Obesity changes Human T cell Metabolism to regulate Age-related Inflammation

Grants and Contracts Details

Description

Inflammation fueled by either obesity or by older age exacerbates the risk of multiple diseases including type 2 diabetes, cardiovascular disease and certain cancers. The possibility that obesity- and age-related inflammation synergize in older people with obesity to compromise healthspan more than either alone remains a critical gap in one goal of diabetes research, the development of safe/effective drugs that slow or prevent age-related health declines in the 40% of U.S. adults with obesity. Our published work on human CD4 T cells highlighted their central role in systemic inflammaging in lean, relatively healthy subjects. New data herein surprisingly showed that obesity modifies the type of T cell inflammation that develops with age: Th17 cytokines dominate inflammatory profiles in lean aging but Th17 cytokines contribute little to inflammatory profiles generated by CD4 T cells from people with obesity. The two profiles associate with differences in T cell metabolism based on extracellular flux analysis. Additional preliminary data indicate that differences in glutamine and glucose/pyruvate metabolism support production of cytokines in the obesity-associated inflammaging profile. Inhibitor data indicate that metabolite flux will be critical to link extracellular flux outcomes to cytokine production through detailed mechanistic approaches. We will use stable isotope resolved metabolomics (SIRM) in collaboration with Dr. Lance Johnson, Metabolomics core director, to analyze T cell metabolite flux in cells from four cohorts: lean/younger, lean/older, younger with obesity, and older with obesity, to test the central hypothesis that obesity changes glutamine and pyruvate metabolism to modify downstream metabolites that control T cell inflammaging. Aim 1 will test the hypothesis that obesity-associated aging changes T cell glutaminolysis. Aim 2 will test the hypothesis that obesity-associated aging changes glycolysis, e.g. pyruvate oxidation and/or reduction, in T cells. Metabolic flux data will be critical to target loss- and gain-of-function approaches and thus establish causal relationships amongst metabolites, and bioinformatically-derived cytokine profiles, the latter an indicator of overall T cell “inflammation", in an R01 project planned for late 2024.
StatusActive
Effective start/end date4/1/243/31/25

Funding

  • Washington University in St. Louis

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