Intramuscular lipid accumulation has been associated with insulin resistance, and after thiazolidinediones (TZD) treatment, it was shown to be reduced in some, but not all, studies. This work was undertaken to investigate the relationships between intramuscular lipids [free fatty acids (FFA), diacylglycerols (DAG), triacylglycerol (TAG) and phospholipids] and plasmalemmal expression of fatty acid (FA) transporter [FAT/CD36 and FABPpm] in the muscles of varying oxidative capacity, after peroxisome proliferator-activated receptors gamma (PPARγ) activation (rosiglitazone) in an animal model of high-fat-diet-induced insulin resistance. Endurance training was also included to further explore the differences in these relationships.
We have used gas liquid chromatography to estimate FA content and composition in each lipid fraction. For sarcolemmal expression of FA transporters, subfractionation of skeletal muscles with subsequent western blot technique was applied.
High-fat diet induced intramuscular accumulation of FFA, DAG and TAG, irrespective of muscle's fibre composition. PPARγ activation (rosiglitazone) and, to a lesser extent, endurance training further increased TAG accumulation, while it reduced DAG in oxidative muscles (soleus and red gastrocnemius). Aforementioned interventions increased also sarcolemmal FAT/CD36 and FABPpm expressions in particular muscles. Irrespective of diet, rosiglitazone and exercise decreased significantly FA saturation status favouring proportionate enhancement in monounsaturated FA (rosiglitazone) or polyunsaturated FAs (endurance training).
These findings support the conclusion that not only the change in total lipid content (DAG and TAG), but also FA composition is affected by rosiglitazone in an animal model of high-fat-diet-induced insulin resistance.
"Whereas a previous study found that OA increases the energy cost of exercise (20), perhaps by promoting mitochondrial uncoupling (45), investigations to delineate the distinct uncoupling properties of specific FAs have produced conflicting results (46,47). Exercise also decreases the saturation index of muscle lipids and promotes synthesis, storage, and turnover of intramuscular TAG (48,49). Thus, the strong interaction between diet and physical activity might relate to adaptations in muscle lipid droplet metabolism (50). "
[Show abstract][Hide abstract] ABSTRACT: Relative to diets enriched in palmitic acid (PA), diets rich in oleic acid (OA) are associated with reduced risk of type 2 diabetes. To gain insight into mechanisms underlying these observations, we applied comprehensive lipidomic profiling to specimens collected from healthy adults enrolled in a randomized, crossover trial comparing a high PA diet to a low PA/high OA diet (HOA). Effects on insulin sensitivity (S(I)) and disposition index (DI) were assessed by intravenous glucose tolerance testing. In women, but not men, S(I) and DI were higher during HOA. The effect of HOA on S(I) correlated positively with physical fitness upon enrollment. Principal components analysis of either fasted or fed-state metabolites identified one factor affected by diet and heavily weighted by the PA/OA ratio of serum and muscle lipids. In women, this factor correlated inversely with S(I) in the fasted and fed states. Medium-chain acylcarnitines emerged as strong negative correlates of S(I), and the HOA diet was accompanied by lower serum and muscle ceramide concentrations and reductions in molecular biomarkers of inflammatory and oxidative stress. This study provides evidence that the dietary PA/OA ratio impacts diabetes risk in women.
[Show abstract][Hide abstract] ABSTRACT: The peroxisome proliferator activated receptors (PPARs) are nuclear receptors that play key roles in the regulation of lipid metabolism, inflammation, cellular growth, and differentiation. The receptors bind and are activated by a broad range of fatty acids and fatty acid derivatives and they thereby serve as major transcriptional sensors of fatty acids. Here we review the function, regulation, and mechanism of the different PPAR subtypes with special emphasis on their role in the regulation of lipid metabolism.
Seminars in Cell and Developmental Biology 01/2012; 23(6):631-9. DOI:10.1016/j.semcdb.2012.01.003 · 6.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARγ, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists.
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