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Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo.

ABSTRACT: T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an Ab-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and identified surrogate agonist peptides, with differing affinities and signaling potencies. The VAT-Treg cells expanded in vivo by one of the surrogate agonists preserved the typical VAT-Treg transcriptional programs. Immunization with this surrogate, especially when coupled with blockade of TNF? signaling, expanded VAT-Treg cells, resulting in protection from inflammation and improved metabolic indices, including promotion of insulin sensitivity. These studies suggest that antigen-specific targeting of VAT-localized Treg cells could eventually be a strategy for improving metabolic disease.

SUBMITTER: Fernandes RA

PROVIDER: S-EPMC7440915 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo.

Fernandes Ricardo A RA Li Chaoran C Wang Gang G Yang Xinbo X Savvides Christina S CS Glassman Caleb R CR Dong Shen S Luxenberg Eric E Sibener Leah V LV Birnbaum Michael E ME Benoist Christophe C Mathis Diane D Garcia K Christopher KC

eLife 20200810

T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an A<sup>b</sup>-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and ide ...[more]

PMID: 32773038

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Project description:BackgroundVisceral adiposity is an important risk factor for cardiometabolic diseases.ObjectiveTo determine whether the Metabolic Score for Visceral Fat (METS-VF) is more effective than other adiposity indices in predicting visceral fat area (VFA).MethodsIn this single-center and cross-sectional study, we included patients aged 20-50 years, without diabetes and coronary artery disease, who underwent computed tomography (CT) including the third lumbar vertebra. Age, blood pressure, waist circumference (WC), hip circumference, fasting lipids, and glucose were assessed. VFA was measured by cross-sectional examination of CT. The correlation of WC, body mass index (BMI), waist-hip ratio (WHR), lipid accumulation product (LAP), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), and METS-VF with VFA was analyzed by correlation analysis. The cut-off values and area under the curve (AUC) for identifying increased VFA (>130 cm2) were determined.ResultsWe included 185 individuals with mean age 38.2 ± 8 and female predominance (58.4%). There was a significant positive correlation between all indices and VFA (p<0.001). ROC analysis revealed that METS-VF and WC demonstrated the highest predictive value for identifying increased VFA. In both men (p=0.001) and women (p<0.001), METS-VF (AUC 0.922 and 0.939, respectively) showed a significant superiority over ABSI (AUC 0.702 and 0.658, respectively), and VAI (AUC 0.731 and 0.725, respectively). Additionally, in women, its superiority over WHR (AUC 0.807) was also statistically significant (p=0.003). We identified a METS-VF cut-off point >6.4 in males >6.5 in females and WC cut-off point >88 cm in males (AUC 0.922), >90.5 cm in females (AUC 0.938).ConclusionMETS-VF is strongly associated with visceral adiposity and better to predict increased VFA. However, its superiority over WC, BMI, BRI, and LAP was not significant. The results emphasize that WC is more appealing as screening indicator for visceral adiposity considering its easy use.Clinical trial registry nameClinicaltrials.gov (http://www.clinicaltrials.gov).Clinical trial registry urlhttps://clinicaltrials.gov/ct2/show/NCT05648409.Clinical trial registry numberNCT05648409.

Project description:ObjectiveTo compare body composition between patients with psoriatic disease (PsD), including cutaneous psoriasis (PsO) and psoriatic arthritis (PsA), and controls, and to explore associations between disease activity and measures of function and metabolic derangement.MethodsBody composition was assessed by air displacement plethysmography (ADP) and MRI-derived fat segmentation using an automated pipeline (FatSegNet). Function was assessed by Health Assessment Questionnaire (HAQ) and metabolic status by fasting lipid profile, insulin and adiponectin. Active and inactive PsO and PsA were defined by body surface area (BSA) and Psoriasis Area Severity Index (PASI) and minimal disease activity (MDA), respectively.ResultsThirty patients (median disease duration 15 years; median age 52 years) and 30 BMI-matched controls were enrolled. Compared with controls, all MRI-derived body composition parameters-whole-body volume, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), abdominal adipose tissue (AAT), VAT/AAT and VAT/SAT-were higher in the PsD group, specifically, those with active disease. Body mass, body fat, whole-body volume and whole-body VAT were correlated with higher triglycerides, cholesterol:HDL (high-density lipoprotein), insulin resistance and lower adiponectin as well as higher HAQ and lower MDA.ConclusionsIn this pilot study, patients with PsD revealed excessive total adipose tissue and a greater volume of metabolically unfavourable ectopic fat, including VAT, compared with BMI-matched controls, which also correlated with HAQ, disease activity and overall dysmetabolism. We also provide the first evidence in patients with PsD for the clinical application of FatSegNet: a novel, automated and rapid deep learning pipeline for providing accurate MRI-based measurement of fat segmentation. Our findings suggest the need for a more integrated approach to the management of PsD, which considers both the metabolic and inflammatory burden of disease. More specifically, visceral fat is a surrogate marker of uncontrolled PsD and may be an important future target for both pharmacological and lifestyle interventions.

Dataset Information

Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo.

Publications

Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo.

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