Investigating fatty acid transport and β- fatty acid oxidation (FAO) in placentas exposed to hyperglycemia

Intramuscular triacylglycerol (IMTG) accumulation in obesity has been attributed to increased fatty acid transport and/or to alterations in mitochondrial fatty acid oxidation. Alternatively, an imbalance in these two processes may channel fatty acids into storage. Therefore, in red and white muscles of lean and obese Zucker rats, we examined whether the increase in IMTG accumulation was attributable to an increased rate of fatty acid transport rather than alterations in subsarcolemmal (SS) or intermyofibrillar (IMF) mitochondrial fatty acid oxidation. In obese animals selected parameters were upregulated, including palmitate transport (red: +100%; white: +51%), plasmalemmal FAT/CD36 (red: +116%; white: +115%; not plasmalemmal FABPpm, FATP1, or FATP4), IMTG concentrations (red: ∼2-fold; white: ∼4-fold), and mitochondrial content (red +30%). Selected mitochondrial parameters were also greater in obese animals, namely, palmitate oxidation (SS red: +91%; SS white: +26%; not IMF mitochondria), FAT/CD36 (SS: +65%; IMF: +65%), citrate synthase (SS: +19%), and β-hydroxyacyl-CoA dehydrogenase activities (SS: +20%); carnitine palmitoyltransferase-I activity did not differ. A comparison of lean and obese rat muscles revealed that the rate of change in IMTG concentration was eightfold greater than that of fatty acid oxidation (SS mitochondria), when both parameters were expressed relative to fatty transport. Thus fatty acid transport, esterification, and oxidation (SS mitochondria) are upregulated in muscles of obese Zucker rats, with these effects being most pronounced in red muscle. The additional fatty acid taken up is channeled primarily to esterification, suggesting that upregulation in fatty acid transport as opposed to altered fatty acid oxidation is the major determinant of intramuscular lipid accumulation.

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Mitochondrial function and dysfunction in exercise and insulin resistanceThis paper article is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-028 ◽

2009 ◽

Vol 34 (3) ◽

pp. 440-446 ◽

Cited By ~ 12

Author(s):

Graham P. Holloway

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Peer Review Process ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport ◽

Mitochondrial Content ◽

Mitochondrial Fatty Acid

Fatty acid translocase (FAT/CD36) represents a novel flexible regulatory system, influencing rates of mitochondrial fatty acid metabolism in both human and rodent skeletal muscle. During exercise, the subcellular redistribution of FAT/CD36 provides a mechanism to increase not only plasma membrane fatty acid transport, but also mitochondrial fatty acid oxidation. This FAT/CD36-mediated coordination of long chain fatty acid (LCFA) transport and oxidation is an intriguing model in the context of insulin resistance. It was believed for almost a decade that reductions in fatty acid oxidation increased intramuscular lipids, thereby contributing to insulin resistance. A reduction in mitochondrial content may reduce the capacity of skeletal muscle LCFA oxidation; however, work from my laboratory has shown that, in some insulin-resistant muscles, mitochondrial content and fatty acid oxidation are both increased, yet these muscles accumulate lipids because of a considerably greater increase in fatty acid transport. Therefore, an alternative model is being considered, in which the balance between LCFA uptake and oxidation is a determining factor in the development of insulin resistance. A permanent redistribution of the LCFA transport protein FAT/CD36 to the sarcolemmal has been consistently found, which results in an increased rate of LCFA transport. This work suggests that the accumulation of skeletal muscle lipids, regardless of changes in mitochondria, is attributable to an increased rate of LCFA transport that exceeds the capacity for oxidation.

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Lipid metabolism, exercise and insulin action

Essays in Biochemistry ◽

10.1042/bse0420047 ◽

2006 ◽

Vol 42 ◽

pp. 47-59 ◽

Cited By ~ 38

Author(s):

Arend Bonen ◽

G. Lynis Dohm ◽

Luc J.C. van Loon

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Insulin Signalling ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport ◽

Severely Obese

Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation.

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Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α)

Cellular Physiology and Biochemistry ◽

10.1159/000489546 ◽

2018 ◽

Vol 46 (5) ◽

pp. 2165-2172 ◽

Cited By ~ 7

Author(s):

Fang He ◽

Jie-Qiong Jin ◽

Qing-Qing Qin ◽

Yong-Qin Zheng ◽

Ting-Ting Li ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Regulatory Genes ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport ◽

Inhibitory Effects ◽

Transcriptional Regulatory

Background/Aims: Abnormal fatty acid β oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid β oxidation needs to be elucidated. Methods: We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial β-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms. Results: Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial β-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid β oxidation. Conclusions: Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid β oxidation.

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Acute insulin deprivation results in altered mitochondrial substrate sensitivity conducive to greater fatty acid transport

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00495.2019 ◽

2020 ◽

Vol 319 (2) ◽

pp. E345-E353

Author(s):

Paula M. Miotto ◽

Heather L. Petrick ◽

Graham P. Holloway

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Insulin Action ◽

Oxidative Capacity ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport ◽

Mitochondrial Fatty Acid ◽

Metabolic Inflexibility ◽

Cpt I

Type 1 and type 2 diabetes are both tightly associated with impaired glucose control. Although both pathologies stem from different mechanisms, a reduction in insulin action coincides with drastic metabolic dysfunction in skeletal muscle and metabolic inflexibility. However, the underlying explanation for this response remains poorly understood, particularly since it is difficult to distinguish the role of attenuated insulin action from the detrimental effects of reactive lipid accumulation, which impairs mitochondrial function and promotes reactive oxygen species (ROS) emission. We therefore utilized streptozotocin to examine the effects of acute insulin deprivation, in the absence of a high-lipid/nutrient excess environment, on the regulation of mitochondrial substrate sensitivity and ROS emission. The ablation of insulin resulted in reductions in absolute mitochondrial oxidative capacity and ADP-supported respiration and reduced the ability for malonyl-CoA to inhibit carnitine palmitoyltransferase I (CPT-I) and suppress fatty acid-supported respiration. These bioenergetic responses coincided with increased mitochondrial-derived H2O2 emission and lipid transporter content, independent of major mitochondrial substrate transporter proteins and enzymes involved in fatty acid oxidation. Together, these data suggest that attenuated/ablated insulin signaling does not affect mitochondrial ADP sensitivity, whereas the increased reliance on fatty acid oxidation in situations where insulin action is reduced may occur as a result of altered regulation of mitochondrial fatty acid transport through CPT-I.

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Diallyl trisulphide inhibits adipogenesis in 3T3-L1 adipocytes through lipogenesis, fatty acid transport, and fatty acid oxidation pathways

Journal of Functional Foods ◽

10.1016/j.jff.2015.05.002 ◽

2015 ◽

Vol 16 ◽

pp. 414-422 ◽

Cited By ~ 10

Author(s):

Wei-Tang Chang ◽

Chi-Hao Wu ◽

Chin-Lin Hsu

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport

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Greater Transport Efficiencies of the Membrane Fatty Acid Transporters FAT/CD36 and FATP4 Compared with FABPpm and FATP1 and Differential Effects on Fatty Acid Esterification and Oxidation in Rat Skeletal Muscle

Journal of Biological Chemistry ◽

10.1074/jbc.m109.004788 ◽

2009 ◽

Vol 284 (24) ◽

pp. 16522-16530 ◽

Cited By ~ 112

Author(s):

James G. Nickerson ◽

Hakam Alkhateeb ◽

Carley R. Benton ◽

James Lally ◽

Jennifer Nickerson ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Chain Fatty Acid ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport ◽

Rat Skeletal Muscle ◽

Long Chain Fatty Acid ◽

Acid Esterification ◽

Long Chain

In selected mammalian tissues, long chain fatty acid transporters (FABPpm, FAT/CD36, FATP1, and FATP4) are co-expressed. There is controversy as to whether they all function as membrane-bound transporters and whether they channel fatty acids to oxidation and/or esterification. Among skeletal muscles, the protein expression of FABPpm, FAT/CD36, and FATP4, but not FATP1, correlated highly with the capacities for oxidative metabolism (r ≥ 0.94), fatty acid oxidation (r ≥ 0.88), and triacylglycerol esterification (r ≥ 0.87). We overexpressed independently FABPpm, FAT/CD36, FATP1, and FATP4, within a normal physiologic range, in rat skeletal muscle, to determine the effects on fatty acid transport and metabolism. Independent overexpression of each fatty acid transporter occurred without altering either the expression or plasmalemmal content of other fatty acid transporters. All transporters increased fatty acid transport, but FAT/CD36 and FATP4 were 2.3- and 1.7-fold more effective than FABPpm and FATP1, respectively. Fatty acid transporters failed to alter the rates of fatty acid esterification into triacylglycerols. In contrast, all transporters increased the rates of long chain fatty acid oxidation, but the effects of FABPpm and FAT/CD36 were 3-fold greater than for FATP1 and FATP4. Thus, fatty acid transporters exhibit different capacities for fatty acid transport and metabolism. In vivo, FAT/CD36 and FATP4 are the most effective fatty acid transporters, whereas FABPpm and FAT/CD36 are key for stimulating fatty acid oxidation.

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Cardiac and skeletal muscle fatty acid transport and transporters and triacylglycerol and fatty acid oxidation in lean and Zucker diabetic fatty rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90820.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. R1202-R1212 ◽

Cited By ~ 43

Author(s):

Arend Bonen ◽

Graham P. Holloway ◽

Narendra N. Tandon ◽

Xiao-Xia Han ◽

Jay McFarlan ◽

...

Keyword(s):

Fatty Acid ◽

White Muscle ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Acid Transport ◽

Insulin Resistant ◽

Red Muscle ◽

Zdf Rats ◽

Red And White Muscles

We examined fatty acid transporters, transport, and metabolism in hearts and red and white muscles of lean and insulin-resistant ( week 6) and type 2 diabetic ( week 24) Zucker diabetic fatty (ZDF) rats. Cardiac fatty acid transport was similar in lean and ZDF hearts at week 6 but was reduced at week 24 (−40%) in lean but not ZDF hearts. Red muscle of ZDF rats exhibited an early susceptibility to upregulation (+66%) of fatty acid transport at week 6 that was increased by 50% in lean and ZDF rats at week 24 but remained 44% greater in red muscle of ZDF rats. In white muscle, no differences were observed in fatty acid transport between groups or from week 6 to week 24. In all tissues (heart and red and white muscle), FAT/CD36 protein and plasmalemmal content paralleled the changes in fatty acid transport. Triacylglycerol content in red and white muscles, but not heart, in lean and ZDF rats correlated with fatty acid transport ( r = 0.91) and sarcolemmal FAT/CD36 ( r = 0.98). Red and white muscle fatty acid oxidation by isolated mitochondria was not impaired in ZDF rats but was reduced by 18–24% in red muscle of lean rats at week 24. Thus, in red, but not white, muscle of insulin-resistant and type 2 diabetic animals, a marked upregulation in fatty acid transport and intramuscular triacylglycerol was associated with increased levels of FAT/CD36 expression and plasmalemmal content. In heart, greater rates of fatty acid transport and FAT/CD36 in ZDF rats ( week 24) were attributable to the inhibition of age-related reductions in these parameters. However, intramuscular triacylglycerol did not accumulate in hearts of ZDF rats. Thus insulin resistance and type 2 diabetes are accompanied by tissue-specific differences in FAT/CD36 and fatty acid transport and metabolism. Upregulation of fatty acid transport increased red muscle, but not cardiac, triacylglycerol accumulation. White muscle lipid metabolism dysregulation was not observed.

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FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.91021.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. R960-R967 ◽

Cited By ~ 48

Author(s):

Graham P. Holloway ◽

Swati S. Jain ◽

Veronic Bezaire ◽

Xiao Xia Han ◽

Jan F. C. Glatz ◽

...

Keyword(s):

Plasma Membrane ◽

Fatty Acid ◽

Muscle Contraction ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Mitochondrial Fatty Acid Oxidation ◽

Palmitate Oxidation ◽

Oxidation Rates ◽

Mitochondrial Fatty Acid

The plasma membrane fatty acid transport protein FAT/CD36 is also present at the mitochondria, where it may contribute to the regulation of fatty acid oxidation, although this has been challenged. Therefore, we have compared enzyme activities and rates of mitochondrial palmitate oxidation in muscles of wild-type (WT) and FAT/CD36 knockout (KO) mice, at rest and after muscle contraction. In WT and KO mice, carnitine palmitoyltransferase-I, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase activities did not differ in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria of WT and FAT/CD36 KO mice. Basal palmitate oxidation rates were lower ( P < 0.05) in KO mice (SS −18%; IMF −13%). Muscle contraction increased fatty acid oxidation (+18%) and mitochondrial FAT/CD36 protein (+16%) in WT IMF but not in WT SS, or in either mitochondrial subpopulation in KO mice. This revealed that the difference in IMF mitochondrial fatty acid oxidation between WT and KO mice can be increased ∼2.5-fold from 13% under basal conditions to 35% during muscle contraction. The FAT/CD36 inhibitor sulfo- N-succinimidyl oleate (SSO), inhibited palmitate transport across the plasma membrane in WT, but not in KO mice. In contrast, SSO bound to mitochondrial membranes and reduced palmitate oxidation rates to a similar extent in both WT and KO mitochondria (∼80%; P < 0.05). In addition, SSO reduced state III respiration with succinate as a substrate, without altering mitochondrial coupling (P/O ratios). Thus, while SSO inhibits FAT/CD36-mediated palmitate transport at the plasma membrane, SSO has undefined effects on mitochondria. Nevertheless, the KO animals reveal that FAT/CD36 contributes to the regulation of mitochondrial fatty acid oxidation, which is especially important for meeting the increased metabolic demands during muscle contraction.

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