Here we report that in skeletal muscle cells the contribution to insulin resistance and inflammation of two common dietary long-chain fatty acids depends on the channeling of these lipids to distinct cellular metabolic fates. Exposure of cells to the saturated fatty acid palmitate led to enhanced diacylglycerol levels and the consequent activation of the protein kinase C/nuclear factor B pathway, finally resulting in enhanced interleukin 6 secretion and down-regulation of the expression of genes involved in the control of the oxidative capacity of skeletal muscle (peroxisome proliferator-activated receptor (PPAR)␥-coactivator 1␣) and triglyceride synthesis (acyl-coenzyme A: diacylglycerol acyltransferase 2). In contrast, exposure to the monounsaturated fatty acid oleate did not lead to these changes. Interestingly, co-incubation of cells with palmitate and oleate reversed both inflammation and impairment of insulin signaling by channeling palmitate into triglycerides and by up-regulating the expression of genes involved in mitochondrial ␤-oxidation, thus reducing its incorporation into diacylglycerol. Our findings support a model of cellular lipid metabolism in which oleate protects against palmitate-induced inflammation and insulin resistance in skeletal muscle cells by promoting triglyceride accumulation and mitochondrial ␤-oxidation through PPAR␣-and protein kinase A-dependent mechanisms.

Fructose makes up a significant proportion of energy intake in westernized diets; its increased consumption has paralleled the growing prevalence of obesity and metabolic syndrome over the past two decades. In the current study, we demonstrate that fructose administration (10% wt/vol) in the drinking water of rats reduces the trans-activating and trans-repressing activity of the hepatic peroxisome proliferator-activated receptor ␣ (PPAR␣). As a consequence, fructose decreases hepatic fatty oxidation and increases pro-inflammatory transcription factor nuclear factor B (NF-B) activity. These changes were not observed in glucose-administered rats (10% wt/ vol), although both carbohydrates produced similar changes in plasma adiponectin and in the hepatic expression of transcription factors and enzymes involved in fatty acid synthesis. Fructosefed, but not glucose-fed, rats were hyperleptinemic and exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) transcription factor, although they did not present a similar increase in the serine phosphorylation of nuclear STAT3. Thus, an impairment in the hepatic transduction of the leptin signal could be responsible for the observed alterations in PPAR␣ activity in fructose-fed rats. Because PPAR␣ activity is lower in human than in rodent liver, fructose ingestion in humans should cause even worse effects, which would partly explain the link between increased consumption of fructose and widening epidemics of obesity and metabolic syndrome. T he prevalence of metabolic syndrome and the risk for developing diabetes mellitus and cardiovascular disease is increasing worldwide. 1,2 Environmental factors (diet, physical activity), in tandem with predisposing genetic factors, may be responsible for this trend. Along with an increase in total energy consumption during recent decades, there has also been a shift in the types of nutrients, with an increased consumption of fructose, largely attributable to the greater intake of beverages containing high levels of fructose. 3 Once absorbed, dietary fructose is mainly taken up by the liver, promoting triacylglycerol synthesis and very low-density lipoprotein (VLDL) production. However, increases in liver fatty acid synthesis alone is not sufficient to account for such elevated triacylglycerol production. 4 Thus, those mechanisms underlying liver lipid metabolic derangements caused by high-fructose diets are not completely understood.The rat offers an effective model of human fructose metabolism. 5 A high-fructose diet in rats induces metabolic derangements similar to those found in the metabolic syndrome. 6 Nevertheless, although experimental designs using 50% to 60% of fructose in pelleted diets induce hypertriglyceridemia and a pronounced state of insulin resistance, 6,7 diets incorporating 10% wt/vol of fructose in drinking water induce hypertriglyceridemia and fatty liver without modifying plasma glucose and insulin levels. 8,9 Because high-carbohydrate diets and chronic hyperin...