The protective effect of vitamin E supplementation on exercise-induced oxidative damage was tested in 21 male volunteers. Nine young (22-29 yr) and 12 older (55-74 yr) sedentary male subjects participated in a double-blind protocol and received either 800 IU dl-alpha-tocopherol or a placebo daily. After 48 days, vitamin E supplementation significantly increased alpha-tocopherol in plasma and skeletal muscle. Subjects then performed a bout of eccentric exercise at 75% of their maximum heart rate by running down an inclined treadmill for 45 min. All vitamin E-supplemented subjects excreted less (P < 0.05) urinary thiobarbituric acid adducts after the exercise bout than placebo subjects at 12 days postexercise (35 and 18% above baseline in young and old supplemented groups, respectively, vs. 60 and 80% in young and old placebo groups, respectively). After exercise, the initial difference in alpha-tocopherol concentration of muscle between young placebo and vitamin E-supplemented groups was diminished and muscle lipid conjugated dienes tended to increase (P = 0.09) in placebo subjects. Placebo subjects had a significant decrease in major fatty acids of muscle biopsy taken immediately after exercise. When normalized for the hemoconcentration effects of exercise, the plasma concentration of vitamins E and C and uric acid showed no significant change. The alterations in fatty acid composition, vitamin E, and lipid conjugated dienes in muscle and in urinary lipid peroxides in controls after eccentric exercise are consistent with the concept that vitamin E provides protection against exercise-induced oxidative injury.

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 ...

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Oxidative stress is linked to the production of reactive lipid aldehydes that non-enzymatically alkylate cysteine, histidine or lysine residues in a reaction termed protein carbonylation. Reactive lipid aldehydes and their derivatives are detoxified via a variety of phase I and phase II systems and when antioxidant defenses are compromised or oxidative conditions are increased protein carbonylation is increased. The resulting modification has been implicated as causative in a variety of metabolic states including neurodegeneration, muscle wasting, insulin resistance and aging. Although such modifications usually result in loss of protein function, protein carbonylation may be regulatory and activate signaling pathways involved in antioxidant biology and cellular homeostasis.

Inflammation plays a critical role in the pathology of obesity-linked insulin resistance and is mechanistically linked to the effects of macrophage-derived cytokines on adipocyte energy metabolism, particularly that of the mitochondrial branched-chain amino acid (BCAA) and tricarboxylic acid (TCA) pathways. To address the role of inflammation on energy metabolism in adipocytes, we used high fat-fed C57BL/6J mice and lean controls and measured the down-regulation of genes linked to BCAA and TCA cycle metabolism selectively in visceral but not in subcutaneous adipose tissue, brown fat, liver, or muscle. Using 3T3-L1 cells, TNFα, and other proinflammatory cytokine treatments reduced the expression of the genes linked to BCAA transport and oxidation. Consistent with this, [(14)C]-leucine uptake and conversion to triglycerides was markedly attenuated in TNFα-treated adipocytes, whereas the conversion to protein was relatively unaffected. Because inflammatory cytokines lead to the induction of endoplasmic reticulum stress, we evaluated the effects of tunicamycin or thapsigargin treatment of 3T3-L1 cells and measured a similar down-regulation in the BCAA/TCA cycle pathway. Moreover, transgenic mice overexpressing X-box binding protein 1 in adipocytes similarly down-regulated genes of BCAA and TCA metabolism in vivo. These results indicate that inflammation and endoplasmic reticulum stress attenuate lipogenesis in visceral adipose depots by down-regulating the BCAA/TCA metabolism pathway and are consistent with a model whereby the accumulation of serum BCAA in the obese insulin-resistant state is linked to adipose inflammation.