Postprandial control of fatty acid transport proteins’ subcellular location is not dependent on insulin

Abstract

Edited by Laszlo NagyFatty acid transport proteins rapidly translocate to the plasma membrane in response to various stimuli, including insulin, influencing lipid uptake into muscle. However, our understanding of the mechanisms regulating postprandial fatty acid transporter subcellular location remains limited. We demonstrate that the response of fatty acid transporters to insulin stimulation is extremely brief and not temporally matched in the postprandial state. We further show that high-fat diet-induced accumulation of fatty acid transporters on the plasma membrane can occur in the absence of insulin. Altogether, these data suggest that insulin is not the primary signal regulating fatty acid transporter relocation in vivo.

Dietary α-linolenic acid supplementation alters skeletal muscle plasma membrane lipid composition, sarcolemmal FAT/CD36 abundance, and palmitate transport rates

“…ing pathways have been implicated in regulating FAT/CD36 subcellular location in muscle. For instance, the pharmacological inhibition of ERK1/2 with PD-98059 prevents exerciseinduced translocation of FAT/CD36 to the plasma membrane, 5-aminoimidazole-4-carboxamide ribonucleotide-mediated activation of AMPK induces FAT/CD36 sarcolemmal translocation in skeletal muscle and in cardiac myocytes (5,23,33), CaMKII signaling temporally aligns with FAT/CD36 translocation during muscle contraction (23), and insulin rapidly induces FAT/CD36 accumulation on the plasma membrane (47). However, our knowledge of the intracellular mechanisms influencing FAT/CD36 location is clearly incomplete, as exercise-induced translocation of FAT/CD36 to the plasma membrane is retained in AMPK␣2 kinase dead (KD) mice (23) and ERK phosphorylation occurs after the induction of FAT/CD36 trafficking (23).…”

“…However, our knowledge of the intracellular mechanisms influencing FAT/CD36 location is clearly incomplete, as exercise-induced translocation of FAT/CD36 to the plasma membrane is retained in AMPK␣2 kinase dead (KD) mice (23) and ERK phosphorylation occurs after the induction of FAT/CD36 trafficking (23). In addition, the classical role of insulin in mediating postprandial FAT/CD36 trafficking has recently been challenged, as fatty acids themselves have been proposed to mediate FAT/CD36 subcellular location through an unknown mechanism (47). In the present study, none of the previously implicated pathways appeared to be activated at the end of the study.…”

“…However, it should be acknowledged in the present study that the ALA diet contained a higher proportion of fat, and therefore, on average, these animals consumed~0.6 g of additional fat per day. This dietary approach was utilized as it is easier to supplement a human diet than to replace macronutrients; however, the additional fat may contribute to the responses observed as we have recently provided evidence that lipids induce fatty acid transport protein trafficking events in a feed-forward manner (47). Therefore, we cannot rule out the possibility that the increased composition of lipids in the ALA-fortified diet caused the observed responses.…”

“…Al-ternatively, n-3 supplementation has been suggested to alter lipid raft structure (44), a region of the plasma membrane where FAT/CD36 resides (41), which may promote FAT/ CD36 retention/accumulation on the plasma membrane. In addition, recent evidence has implicated a rise in serum fatty acid concentration as a key mechanism involved in fatty acid transport protein redistribution to the plasma membrane (47), further suggesting that dietary lipid supplementation may promote sarcolemmal fatty acid transport. Although this possibility has not been investigated, n-3 feeding has been shown to alter the unsaturation of plasma membrane phospholipids, as well as the ability of insulin to bind to its plasma membrane receptor (31), supporting the assertion that membrane saturation influences the biological function of the phospholipid bilayer.…”

Regulation of nutrient uptake by AMP-activated protein kinase

“…Importantly, the very concept that insulin is a physiologically relevant stimulus for FA uptake in muscle has been challenged, as the response of CD36/SR-B2 and FATP1 in rodent muscle is transient and also does not match the timing of the postprandial rise in insulin concentrations [261].…”