CD4 and T cells, NK cells, neivational granulocytes, and .
In contrast, the frequency of anti-inflammatory immune cells associated with insulin resistance (e.g. M2 macrophages, Foxp3 plus regulatory T-cells (Treg), eosinophils, and type 2 congenital lymphocytes (ILC2)) decreased through local control of inflammation in VAT.
mucous membranes contain many immune cells because it is continuously ingested from dietary exposure to microbial antigens and antigens.
Obesity promotes an inflammatory transformation of the intestinal immune cell population, characterized by a decrease in Foxp3 and Treg cells in the inherent layer, an increase in the number of Th1 and CD8 and T cells that produce IFN-17, and an increase in the number of cells producing IL-17.
obesity is also associated with changes in the gastrointestinal microbiome, which affects the expansion of body fat, systemic inflammation and insulin resistance in obese patients or mice.
mucous membrane-related constant T (MAIT) cells are congenital T-cells that usually express the same TCR alpha chain (V alpha 7.2-J alpha33 in human beings, V alpha 19-J alpha 33 in mice), and a limited number of beta chains.
main tissue compatibility complex-related molecules 1 (MR1) are identified by MAIT cells, presenting antigens from certain bacteria and yeasts.
MAIT cell antigens derived from vitamin B2 anabolic bacterial metabolites.
researchers and others to reveal major MAIT cell changes in T2D and obese patients.
in these patients, MAIT cells had lower blood levels and produced high levels of IL-17 in VAT.
addition, weight loss due to bariatric surgery and associated improvements in metabolism and inflammatory states were accompanied by a significant increase in the frequency of blood MAIT cells.
all of these observations prompted researchers to study the role of MAIT cells in mouse models during obesity and T2D.
The researchers first analyzed MAIT cell changes in obese C57BL / 6J(B6) mice, who were either fed a high-fat diet (HFD) or lacked leptin (-/-mice), and then used the following methods to interpret the effects of MAIT cells on obesity V alpha19 GM B6 mice expressed increased frequency of MAIT cells, while MR1-/-disease states, immune cells in these tissues and intestinal bacteria.
researchers also assessed the therapeutic potential of blocking MAIT cell function with inactive parts.
the researchers' findings suggest that MAIT cells play a harmful role in the development of metabolic dysfunction, involving the polarization of macrophage M in adipose tissue, as well as malnutrition and intestinal leakage.
study of damaged MAIT cell accumulation in adipose tissue and the intestinal intestinal system first analyzed the frequency of MAIT cells in several tissues fed TOD or normal diet (ND) for 12 weeks.
MAIT cells have been identified as CD45 and CD19 - Cell CD11b - TCR xenon - TCR alpha beta and TetMR1 .
as previously observed in obese and T2D patients, the frequency of MAIT cells in the blood of obese B6 mice was lower than in lean mice.
compared to lean mice, the frequency of testicular adipose tissue (Epi-AT) and MAIT cells in the intestinal system decreased in obese mice, while the frequency of MAIT cells in the spleen, liver and colon remained the same.
noteworthy, in absolute terms, a decrease in the frequency of MAIT cells in Epi-AT and the rectum was also observed.
in these tissues, most MAIT cells are CD4 - CD8 alpha - (80% of MAIT cells), and the ratio has not changed under HFD.
obesity can induce early modification of immune cell stability in adipose tissues and intestines, the researchers conducted dynamic analysis of the frequency of MAIT cells in these tissues.
no significant difference was observed 6 weeks after the start of HFD, but after 16 weeks of eating, the difference observed after 12 weeks of HFD remained.
Interestingly, using another obese mouse model, mice lacking leptin (-/-), the researchers also observed significant reductions in the frequency of MAIT cells in both the intestinal and Epi-AT cells compared to (-//) co-nest controls.
decrease in the frequency and number of MAIT cells in obese mice may be due to impaired collection and proliferation and increased cell death.
to analyze MAIT cell migration, CD45.1 and MAIT cells were injected into obese and obese B6 mice and analyzed in Epi-AT and the rectum after 5 days.
in thin and obese B6 mice, the frequency of CD45.1 plus MAIT cells was similar in alpha beta T lymphocytes and CD45 plus cells.
MaIT cell proliferation analysis based on Ki67 staining did not show any difference between MAIT cells in obese and lean mice.
contrast, analysis of antioptosis and apoptosis molecular expression in MAIT cells showed an increase in MAIT apoptosis in obese mice compared to lean mice.
obesity, transcription levels of apoptosis-promoting molecules in MAIT cells (e.g. cMyc, Casp9, and Bax) increased, while Bcl-2 mRNA levels decreased.
BCL-2 expression in the intestinal echo and Epi-AT was confirmed at protein levels, but was not observed in the spleen, liver and colon.
, these data suggest that Epi-AT and MAIT cells in the intestinal back intestine in obese mice are experiencing apoptosis, leading to lower frequencies.
maIT cells exhibited inflammatory characteristics, the researchers analyzed the dedication and cytokines of MAIT cells fed to different tissues in mice fed ND or HFD.
compared to mice under ND, there was a significant increase in expression of Epi-AT and MAIT cell surface maturation/effect markers CD44 in mice with HFD.
, CD69 activation/retention markers were significantly reduced in both tissues of obese mice.
notably, CD44 and CD69 expressions on MAIT cells from the spleen were not modified and only a small number of modifications were observed in the liver and colon.
analysis of cytokine production through qPCR and flow cytometers showed that obese mice's intestinal MAIT cells produced more IL-17A, and Epi-AT MAIT cells produced more TNF-alpha and IL-17A.
increase in cytokine production was also observed in MAIT cells in the liver, but not in the colon.
Compared to lean mice, analysis of cytokines and chemic factor receptured transcripts commonly associated with the Th1 reaction (IL-18R) and Th17 reaction (CCR6) in obese MAIT cells showed that MAIT cells isolated from the rectum and Epi-AT overextended these receptors, respectively.
according to Il18r's over-expression of mRNA from MAIT cells in the intestinal cells of obese mice, immunofluorescence staining showed an increase in expression of T-bet, a key transcription factor for Th1 cytokines.
data together showed that Epi-AT and MAIT cells in the intestinal back intestines in obese mice were activated and produced inflammatory cytokines.
in mice, similar to those fed HFD, CD44 expression on Epi-AT's MAIT cells increased, and CD69 expression decreased on MAIT cells in the intestinal and Epi-AT cells.
addition, MAIT cells from the intestinal and Epi-AT produce anti-inflammatory cytokines more frequently (IL-17A in the rectum, TNF and IL-17A in Epi-AT).
, the researchers looked at whether MAIT cellactation was associated with increased maIT cell listation abundance produced by intestinal bacteria in obese mice.
using two biometrics, the researchers assessed the ability of gut bacteria from thin and obese mice to activate MAIT cells.
compared to lean mice, the blind colony microbiome in obese mice had less activation of MAIT cells.
it is important to note that the actification is MR1 specific because it inhibits or blocks mr1 antibodies in the presence of the inactive ligand acetyl-6-formylpterin (AC-6-FP).
to determine whether the genetic content of the post-HFD microbiome helped reduce levels of MAIT cell agonist ligands, the researchers sequenced the blind gut microbial DNA of mice fed ND or HFD.
analysis of KEGG showed that the biosynthesis pathway of nucleonin in HFD samples was significantly reduced compared to ND-fed mice.
To be more precise, the ribBA, ribD, ribH, and ribE genes were less abundant in the microbiome fed TOD mice, while the ribB gene was more abundant, and these differences may lead to a decrease in the synthesis of MAIT cell agonists.
biometrics and macrogenomics data together show that local activation of MAIT cells is not due to an increase in the presence of activation litisomes, but rather to the inflammatory environment of Epi-AT and the intestinal intestinal backs of obese mice.
MAIT cells promote metabolic dysfunction during obesity In order to determine the role of MAIT cells in the pathogenesis of T2D and obesity, the researchers analyzed MR1 - / - B6 mice lacking MAIT cells because THE1 molecules require MAIT cell thymus development.
, mice showing a tenfold increase in the frequency of MAIT cells were also analyzed.
to induce obesity, these mice were fed HFD for 12 weeks in contrast to their respective co-breeds, MR1 s/- and V alpha19 -/-mice.
the researchers first studied the steady state of glucose in MR1 -/- and V-alpha19 plus//
mice were tested for insulin tolerance (ITT) and oral glucose tolerance (OGTT) 12-16 weeks after HFD.
compared with the same nest control, the insulin sensitivity of V alpha19 plus/- mice was reduced, while the insulin tolerance of MR1-/- mice increased compared to the same nest control.
same, although mice were more resistant to glucose, MR1-/-mice had higher glucose tolerance.
glucose metabolism is not caused by impaired insulin secretion.
effects of MAIT cells on insulin resistance are confirmed at the tissue level by analyzing Akt phosphorylation, which is the reading of insulin signals in cells.
The relative amount of Akt in extended AT phosphorylation increased in MR1 / - mice and V alpha19 decreased by plus/- compared to their co-nest-controlled mice, similar data were observed in the liver and muscles from V alpha19 in mice.
the basic blood sugar level decreased significantly in fasting and eating MR1-/-mice compared to the control group.
contrast, the level of underlying blood sugar increased significantly in fasting and feeding mice.
addition, MR1 -/- reduced the base serum insulin concentration and insulin resistance steady-state model assessment (HOMA-IR) index under HFD, increased in mice with V alpha19 plus/- and increased in mice with V alpha19 plus/-
It is important to note that there was no difference in weight gain during high-fat feeding, and at the end of the programme, there was no difference in weight, lean meat or fat mass percentage, and Epi-AT weight/and MR1-/- mice with their nests.
no differences were observed in food intake, respiratory exchange rate (RER).
, however, histological analysis showed that, under HFD, fat cell size increased in Epi-AT by V alpha19 plus/- compared to its co-nest control.
contrast, under HFD, the size of fat cells in Epi-AT in MR1-/-mice was smaller than that in the same armpit control.
further evaluate the function of Epi-AT on MAIT cells, the effects of the expression of two key fat factors, lipoproteins and lean proteins, are passed through qPCR.
compared to the same nest control, the expression of lipoglobin decreased in mice, while the expression of lean protein increased.
obtained the opposite result in MR1 -/-mice.
results suggest that MAIT cells are involved in the imbalance of Epi-AT steady state.
, the researchers analyzed the expression of two lipases, fat triglycerides (Atgl) and hormone-sensitive lipase (Hsl).