12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake.
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ABSTRACT:
SUBMITTER: Stanford KI
PROVIDER: S-EPMC5935136 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
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12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake.
Stanford Kristin I KI Lynes Matthew D MD Takahashi Hirokazu H Baer Lisa A LA Arts Peter J PJ May Francis J FJ Lehnig Adam C AC Middelbeek Roeland J W RJW Richard Jeffrey J JJ So Kawai K Chen Emily Y EY Gao Fei F Narain Niven R NR Distefano Giovanna G Shettigar Vikram K VK Hirshman Michael F MF Ziolo Mark T MT Kiebish Michael A MA Tseng Yu-Hua YH Coen Paul M PM Goodyear Laurie J LJ
Cell metabolism 20180501 5
Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active ...[more]
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Project description:Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.
| S-EPMC5699924 | biostudies-literature
Project description:ContextLittle is known about the specific breastmilk components responsible for protective effects on infant obesity. Whether 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), an oxidized linoleic acid metabolite and activator of brown fat metabolism, is present in human milk, or linked to infant adiposity, is unknown.ObjectiveTo examine associations between concentrations of 12,13-diHOME in human milk and infant adiposity.DesignProspective cohort study from 2015 to 2019, following participants from birth to 6 months of age.SettingAcademic medical centers.ParticipantsVolunteer sample of 58 exclusively breastfeeding mother-infant pairs; exclusion criteria included smoking, gestational diabetes, and health conditions with the potential to influence maternal or infant weight gain.Main outcome measuresInfant anthropometric measures including weight, length, body mass index (BMI), and body composition at birth and at 1, 3, and 6 months postpartum.ResultsWe report for the first time that 12,13-diHOME is present in human milk. Higher milk 12,13-diHOME level was associated with increased weight-for-length Z-score at birth (β = 0.5742, P = 0.0008), lower infant fat mass at 1 month (P = 0.021), and reduced gain in BMI Z-score from 0 to 6 months (β = -0.3997, P = 0.025). We observed similar associations between infant adiposity and milk abundance of related oxidized linoleic acid metabolites 12,13-Epoxy-9(Z)-octadecenoic acid (12,13-epOME) and 9,10-Dihydroxy-12-octadecenoic acid (9,10-diHOME), and metabolites linked to thermogenesis including succinate and lyso-phosphatidylglycerol 18:0. Milk abundance of 12,13-diHOME was not associated with maternal BMI, but was positively associated with maternal height, milk glucose concentration, and was significantly increased after a bout of moderate exercise.ConclusionsWe report novel associations between milk abundance of 12,13-diHOME and adiposity during infancy.
| S-EPMC7823229 | biostudies-literature
Project description:BackgroundBrown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function.MethodsTo determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease.ResultsHere, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease.ConclusionsOur results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.
| S-EPMC7856257 | biostudies-literature
Project description:Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance. Keywords: expression profiling by array randomized crossover dietary intervention study
2012-02-21 | E-GEOD-31901 | biostudies-arrayexpress
Project description:Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance. Keywords: expression profiling by array
2012-02-21 | GSE31901 | GEO
Project description:Exercise and weight loss are cornerstones in the treatment and prevention of type 2 diabetes, and both interventions function to increase insulin sensitivity and glucose uptake into skeletal muscle. Studies in rodents demonstrate that the underlying mechanism for glucose uptake in muscle involves site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 (TBC1D4) and TBC1D1. Multiple kinases, including Akt and AMPK, phosphorylate TBC1D1 and AS160 on distinct residues, regulating their activity and allowing for GLUT4 translocation. In contrast to extensive rodent-based studies, the regulation of AS160 and TBC1D1 in human skeletal muscle is not well understood. In this study, we determined the effects of dietary intervention and a single bout of exercise on TBC1D1 and AS160 site-specific phosphorylation in human skeletal muscle. Ten obese (BMI 33.4 ± 2.4, M-value 4.3 ± 0.5) subjects were studied at baseline and after a 2-wk dietary intervention. Muscle biopsies were obtained from the subjects in the resting (basal) state and immediately following a 30-min exercise bout (70% Vo(2 max)). Muscle lysates were analyzed for AMPK activity and Akt phosphorylation and for TBC1D1 and AS160 phosphorylation on known or putative AMPK and Akt sites as follows: AS160 Ser(711) (AMPK), TBC1D1 Ser(231) (AMPK), TBC1D1 Ser(660) (AMPK), TBC1D1 Ser(700) (AMPK), and TBC1D1 Thr(590) (Akt). The diet intervention that consisted of a major shift in the macronutrient composition resulted in a 4.2 ± 0.4 kg weight loss (P < 0.001) and a significant increase in insulin sensitivity (M value 5.6 ± 0.6), but surprisingly, there was no effect on expression or phosphorylation of any of the muscle-signaling proteins. Exercise increased muscle AMPK?2 activity but did not increase Akt phosphorylation. Exercise increased phosphorylation on AS160 Ser(711), TBC1D1 Ser(231), and TBC1D1 Ser(660) but had no effect on TBC1D1 Ser(700). Exercise did not increase TBC1D1 Thr(590) phosphorylation or TBC1D1/AS160 PAS phosphorylation, consistent with the lack of Akt activation. These data demonstrate that a single bout of exercise regulates TBC1D1 and AS160 phosphorylation on multiple sites in human skeletal muscle.
| S-EPMC3129834 | biostudies-other
Project description:Existing controversy regarding the importance of AMP-activated protein kinase (AMPK) in fatty acid (FA) oxidation in skeletal muscle with contraction/exercise may to some extent pertain to redundant AMPKα1 signaling. Using a mouse model lacking both AMPKα1 and -α2 in skeletal muscle specifically (mdKO) we hypothesized that FA utilization would be impaired in skeletal muscle. Calorimetric analysis showed a similar respiratory exchange ratio (RER) of AMPKα WT and mdKO mice when fed normal chow, a high fat diet or with prolonged fasting. Though, in vivo treadmill exercise at the same relative intensity induced a higher RER in mdKO mice compared to WT (WT=0.81; mdKO=0.87; p<0.01) indicating a decreased utilization of FA. Ex vivo incubation of soleus muscle revealed that basal and contraction-induced FA oxidation was impaired in mdKO mice, suggesting that the increased RER during in vivo running exercise originated from decreased skeletal muscle FA oxidation. A decreased muscle protein expression of CD36 and FABPpm (by 17-40%) together with abolishment of TBC1D1 Ser237 phosphorylation in mdKO mice, may result in lower FA transport capacity and FA transport protein translocation to sarcolemma, respectively. In summary this study shows that the catalytically active AMPKα subunits are required for normal stimulation of FA utilization during exercise and contractions.
2015-09-30 | GSE61904 | GEO
Project description:ObjectiveFatty acids (FAs) are the major substrate for energy production in the heart. Here, we hypothesize that capillary endothelial fatty acid binding protein 4 (FABP4) and FABP5 play an important role in providing sufficient FAs to the myocardium.Approach and resultsBoth FABP4/5 were abundantly expressed in capillary endothelium in the heart and skeletal muscle. The uptake of a FA analogue, 125I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid, was significantly reduced in these tissues in double-knockout (DKO) mice for FABP4/5 compared with wild-type mice. In contrast, the uptake of a glucose analogue, 18F-fluorodeoxyglucose, was remarkably increased in DKO mice. The expression of transcripts for the oxidative catabolism of FAs was reduced during fasting, whereas transcripts for the glycolytic pathway were not altered in DKO hearts. Notably, metabolome analysis revealed that phosphocreatine and ADP levels were significantly lower in DKO hearts, whereas ATP content was kept at a normal level. The protein expression levels of the glucose transporter Glut4 and the phosphorylated form of phosphofructokinase-2 were increased in DKO hearts, whereas the phosphorylation of insulin receptor-β and Akt was comparable between wild-type and DKO hearts during fasting, suggesting that a dramatic increase in glucose usage during fasting is insulin independent and is at least partly attributed to the post-transcriptional and allosteric regulation of key proteins that regulate glucose uptake and glycolysis.ConclusionsCapillary endothelial FABP4/5 are required for FA transport into FA-consuming tissues that include the heart. These findings identify FABP4/5 as promising targets for controlling the metabolism of energy substrates in FA-consuming organs that have muscle-type continuous capillary.
| S-EPMC3979458 | biostudies-literature
Project description:Among all cancers, glioblastoma (GBM) remains one of the least treatable. One key factor in this resistance is a subpopulation of tumor cells termed glioma stem cells (GSCs). These cells are highly resistant to current treatment modalities, possess marked self-renewal capacity, and are considered key drivers of tumor recurrence. Further complicating an understanding of GBM, evidence shows that the GSC population is not a pre-ordained and static group of cells but also includes previously differentiated GBM cells that have attained a GSC state secondary to environmental cues. The metabolic behavior of GBM cells undergoing plasticity remains incompletely understood. To that end, we probed the connection between GSCs, environmental cues, and metabolism. Using patient-derived xenograft cells, mouse models, transcriptomics, and metabolic analyses, we found that cell state changes are accompanied by sharp changes in metabolic phenotype. Further, treatment with temozolomide, the current standard of care drug for GBM, altered the metabolism of GBM cells and increased fatty acid uptake both in vitro and in vivo in the plasticity driven GSC population. These results indicate that temozolomide-induced changes in cell state are accompanied by metabolic shifts-a potentially novel target for enhancing the effectiveness of current treatment modalities.
| S-EPMC7693784 | biostudies-literature
Project description:ObjectiveThe effects of 6-month weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity.MethodsFat (gluteal and abdominal) lipoprotein lipase (LPL), skeletal muscle LPL, acyl-CoA synthase (ACS), ß-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate synthase (CS) activities were measured at baseline (n = 104) and before and after WL (n = 34) and AEX+WL (n = 37).ResultsAfter controlling for age and race, muscle LPL and CPT-1 were lower in IGT, and the ratios of fat/muscle LPL activity were higher in IGT compared to NGT. Muscle LPL was related to insulin sensitivity (M value) and inversely related to G120 , fasting insulin, and homeostatic model assessment of insulin resistance. AEX+WL decreased abdominal fat LPL and increased muscle LPL, ACS, and CS. The ratios of fat/muscle LPL decreased after AEX+WL. The change in VO2 max was related to the changes in LPL, ACS, and CS and inversely related to the changes in fat/muscle LPL activity ratios.ConclusionsSix-month AEX+WL, and not WL alone, is capable of enhancing skeletal muscle fatty acid metabolism in postmenopausal African-American and Caucasian women with NGT, IGT, and overweight/obesity.
| S-EPMC5487288 | biostudies-literature