Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics

Abstract

DA. Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am J Physiol Endocrinol Metab 306: E1033-E1045, 2014. First published March 4, 2014 doi:10.1152/ajpendo.00422.2013.-Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. 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 TNF␣, IL-6, and IL-1␤ on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNF␣ treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ⌬⌿m, increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1␤ decreased maximal respiratory capacity, they had no effect on ⌬⌿m and varied effects on ATP turnover, proton leak, or basal respiration. Only TNF␣ 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 PGC-1␣ and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNF␣ exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology. mitochondria; cytokine; fusion; adipocyte; respiration THE ADIPOSE ORGAN IS HIGHLY SPECIALIZED in storage and release of energy in times of nutrient excess and deficit, respectively (11,30). It also plays a vital role in communicating to the brain and other tissues as to the energy status of the entire organism and hence, can influence feeding behavior and energy utilization (9, 21, 52). Low-grade chronic inflammation of adipose tissue has been characterized as a hallmark of obesity and insulin resistance (14,17,50). Current models of obesitylinked adipose inflammation include leukocyte infiltration, increased levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factor-␣ (TNF␣), interleukin-6 (IL-6), and interleukin-1␤ (IL-1␤) and increased oxidative stress (14, 23). The dysfunction of the adipose tissue that occurs in the metabolic syndrome includes increased lipolysis in a fed state (20, 34) and alterations in adipokine secretion (8, 16), promoting the hypothesis that adipose ...

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

“…Diabetic animal models (Akude et al 2011) and other inflammatory scenarios display lower COX IV expression and decreased respiratory chain activity (Hahn et al 2014, Krause et al 2014. In turn, this contributes to abnormalities in cellular energy metabolism and a lowering of insulin secretion (Akude et al 2011, Hahn et al 2014. Our results are in agreement with these findings, as the absence of Ala-Gln per se, and exposure to IMMC and IMMK decreased COX IV levels (Fig.…”

“…COX IV is required to catalyse the reduction of molecular oxygen to water coupled to the translocation of protons across the mitochondrial inner membrane to the matrix, which drives ATP synthesis. Diabetic animal models (Akude et al 2011) and other inflammatory scenarios display lower COX IV expression and decreased respiratory chain activity (Hahn et al 2014, Krause et al 2014. In turn, this contributes to abnormalities in cellular energy metabolism and a lowering of insulin secretion (Akude et al 2011, Hahn et al 2014.…”

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

“…Mitochondrial dynamics have generally been associated with different metabolic states; cells relying on fatty acid oxidation or oxidative phosphorylation often display fused networks of mitochondria, whereas those relying on glycolysis tend to have more punctate mitochondria (71)(72)(73)(74)(75). Further, promoting mitochondrial fission and/or blocking fusion can stimulate pro-inflammatory cytokine production (55,59,76,77). Nevertheless, our results suggest that the punctate mitochondrial morphology seen in Irgm1-deficient cells is secondary to accumulation of LC-AC in those cells, because treatment of the cells with fatty acid synthase inhibitors to reduce fatty acid concentrations not only blunted RANTES production in IFN-␥-primed, Irgm1-deficient macrophages, it also eliminated the punctate mitochondrial phenotype.…”

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

“…While previous studies have evaluated ROS emissions in cultured cell systems or isolated adipocytes [38][39][40], the advantage of permeabilised WAT over these traditional methods is the ability to assess adipocyte function within its cellular milieu. Approximately 25% of WAT is composed of adipocytes, the remaining cell population is made up of the stromal vascular cells (SVC), including macrophages [41].…”