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Pro-inflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress and dynamics

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AJP Endocrinology and Metabolism

Published online on

Abstract

Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study we evaluated the chronic effects of TNFα, IL-6 and IL-1β on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNFα treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics including increased proton leak, decreased membrane potential, increased basal respiration and decreased ATP turnover. In contrast, while IL-6 and IL-1β decreased maximal respiratory capacity, they had no effect on membrane potential and varied effects on ATP turnover, proton leak and basal respiration. Only TNFα treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis including PGC1α and eNOS as well as deceased expression of COXIV and Cyt CCyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNFα exclusively led to mitochondrial fragmentation, decreased the total level of Opa1 while increasing Opa1 cleavage without affecting expression of levels of mitofusin 2, DRP1 or mitofilin. In sum, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism but each leads to decreased mitochondrial function and a re-programming of fat cell biology.