Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

Abstract

Aims/hypothesis Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. Methods Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both ON, Canada Diabetologia (2010) 53:1151-1163 DOI 10.1007/s00125-010-1708 accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

Reduced Incorporation of Fatty Acids Into Triacylglycerol in Myotubes From Obese Individuals With Type 2 Diabetes

“…Palmitate oxidation was measured as production of 14 CO 2 and 14 C-ASMs from [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]-palmitate (1 mCi/mL), nonlabeled palmitate (100 mmol/L), and 1 mmol/L carnitine after 3 h. Lipids were extracted from the myotubes, and lipid incorporation was measured by thin-layer chromatography. Bands corresponding to TAG and diacylglycerol (DAG) were quantified by liquid scintillation as previously described (16).…”

“…Hulver et al (5) used such a model to demonstrate that myotubes of nondiabetic, severely obese individuals retain abnormal lipid partitioning (i.e., elevated triacylglycerol [TAG]-to-blunted fatty acid [FA] oxidation ratio) (5). Of note, Aguer et al (6) showed that T2D subjects had increased IMCL content in muscle tissue and that this elevation was maintained in primary myotubes from these subjects compared with obese nondiabetic control subjects, indicating that increased IMCL content is preserved in vitro. However, the underlying reason for this finding was not examined.…”

“…Some studies showed no difference in uptake of FAs (7,8), whereas others showed increased FA uptake in skeletal muscle of obese and T2D individuals (9). Likewise, studies in primary human myotubes showed inconsistent results (6,10,11). Taken together, whether disturbances that exist in skeletal muscle tissue lipid metabolism of T2D individuals are preserved in the myotubes is unclear.…”

Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

“…Suggestions [2,3] that mitochondrial dysfunction is a determinant of intramuscular lipid accumulation and insulin resistance have been questioned [4][5][6][7][8]. In contrast, evidence for the excess influx of fatty acids [6,[9][10][11] and for an inability to completely oxidise them [12,13] provides an alternative explanation for intramuscular lipid accumulation in insulin-resistant muscle.…”

“…oxidation or esterification). Several studies have associated skeletal muscle sarcolemmal FAT/CD36 with insulin resistance in animals and in humans [6,[9][10][11].…”