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While a definitive mechanism‐of‐action remains to be identified, recent findings indicate that ghrelin, particularly the unacylated form (UnAG), stimulates skeletal muscle fatty acid oxidation. The biological importance of UnAG‐mediated increases in fat oxidation remains unclear, as UnAG peaks in the circulation before mealtimes, and decreases rapidly during the postprandial situation before increases in postabsorptive circulating lipids. Therefore, we aimed to determine if the UnAG‐mediated stimulation of fat oxidation would persist long enough to affect the oxidation of meal‐derived fatty acids, and if UnAG stimulated the translocation of fatty acid transporters to the sarcolemma as a mechanism‐of‐action. In isolated soleus muscle strips from male rats, short‐term pre‐treatment with UnAG elicited a persisting stimulus on fatty acid oxidation 2 h after the removal of UnAG. UnAG also caused an immediate phosphorylation of AMPK, but not an increase in plasma membrane FAT/CD36 or FABPpm. There was also no increase in AMPK signaling or increased FAT/CD36 or FABPpm content at the plasma membrane at 2 h which might explain the sustained increase in fatty acid oxidation. These findings confirm UnAG as a stimulator of fatty acid oxidation and provide evidence that UnAG may influence the handling of postprandial lipids. The underlying mechanisms are not known. [ABSTRACT FROM AUTHOR]

We aimed to determine the combined effects of overexpressing plasma membrane fatty acid binding protein (FABPpm) and fatty acid translocase (CD36) on skeletal muscle fatty acid transport to establish if these transport proteins function collaboratively. Electrotransfection with either FABPpm or CD36 increased their protein content at the plasma membrane (+75% and +64%), increased fatty acid transport rates by +24% for FABPpm and +62% for CD36, resulting in a calculated transport efficiency of (0.019 and (0.053 per unit protein change for FABPpm and CD36, respectively. We subsequently used these data to determine if increasing both proteins additively or synergistically increased fatty acid transport. Cotransfection of FABPpm and CD36 simultaneously increased protein content in whole muscle (FABPpm, +46%; CD36, +45%) and at the sarcolemma (FABPpm, +41%; CD36, +42%), as well as fatty acid transport rates (+50%). Since the relative effects of changing FABPpm and CD36 content had been independently determined, we were able to a predict a change in fatty acid transport based on the overexpression of plasmalemmal transporters in the cotransfection experiments. This prediction yielded an increase in fatty acid transport of +0.984 and +1.722 pmol/mg prot/15 s for FABPpm and CD36, respectively, for a total increase of +2.96 pmol/mg prot/15 s. This calculated determination was remarkably consistent with the measured change in transport, namely +2.89 pmol/mg prot/15 s. Altogether, these data indicate that increasing CD36 and FABPpm alters fatty acid transport rates additively, but not synergistically, suggesting an independent mechanism of action within muscle for each transporter. This conclusion was further supported by the observation that plasmalemmal CD36 and FABPpm did not coimmunoprecipitate. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the anti-obesity effect of peptides derived from defatted mealworm (Tenebrio molitor larvae) and to determine the expression level of obesity-related membrane-associated proteins in the rat muscle. The production of functional peptide was produced by hydrolysis of mealworm protein using commercial enzymes. To evaluate anti-obesity effects through animal feeding experiments, a total of thirty-two rats were randomly divided into control diet (CD), 5% mealworm peptide supplemented control diet (CT), high-fat diet (HD), and 5% mealworm peptide supplemented high-fat diet group (HT). The weight loss of HT was confirmed by mealworm peptides feeding. The weights of fat tissues (perirenal and epididymal) of HT were significantly decreased, however, soleus muscle weight of HT was significantly increased compared to those of the HD, respectively. The expression levels of obesity-related membrane-associated proteins (FABPpm, PGC-1α, and PPAR) in HT group involved in fatty acid transport and utilization were significantly higher than that of the HD. From these results, mealworm peptide supplement showed an anti-obesity effect by stimulation of FABPpm, PGC-1α, and PPAR-δ in skeletal muscle and then showed an increase in muscle weight along with body weight loss in HT group. [ABSTRACT FROM AUTHOR]

A prominent example of seasonal phenotypic flexibility is the winter increase in thermogenic capacity (=summit metabolism, M sum) in small birds, which is often accompanied by increases in pectoralis muscle mass and lipid catabolic capacity. Temperature or photoperiod may be drivers of the winter phenotype, but their relative impacts on muscle remodeling or lipid transport pathways are little known. We examined photoperiod and temperature effects on pectoralis muscle expression of myostatin, a muscle growth inhibitor, and its tolloid-like protein activators (TLL-1 and TLL-2), and sarcolemmal and intracellular lipid transporters in dark-eyed juncos Junco hyemalis. We acclimated winter juncos to four temperature (3 °C or 24°C) and photoperiod [short-day (SD)=8L:16D; long-day (LD)=16L:8D] treatments. We found that myostatin, TLL-1, TLL-2, and lipid transporter mRNA expression and myostatin protein expression did not differ among treatments, but treatments interacted to influence lipid transporter protein expression. Fatty acid translocase (FAT/CD36) levels were higher for cold SD than for other treatments. Membrane-bound fatty acid binding protein (FABPpm) levels, however, were higher for the cold LD treatment than for cold SD and warm LD treatments. Cytosolic fatty acid binding protein (FABPc) levels were higher on LD than on SD at 3 °C, but higher on SD than on LD at 24 °C. Cold temperature groups showed upregulation of these lipid transporters, which could contribute to elevated Msum compared to warm groups on the same photoperiod. However, interactions of temperature or photoperiod effects on muscle remodeling and lipid transport pathways suggest that these effects are context-dependent. [ABSTRACT FROM AUTHOR]

Abstract: Insulin-, and contraction-induced GLUT4 and fatty acid (FA) transporter translocation may share common trafficking mechanisms. Our objective was to examine the effects of partial Munc18c ablation on muscle glucose and FA transport, FA oxidation, GLUT4 and FA transporter (FAT/CD36, FABPpm, FATP1, FATP4) trafficking to the sarcolemma, and FAT/CD36 to mitochondria. In Munc18c−/+ mice, insulin-stimulated glucose transport and GLUT4 sarcolemmal appearance were impaired, but were unaffected by contraction. Insulin- and contraction-stimulated FA transport, sarcolemmal FA transporter appearance, and contraction-mediated mitochondrial FAT/CD36 were increased normally in Munc18c−/+ mice. Hence, Munc18c provides stimulus-specific regulation of GLUT4 trafficking, but not FA transporter trafficking. [Copyright &y& Elsevier]

Abstract: This study reveals that the activation of either PPARα (WY 14643) or PPARβ (GW0742) each induce the translocation of FAT/CD36 from an intracellular pool(s) to the plasma membrane, while PPARβ also induces the subcellular redistribution of FABPpm(Got2) to the plasma membrane. In contrast, activation of PPARγ failed to induce the subcellular redistribution of FAT/CD36 and FABPpm. These PPARα-, and PPARβ-induced changes in the plasmalemmal content of these fatty acid transporters were associated with the concurrent upregulation of fatty acid triacylglycerol esterification (PPARβ) and oxidation (PPARα and PPARβ). Observed effects of chronic PPAR stimulation were not related to either AMPK or ERK1/2 activation. [Copyright &y& Elsevier]

Cardiomyopathy and heart failure are frequent comorbid conditions in type-2 diabetic patients. However, it has become increasingly evident that insulin resistance, type-2 diabetes, and cardiomyopathy are not independent variables, and are linked through changes in metabolism. Specifically, elevated intracellular levels of long-chain fatty acid (LCFA) metabolites are a central feature in the development of cardiac insulin resistance, and their prolonged accumulation is an important cause of heart failure. In the insulin-resistant heart, the abundance of the LCFA transporters CD36 and FABPpm at the sarcolemma of cardiac myocytes appears to be markedly increased. Because circulating LCFA levels are increased in insulin resistance, the cardiac LCFA metabolizing machinery is confronted with drastic increases in substrate supply. Indeed, LCFA esterification into triacylglycerol and other lipid intermediates is increased, as is β-oxidation and reactive oxygen species production. Therapeutic strategies to normalize the cardiac LCFA flux would be most successful when the target is the rate-limiting step in cardiac LCFA utilization. Carnitine palmitoyltransferase (CPT)-I has long been considered to be this rate-limiting site and, accordingly, pharmacological inhibition of CPT-I, or β-oxidation enzymes, has been proposed as an insulin-resistance-antagonizing strategy. However, recent evidence indicates that, instead, sarcolemmal LCFA transport mediated by CD36 in concert with FABPpm provides a major site of flux control. In this review, it is proposed that a pharmacologically imposed net internalization of CD36 and FABPpm is the preferable strategy to limit LCFA entry and accumulation of LCFA metabolites, to regress cardiac insulin resistance and, eventually, prevent diabetic heart failure. [ABSTRACT FROM AUTHOR]

Fatty acid transport into heart and skeletal muscle occurs largely through a highly regulated protein-mediated mechanism involving a number of fatty acid transporters. Chronically altered muscle activity (chronic muscle stimulation, denervation) alters fatty acid transport by altering the expression of fatty acid transporters and (or) their subcellular location. Chronic exposure to leptin downregulates while insulin upregulates fatty acid transport by altering concomitantly the expression of fatty acid transporters. Fatty acid transport can also be regulated within minutes, by muscle contraction, AMP-activated protein kinase activation, leptin, and insulin, through induction of the translocation of fatty acid translocase (FAT)/CD36 from its intracellular depot to the plasma membrane. In insulin-resistant muscle, a permanent relocation of FAT/CD36 to the sarcolemma appears to account for the excess accretion of intracellular lipids that interfere with insulin signaling. Recent work has also shown that FAT/ CD36, but not plasma membrane associated fatty acid binding protein, is involved, along with carnitine palmitoyltransferase, in regulating mitochondrial fatty acid oxidation. Finally, studies in FAT/CD36 null mice indicate that this transporter has a key role in regulating fatty acid metabolism in muscle. [ABSTRACT FROM AUTHOR]

Aim: Membrane fatty acid transporters can modulate the balance between fatty acid uptake and subsequent storage and/or oxidation in muscle tissue. As such, skeletal muscle fatty acid transporter protein expression could play an important role in the etiology of insulin resistance and/or type 2 diabetes. Methods: In the present study, fatty acid translocase (FAT/CD36), plasma membrane-bound fatty acid-binding protein (FABPpm) and fatty acid transport protein 1 (FATP1) mRNA and protein expression were assessed in muscle tissue obtained from 10 sedentary, overweight type 2 diabetes patients (60 ± 2 years), 10 sedentary, weight-matched normoglycemic controls (60 ± 2 years) and 10 age-matched, endurance trained cyclists (57 ± 1 years). Results: Both FAT/CD36 and FATP1 mRNA and protein expression did not differ between groups. In contrast, FABPpm mRNA and protein expression were approx. 30–40% higher in the trained men compared with the diabetes patients ( P < 0.01) and sedentary controls ( P < 0.05). Conclusions: Skeletal muscle FAT/CD36, FABPpm and FATP1 mRNA and protein expression are not up- or downregulated in a sedentary and/or insulin resistant state. In contrast, FABPpm expression is upregulated in the endurance trained state and likely instrumental to allow greater fatty acid oxidation rates. [ABSTRACT FROM AUTHOR]

Skeletal muscle metabolism has been examined in perfused hindlimb muscles and in isolated muscle preparations. While long-term viability of the fast-twitch epitrochlearis has been documented with respect to glucose transport, it appears that long-term incubated soleus muscles are less stable when incubated ex vivo for many hours. Therefore, in the present study, we have examined whether the isolated soleus muscle remains metabolically viable for up to 18 h with respect to maintaining ATP and phosphocreatine (PCr) concentrations, carbohydrate and fatty-acid metabolism, insulin signalling, and protein expression. Soleus muscles were incubated in well-oxygenated Medium 199 (M199) supplemented with low concentrations of insulin (14.3 µU/mL) for 0, 6, 12, and 18 h. During this incubating period the concentrations of ATP and PCr were stable, indicating that oxygenation and substrate supply were being maintained. In addition, the concentrations of proglycogen and macroglycogen were not altered, whereas an increase (+30%) in intramuscular triacylglycerol concentration was observed at the end of 18 h of incubation (p < 0.05). Complex molecular processes in the long-term incubated muscles were also stable. This was shown by maintenance of basal as well as insulin-stimulated rates of 3-O-methyl glucose transport, and by the maintenance of protein expression of the glucose transporter GLUT4 and the fatty acid transporters FAT/CD36 and FABPpm. In addition, the insulin-stimulated translocation of GLUT4 to the plasma membrane, which involves a complex signalling cascade, was fully preserved. In conclusion, in well-oxygenated soleus muscles maintained in M199 supplemented with extremely low concentrations of insulin, ATP and PCr concentrations, carbohydrate and fatty acid metabolism, insulin signalling, and protein expression were stably maintained for up to 18 h. This provides for opportunities to examine muscle metabolic function under very highly controlled conditions. [ABSTRACT FROM AUTHOR]

Abstract: Protein-mediated LCFA transport across plasma membranes is highly regulated by the fatty acid transporters FAT/CD36 and FABPpm. Physiologic stimuli (insulin stimulation, AMP kinase activation) induce the translocation of one or both transporters to the plasma membrane and increase the rate of LCFA transport. In the hypoxic/ischemic heart, intramyocardial lipid accumulation has been attributed to a reduced rate of fatty acid oxidation. However, since acute hypoxia (15min) activates AMPK, we examined whether an increased accumulation of intramyocardial lipid during hypoxia was also attributable to an increased rate of LCFA uptake as a result AMPK-induced translocation of FAT/CD36 and FABPpm. In cardiac myocytes, hypoxia (15min) induced the redistribution of FAT/CD36 from an intracellular pool (LDM) (−25%, P <0.05) to the plasma membranes (PM) (+54%, P <0.05). Hypoxia also induced an increase in FABPpm at the PM (+56%, P <0.05) and a concomitant FABPpm reduction in the LDM (−24%, P <0.05). Similarly, in intact, Langendorff perfused hearts, hypoxia induced the translocation of a both FAT/CD36 and FABPpm to the PM (+66% and +61%, respectively, P <0.05), with a concomitant decline in FAT/CD36 and FABPpm in the LDM (−24% and −23%, respectively, P <0.05). Importantly, the increased plasmalemmal content of these transporters was associated with increases in the initial rates of palmitate uptake into cardiac myocytes (+40%, P <0.05). Acute hypoxia also redirected palmitate into intracellular lipid pools, mainly to PL and TG (+48% and +28%, respectively, P <0.05), while fatty acid oxidation was reduced (−35%, P <0.05). Thus, our data indicate that the increased intracellular lipid accumulation in hypoxic hearts is attributable to both: (a) a reduced rate of fatty acid oxidation and (b) an increased rate of fatty acid transport into the heart, the latter being attributable to a hypoxia-induced translocation of fatty acid transporters. [Copyright &y& Elsevier]

Abstract: Cellular fatty acid uptake is facilitated by a number of fatty acid transporters, FAT/CD36, FABPpm and FATP1. It had been presumed that FABPpm, was confined to the plasma membrane and was not regulated. Here, we demonstrate for the first time that FABPpm and FATP1 are also present in intracellular depots in cardiac myocytes. While we confirmed previous work that insulin and AICAR each induced the translocation of FAT/CD36 from an intracellular depot to the PM, only AICAR, but not insulin, induced the translocation of FABPpm. Moreover, neither insulin nor AICAR induced the translocation of FATP1. Importantly, the increased plasmalemmal content of these LCFA transporters was associated with a concomitant increase in the initial rate of palmitate uptake into cardiac myocytes. Specifically, the insulin-stimulated increase in the rate of palmitate uptake (+60%) paralleled the insulin-stimulated increase in plasmalemmal FAT/CD36 (+34%). Similarly, the greater AICAR-stimulated increase in the rate of palmitate uptake (+90%) paralleled the AICAR-induced increase in both plasmalemmal proteins (FAT/CD36 (+40%)+FABPpm (+36%)). Inhibition of palmitate uptake with the specific FAT/CD36 inhibitor SSO indicated that FABPpm interacts with FAT/CD36 at the plasma membrane to facilitate the uptake of palmitate. In conclusion, (1) there appears to be tissue-specific sensitivity to insulin-induced FATP1 translocation, as it has been shown elsewhere that insulin induces FATP1 translocation in 3T3-L1 adipocytes, and (2) clearly, the subcellular distribution of FABPpm, as well as FAT/CD36, is acutely regulated in cardiac myocytes, although FABPpm and FAT/CD36 do not necessarily respond identically to the same stimuli. [Copyright &y& Elsevier]

Abstract It has been assumed that the uptake of long chain fatty acids (LCFAs) into skeletal muscle and the heart muscle, as well as other tissues, occurred via passive diffusion. In recent years our work has shown that the LCFA uptake into skeletal muscle is a highly regulated process. The use of giant sarcolemmal vesicles obtained from skeletal muscle and heart has been used to demonstrate that LCFA uptake into these tissues occurs via a protein-mediated mechanism involving the 40 kDa plasma membrane associated fatty acid binding protein (FABPpm) and the 88 kDa fatty acid translocase, the homologue of human CD36 (FAT/CD36). Both are ubiquitously expressed proteins and correlate with LCFA uptake into heart and muscle, consistent with the known differences in LCFA metabolism in these tissues. It has recently been found that FAT/CD36 is present in an intracellular (endosomal) compartment from which it can be translocated to the plasma membrane within minutes by muscle contraction and by insulin, to stimulate LCFA uptake. In rodent models of obesity and type 1 diabetes LCFA uptake into heart and muscle is also increased, either by permanently relocating FAT/CD36 to the plasma membrane without altering its expression (obesity) or by increasing the expression of both FAT/CD36 and FABPpm (type 1 diabetes). Chronic leptin treatment decreases LCFA transporters and transport in muscle. Clearly, recent evidence has established that LCFA uptake into heart and muscle is regulated acutely and chronically. [ABSTRACT FROM AUTHOR]

The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers. Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes. [ABSTRACT FROM AUTHOR]

TBC1D4 (AS160) and TBC1D1 are Rab GTPase-activating proteins that play a key role in the regulation of glucose and possibly the transport of long chain fatty acids (LCFAs) into muscle and fat cells. Knockdown (KD) of TBC1D4 increased CD36/SR-B2 and FABPpm protein expressions in L6 myotubes, whereas in murine cardiomyocytes, TBC1D4 deficiency led to a redistribution of CD36/SR-B2 to the sarcolemma. In our study, we investigated the previously unexplored role of both Rab-GAPs in LCFAs uptake in human adipocytes differentiated from the ADMSCs of subcutaneous and visceral adipose tissue origin. To this end we performed a single- and double-knockdown of the proteins (TBC1D1 and TBC1D4). Herein, we provide evidence that AS160 mediates fatty acid entry into the adipocytes derived from ADMSCs. TBC1D4 KD resulted in quite a few alterations to the cellular phenotype, the most obvious of which was the shift of the CD36/SR-B2 transport protein to the plasma membrane. The above translated into an increased uptake of saturated long-chain fatty acid. Interestingly, we observed a tissue-specific pattern, with more pronounced changes present in the adipocytes derived from subADMSCs. Altogether, our data show that in human adipocytes, TBC1D4, but not TBC1D1, deficiency increases LCFAs transport via CD36/SR-B2 translocation. [ABSTRACT FROM AUTHOR]