Details

Autor(en) / Beteiligte

• Alwarawrah, Yazan
• Nichols, Amanda
• Eisner, William
• MacIver, Nancie

Titel

OR12-2 Obesity Induces Changes in T Cell Metabolism and Function

Ist Teil von

• Journal of the Endocrine Society, 2019-04, Vol.3 (Supplement_1)

Ort / Verlag

Washington, DC: Endocrine Society

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Low-grade inflammation is responsible for many obesity-associated pathologies such as insulin resistance, type 2 diabetes and reduction in protective immunity. T cells play an important role in mounting an effective immune response and the modulation of inflammation, and have been identified as a key player in obesity-associated inflammation. Altered T cell metabolism can influence T cell differentiation and function; however, it is not yet known if or how obesity influences the T cell metabolic state. We hypothesized that diet induced obesity promotes changes in T cell metabolism leading to increased pro-inflammatory T cells function. To test our hypothesis, we assessed the effect of diet-induced obesity (DIO) on T cell subpopulation number and metabolism in the visceral adipose tissue (VAT) and peripheral lymphoid tissue (spleen). To achieve that, C57BL/6 mice were placed on high fat (DIO mice) or regular chow diet (control mice) at weaning and remained on diet for 18 weeks. VAT and spleen were collected and T cells were isolated and analyzed by flow cytometry for: T cells subpopulation markers, glucose uptake, and cytokine production. In addition, the expression of almost 240 enzymes involved in several metabolic pathways were measured in CD4+ T cells by RT-qPCR. We found that proportions of Treg cells were decreased in the VAT of DIO mice while CD8+ T cells increased, indicating an inflammatory environment in the adipose tissue of the DIO mice. CD4+ T cells isolated from the spleen of DIO mice were also found to be metabolically altered with increased glucose uptake and elevated oxygen consumption rate (OCR; a marker of mitochondrial metabolism). The spare respiratory capacity, an indicator of mitochondrial reserve, of CD4+ T cells from DIO mice was found to be reduced by the fatty acids oxidation inhibitor Etomoxir, while the pyruvate transport inhibitor UK5099 was found to have no significant effect, indicating a preference toward the use of fatty acids as a mitochondrial fuel source. The metabolic qPCR panel showed slight differences in expression between control vs. DIO mice with a tendency toward a decrease in the expression of enzymes involved in oxidative phosphorylation and fatty acid transport along with an increase in enzymes that positively influence glycolysis in DIO mice. Lastly, the antidiabetic drug metformin was found to inhibit OCR and alter the expression of several activation markers in CD4+ cells in vitro and in vivo , indicating that metformin may be an effective candidate to reverse T cell metabolic dysfunction and thereby restore T cell dysfunction in obesity. Research Support: National Institutes of Health grant R01-DK106090 and Derfner Foundation Research Award 2018.