Not only accumulation, but also saturation status of intramuscular lipids is significantly affected by PPARγ activation.
ABSTRACT 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.
- SourceAvailable from: Susanne Mandrup[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 · 5.97 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.Obesity Reviews 09/2012; 13(12). DOI:10.1111/j.1467-789X.2012.01026.x · 7.86 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: AIMS: To determine the presence and possible involvement of FAT/CD36, FABPpm and FATP-2, transporters in (i) fatty acids movement across plasma membrane and (ii) an induction of insulin resistance by palmitic (PA) and oleic (OA) fatty acids in primary hepatocytes. METHODS: Primary hepatocytes were treated with either PA and OA or combination of activators (AICAR, Insulin) or inhibitors (SSO, phloretin) of FA transport. Expression of FA and glucose transporters as well as insulin signalling proteins was determined using Western blot analyses. Palmitate and glucose transport was measured using radioactive isotopes. Intracellular lipid content [ceramide, diacylglycerols (DG) and triacylglycerols] and FA composition were estimated by GLC. RESULTS: In primary hepatocytes, adding phloretin diminished insulin, and AICAR stimulated palmitate transport. Both PA and OA fatty acids induced the protein expression of FAT/CD36 and FATP-2 with concomitant: (i) reduction in GLUT-2 protein content, (ii) inhibition of insulin-stimulated glucose uptake, (iii) reduction in insulin-stimulated activation of AKT and GSK, (iv) accumulation of either DG (PA and OA) or ceramide (only PA). CONCLUSIONS: FA transport into hepatocytes is, at least in part, protein-mediated process, and both PA and OA induce the protein expression of FAT/CD36 and FATP-2. Both saturated (PA) and unsaturated (OA) fatty acids induce insulin resistance in primary hepatocytes, associated with the accumulation of DG and/or ceramide.Acta Physiologica 11/2012; 207(2). DOI:10.1111/apha.12022 · 4.25 Impact Factor