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This review is the last of four review articles addressing covalent modifications of proteins and lipids. Two of the reviews in this series were previously published (15, 28) and dealt with modifications of signaling proteins by GlcNAcylation and serine phosphorylation. In the current issue of the Journal, we complete this series with two reviews, one by Riahi eta!. (102a) on the signa!ing and cellular functions of 4-hydroxyalkenals, key products of !ipid per- oxidation processes, and our present review on the effects of nitrosative modifica- tions of protein and lipid signa!ing molecules by reactive nitrogen species. The aim of this Perspectives review is to highlight the significant role that reactive nitrogen species may play in the regulation of cellular metabolism through this important class of posttranslational modification. The potential role of nitrosative modifica- tions in the regulation of insulin signal transduction, mitochondrial energy metab- olism, mRNA transcription, stress signaling, and endoplasmic reticulum function will each be discussed. Since nitrosative modifications are not restricted to proteins, the current understanding of a recently described genus of "nitro-fatty acids" will also be addressed. [ABSTRACT FROM AUTHOR]

The present study examined the acute effects of metformin on fatty acid (FA) metabolism in oxidative soleus (SOL) and glycolytic epitrochlearis (EPT) rodent muscle. SOL and EPT were incubated for either 30 or 180 min in the absence or presence of 2 mM metformin and with or without insulin (10 mU/ml). Metformin did not alter basal FA metabolism but countered the effects of insulin on FA oxidation and incorporation into triacylglyerol (TAG). Specifically, metformin prevented the insulin-induced suppression of FA oxidation in SOL but did not alter FA incorporation into lipid pools. In contrast, in EPT metformin blunted the incorporation of FA into TAG when insulin was present but did not alter FA oxidation. In SOL, metformin resulted in a 50% increase in AMP-activated protein kinase α2 activity and prevented the insulin-induced increase in malonyl-CoA content. In both fiber types, basal and insulin-stimulated glucose oxidation were not significantly altered by metformin. All effects were similar regardless of whether they were measured after 30 or 180 min. Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity. The present data also suggest that increased glucose clearance is not due to its enhanced subsequent oxidation. Additional studies are warranted to determine whether chronic metformin treatment has similar effects on muscle FA metabolism. [ABSTRACT FROM AUTHOR]

Muscle fatty acid (FA) metabolism is impaired in obesity and insulin resistance, reflected by reduced rates of FA oxidation and accumulation of lipids. It has been suggested that interventions that increase FA oxidation may enhance insulin action by reducing these lipid pools. Here, we examined the effect of endurance training on rates of mitochondrial FA oxidation, the activity of carnitine palmitoyltransferase I (CPT I), and the lipid content in muscle of obese individuals and related these to measures of glucose tolerance. Nine obese subjects completed 8 wk of moderate-intensity endurance training, and muscle biopsies were obtained before and after training. Training significantly improved glucose tolerance, with a reduction in the area under the curve for glucose (P < 0.05) and insulin (P = 0.01) during an oral glucose tolerance test. CPT I activity increased 250% (P = 0.001) with training and became less sensitive to inhibition by malonyl-CoA. This was associated with an increase in mitochondrial FA oxidation (+ 120%, P <0.001). Training had no effect on muscle triacylglycerol content; however, there was a trend for training to reduce both the total diacylglcyerol (DAG) content (-15%, P 0.06) and the saturated DAG-FA species (-27%, P = 0.06). Training reduced both total ceramide content (-42%, P = 0.01) and the saturated ceramide species (-32%, P < 0.05). These findings suggest that the improved capacity for mitochondrial FA uptake and oxidation leads not only to a reduction in muscle lipid content but also a to change in the saturation status of lipids, which may, at least in part, provide a mechanism for the enhanced insulin action observed with endurance training in obese individuals. [ABSTRACT FROM AUTHOR]

Bruce, Clinton R., and David J. Dyck. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-α. Am J Physiol Endocrinol Metab 287: E616- E621, 2004. First published May 18, 2004; 10.1152/ajpendo.00150. 2004.—IL-6 and TNF-α have been associated with insulin resistance and type 2 diabetes. Furthermore, abnormalities in muscle fatty acid (FA) metabolism are strongly associated with the development of insulin resistance. However, few studies have directly examined the effects of either IL-6 or TNF-α on skeletal muscle FA metabolism. Here, we used a pulse-chase technique to determine the effect of IL-6 (50–5,000 pg/ml) and TNF-α (50–5,000 pg/ml) on FA metabolism in isolated rat soleus muscle. IL-6 (5,000 pg/ml) increased exogenous and endogenous FA oxidation by ∼50% (P < 0.05) but had no effect on FA uptake or incorporation of FA into endogenous lipid pools. In contrast, TNF-α had no effect on FA oxidation but increased FA incorporation into diacylglycerol (DAG) by 45% (P < 0.05). When both IL-6 (5,000 pg/ml) and insulin (10 mU/ml) were present, IL-6 attenuated insulin's suppressive effect on FA oxidation, increasing exogenous FA oxidation (+37%, P < 0.05). Furthermore, in the presence of insulin, IL-6 reduced the esterification of FA to triacyl- glycerol by 22% (P < 0.05). When added in combination with IL-6 or leptin (10 μg/ml), the TNF-α-induced increase in DAG synthesis was inhibited. In conclusion, the results demonstrate that IL-6 plays an important role in regulating fat metabolism in muscle, increasing rates of FA oxidation, and attenuating insulin's lipogenic effects. In contrast, TNF-α had no effect on FA oxidation but increased FA incorporation into DAG, which may be involved in the development of TNF-α-induced insulin resistance in skeletal muscle. [ABSTRACT FROM AUTHOR]

The objectives of this study were to 1) examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2) determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [n = 8; body mass index (BMI) 23.8 ± 0.58 kg/m²], overweight/obese (n = 8; BMI 30.2 ± 0.81 kg/m2), and extremely obese (n = 8; BMI 53.8 -+ 3.5 kg/m²) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 ± 5.2 nmol·g[sup -1]·h[sup -1]) patients compared with normal-weight (71.0 ± 5.0 nmol·g[sup -1]·h[sup -1]) and overweight/obese (82.2 ± 8.7 nmol·g[sup -1]·h[sup -1]) patients, respectively. Palmitate oxidation was negatively (R = -0.44, P = 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation. [ABSTRACT FROM AUTHOR]