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Diabetes mellitus is a highly prevalent disease characterized by hyperglycaemia that damages the vascular system, leading to micro‐ (retinopathy, neuropathy, nephropathy) and macrovascular diseases (cardiovascular disease). There are also secondary complications of diabetes (cardiomyopathy, erectile dysfunction or diabetic foot ulcers). Stem cell‐based therapies have become a promising tool targeting diabetes symptoms and its chronic complications. Among all stem cells, adipose‐derived mesenchymal stem cells (ADMSCs) are of great importance because of their abundance, non‐invasive isolation and no ethical limitations. Characteristics that make ADMSCs good candidates for cell‐based therapy are their wide immunomodulatory properties and paracrine activities through the secretion of an array of growth factors, chemokines, cytokines, angiogenic factors and anti‐apoptotic molecules. Besides, after transplantation, ADMSCs show great ex vivo expansion capacity and differentiation to other cell types, including insulin‐producing cells, cardiomyocytes, chondrocytes, hepatocyte‐like cells, neurons, endothelial cells, photoreceptor‐like cells, or astrocytes. Preclinical studies have shown that ADMSC‐based therapy effectively improved visual acuity, ameliorated polyneuropathy and foot ulceration, arrested the development and progression of diabetic kidney disease, or alleviated the diabetes‐induced cardiomyocyte hypertrophy. However, despite the positive results obtained in animal models, there are still several challenges that need to be overcome before the results of preclinical studies can be translated into clinical applications. To date, there are several clinical trials or ongoing trials using ADMSCs in the treatment of diabetic complications, most of them in the treatment of diabetic foot ulcers. This narrative review summarizes the most recent outcomes on the usage of ADMSCs in the treatment of long‐term complications of diabetes in both animal models and clinical trials. [ABSTRACT FROM AUTHOR]

Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid found in all eukaryotic cells. Although it may function as an intracellular second messenger, most of its effects are induced extracellularly via activation of a family of five specific membrane receptors. Sphingosine‐1‐phosphate is enriched in plasma, where it is transported by high‐density lipoprotein and albumin, as well as in erythrocytes and platelets which store and release large amounts of this sphingolipid. Sphingosine‐1‐phosphate regulates a host of cellular processes such as growth, proliferation, differentiation, migration, and apoptosis suppression. It was also shown to play an important role in skeletal muscle physiology and pathophysiology. In recent years, S1P metabolism in both muscle and blood was found to be modulated by exercise. In this review, we summarize the current knowledge on the effect of acute exercise and training on S1P metabolism, highlighting the role of this sphingolipid in skeletal muscle adaptation to physical effort. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder affecting a significant part of the global population. This study aimed to investigate the potential therapeutic effects of α-lipoic acid (α-LA) on the inflammatory response during simple steatosis development and progression into steatohepatitis. The study used the MASLD model in male Wistar rats that were fed a standard diet or a high-fat diet (HFD) for 8 weeks. Throughout the entire experiment, half of the animals received α-LA supplementation. The hepatic activity of pro-inflammatory n-6 and anti-inflammatory n-3 polyunsaturated fatty acid (PUFA) pathways and the concentration of arachidonic acid (AA) in selected lipid fractions were determined by the gas-liquid chromatography (GLC). The hepatic expression of proteins from inflammatory pathway was measured by the Western blot technique. The level of eicosanoids, cytokines and chemokines was assessed by the ELISA or multiplex assay kits. The results showed that α-LA supplementation attenuated the activity of n-6 PUFA pathway in FFA and DAG and increased the activity of n-3 PUFA pathway in PL, TAG and DAG. In addition, the administration of α-LA decreased the concentration of AA in DAG and FFA, indicating its potential protective effect on the deterioration of simple hepatic steatosis. The supplementation of α-LA also increased the expression of COX-1 and COX-2 with the lack of significant changes in prostaglandins profile. We observed an increase in the expression of 12/15-LOX, which was reflected in an increase in lipoxin A4 (LXA4) level. A decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines was also noticed in the liver of rats treated with HFD and α-LA. Our observations confirm that α-LA treatment has potential protective effects on inflammation development in the MASLD model. We believe that α-LA has a preventive impact when it comes to the progression of simple steatosis lesions to steatohepatitis. • α-LA has a protective effect on the development of inflammation in the liver tissue. • α-LA protects against the simple steatosis progression to fatty liver hepatitis. • HFD promotes the occurrence of inflammation, a key factor for MASLD progression. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, complex, and immunologically mediated systemic disease that not only affects the skin, but also the joints and nails. It may coexist with various other disorders, such as depression, psoriatic arthritis, cardiovascular diseases, diabetes mellitus, and metabolic syndrome. In particular, the potential link between psoriasis and metabolic syndrome is an issue worthy of attention. The dysregulation of growth factors could potentially contribute to the disturbances of keratinocyte proliferation, inflammation, and itch severity. However, the pathophysiology of psoriasis and its comorbidities, such as metabolic syndrome, remains incompletely elucidated. Growth factors and their abnormal metabolism may be a potential link connecting these conditions. Overall, the objective of this review is to analyze the role of growth factor disturbances in both psoriasis and metabolic syndrome. [ABSTRACT FROM AUTHOR]

Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/ CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-β-D-arabinofuranoside or Compound C. In wild-type mice, leptin induced the translocation of FAT/CD36 to the plasma membrane and increased fatty acid uptake into giant sarcolemmal vesicles and into cardiomyocytes. In muscles of FAT/CD36-KO mice, and in cardiomyocytes in which cell surface FAT/CD36 action was blocked by sulfo-N-succinimidyl oleate, the leptin-stimulated influx of fatty acids was inhibited; concomitantly, the normal leptin-stimulated increase in fatty acid oxidation was also prevented, despite the normal leptin-induced increase in AMPK phosphorylation. Conversely, in muscle of AMPK kinase-dead mice, leptin failed to induce the translocation of FAT/CD36, along with a failure to stimulate fatty acid uptake and oxidation. Similarly, when siRNA was used to reduce AMPK in HL-1 cardiomyocytes, leptin failed to induce the translocation of FAT/CD36. Our studies have revealed a novel mechanism of leptin-induced fatty acid oxidation in muscle tissue; namely, this process is dependent on the activation of AMPK to induce the translocation of FAT/CD36 to the plasma membrane, thereby stimulating fatty acid uptake. Without increasing this leptin-stimulated, FAT/CD36-dependent fatty acid uptake process, leptinstimulated AMPK phosphorylation does not enhance fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Proliferating cells exhibit accelerated rates of substrate utilization, favoring glucose over fatty acids (FA’s) oxidation. Protein-mediated transport is thought to play a predominant role in facilitating either glucose or FA routing into the cells. In the present study, we examined the expression of glucose transporters (GLUT-1, GLUT-4) and fatty acids transporters (FAT/CD36, FATP-1, FATP-4) at transcript and protein levels as well as cytosolic fatty acid binding proteins (H-FABP, ACBP) in human fibroids (n = 74, size up to 3 cm diameter) and compared with pair-matched healthy myometrium. Additionally lipid content (diacylglycerols, triacylglycerols and ceramide) was estimated by gas liquid chromatography (GLC). Uterine fibroids displayed decreased expression of both FAT/CD36 and FATP-1 proteins along with lower diacylglycerol (DAG) and triacylglycerol (TAG) content as compared to healthy pair-matched myometrium. The expression of glucose transport proteins (GLUT-4 and GLUT-1) remained relatively constant, although the higher expression of GLUT-1 in uterine fibroids did not reach the minimum significance threshold (p = 0.056). However, no change in either cytochrome c oxidase (COX IV) or hydroxyacyl-CoA dehydrogenase (HADHSC) was observed and these data confirm a possible metabolic shift favoring glucose utilization over fatty acid oxidation in human uterine fibroids. [ABSTRACT FROM AUTHOR]

Branched chain amino acids (BCAA) and their derivatives are bioactive molecules with pleiotropic functions in the human body. Elevated fasting blood BCAA concentrations are considered as a metabolic hallmark of obesity, insulin resistance, dyslipidaemia, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease. However, since increased BCAA amount is observed both in metabolically healthy and obese subjects, a question whether BCAA are mechanistic drivers of insulin resistance and its morbidities or only markers of metabolic dysregulation, still remains open. The beneficial effects of BCAA on body weight and composition, aerobic capacity, insulin secretion and sensitivity demand high catabolic potential toward amino acids and/or adequate BCAA intake. On the opposite, BCAA-related inhibition of lipogenesis and lipolysis enhancement may preclude impairment in insulin sensitivity. Thereby, the following review addresses various strategies pertaining to the modulation of BCAA catabolism and the possible roles of BCAA in energy homeostasis. We also aim to elucidate mechanisms behind the heterogeneity of ramifications associated with BCAA modulation. [ABSTRACT FROM AUTHOR]

Uterine fibroids are the most common benign tumors of the female genital tract. However, true epidemiological data analyzing the incidence rate are still under-estimated. This is because fibroids remain undiagnosed since most of them are asymptomatic and confirmed during a histology examination after hysterectomy. Uterine fibroids are clinically apparent in up to 25% of all women and up to 30-40% of women over 40 years of age. Several risk factors have been identified, such as ethnicity, nulliparity, hormonal factors and genetics. Several epidemiological data have also demonstrated that the incidence of uterine fibroids is higher in blacks than in whites. Although the etiology of uterine fibroids is unknown, there have been some major advances in understanding the pathogenesis of this condition [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear hormone receptors acting as transcriptional factors, recently involved also in carcinogenesis. Present study was undertaken to evaluate the presence and subcellular localization of different PPAR isoforms (α, β, γ) in healthy endometrial tissue (n = 10) and endometrial carcinoma (FIGO I, endometrioides type, G1, n = 35).We sought to analyze PPARsmRNA content as well as protein immunohistochemical expression that was further quantified by Western Blot technique. For both PPARα and PPARβ, protein expression was significantly higher in endometrial cancers compared to normal endometrial mucosa. In opposite, PPARγ protein expression was lower in endometrial cancer cells. In each case, immunohistochemical reaction was confined to the perinuclear and/or nuclear region. At the transcriptional level, the content of mRNA of all PPAR subunits did not follow the protein pattern of changes. These results provide evidence for altered PPAR's protein expression and disregulation of posttranslational processes in endometrial cancers. [ABSTRACT FROM AUTHOR]

Uterine fibroids are the most common benign tumor of the female genital tract. Their epidemiology is probably highly underestimated because a high percentage of them are in the asymptomatic stage. The etiology of fibroids and their biology are still poorly understood, although steroid ovarian hormones, both estrogen and progestins, have played an important role in etiopathogenesis of this disease. Also no single candidate gene has been detected for commonly occurring uterine fibroids. Cytogenetic abnormalities, particularly translocation, duplication and deletions of chromosome 7, which are found in up to 50% of fibroid specimens, seem to play an important role during abnormal transformation of uterus smooth muscle. The key regulators that transform normal uterine tissue to fibroids are growth factors (VEGF, TGF, PDGF, etc.), angiogenesis and the process of apoptosis. In this review, current knowledge about molecular and cytogenetic evidence on fibroid development is presented. [ABSTRACT FROM AUTHOR]

We examined whether AICAR or leptin rapidly rescued skeletal muscle insulin resistance via increased palmitate oxidation, reductions in intramuscular lipids, and/or restoration of insulin-stimulated AS60 phosphorylation. Incubation with palmitate (2 mM, 0-18 h) induced insulin resistance in soleus muscle. From 12-18 h, palmitate was removed or AICAR or leptin was provided while 2 mM palmitate was maintained. Palmitate oxidation, intramuscular triacylglycerol, diacylglycerol, ceramide, AMPK phosphorylation, basal and insulinstimulated glucose transport, plasmalemmal GLUT4, and Akt and AS 160 phosphorylation were examined at 0, 6, 12, and 18 h. Palmitate treatment (12 h) increased intramuscular lipids (triacylglycerol +54%, diacylglycerol + 11%, total ceramide + 18%, C 16:0 ceramide +60%) and AMPK phosphorylation (+118%), whereas it reduced fatty acid oxidation (-60%) and insulin-stimulated glucose transport (-70%), GLUT4 translocation (-50%), and AS 160 phosphorylation (-40%). Palmitate removal did not rescue insulin resistance or associated parameters. The AICAR and leptin treatments did not consistently reduce intramuscular lipids, but they did rescue palmitate oxidation and insulin-stimulated glucose transport, GLUT4 translocation, and AS 160 phosphorylation. Increased AMPK phosphorylation was associated with these improvements only when AICAR and leptin were present. Hence, across all experiments, AMPK phosphorylation did not correlate with any parameters. In contrast, palmitate oxidation and insulin-stimulated AS 160 phosphorylation were highly correlated (r = 0.83). We speculate that AICAR and leptin activate both of these processes concomitantly, involving activation of unknown kinases in addition to AMPK. In conclusion, despite the maintenance of high concentrations of palmitate (2 mM), as well as increased concentrations of intramuscular lipids (triacylglycerol, diacylglycerol, and ceramide), the rapid AICARand leptin-mediated rescue of palmitate-induced insulin resistance is attributable to the restoration of insulinstimulated AS 160 phosphorylation and GLUT4 translocation. [ABSTRACT FROM AUTHOR]

We examined, in soleus muscle, the effects of prolonged palmitate exposure (0, 6, 12, 18 h) on insulin-stimulated glucose transport, intramuscular lipid accumulation and oxidation, activation of selected insulin-signaling proteins, and the insulin-stimulated translocation of GLUT4. Insulin-stimulated glucose transport was progressively reduced after 6 h (-33%), 12 h (-66%), and 18 h (-89%) of palmitate exposure. These decrements were closely associated with concurrent reductions in palmitate oxidation at 6 h (-40%), 12 h (-60%), and 18 h (-67%). In contrast, intramuscular ceramide (+24%) and diacylglycerol (+32%) concentrations, insulin-stimulated AS160 (-36%) and PRAS40 (-33%) phosphorylations, and Akt (-40%), PKCθ (-50%), and GLUT4 translocation (-40%) to the plasma membrane were all maximally altered within the first 6 h of palmitate treatment. No further changes were observed in any of these parameters after 12 and 18 h of palmitate exposure. Thus, the intrinsic activity of GLUT4 was markedly reduced after 12 and 18 h of palmitate treatment. During this reduced GLUT4 intrinsic activity phase at 12 and 18 h, the reduction in glucose transport was twofold greater compared with the early phase (≤6 h), when only GLUT4 translocation was impaired. Our study indicates that palmitate-induced insulin resistance is provoked by two distinct mechanisms: 1) an early phase (≤6 h), during which lipid-mediated impairments in insulin signaling and GLUT4 translocation reduce insulin-stimulated glucose transport, followed by 2) a later phase (12 and 18 h), during which the intrinsic activity of GLUT4 is markedly reduced independently of any further alterations in intramuscular lipid accumulation, insulin signaling and GLUT4 translocation. [ABSTRACT FROM AUTHOR]

We examined, in muscle of lean and obese Zucker rats, basal, insulin-induced, and contraction-induced fatty acid transporter translocation and fatty acid uptake, esterification, and oxidation. In lean rats, insulin and contraction induced the translocation of the fatty acid transporter FAT/CD36 (43 and 41%, respectively) and plasma membrane-associated fatty acid binding protein (FABPpm; 19 and 60%) and increased fatty acid uptake (63 and 40%, respectively). Insulin and contraction increased lean muscle palmitate esterification and oxidation 72 and 61%, respectively. In obese rat muscle, basal levels of sarcolemmal FAT/CD36 (+33%) and FABPpm (+ 14%) and fatty acid uptake (+30%) and esterification (+32%) were increased, whereas fatty acid oxidation was reduced (-28%). Insulin stimulation of obese rat muscle increased plasmalemmal FABPpm (+ 15%) but not plasmalemmal FAT/CD36, blunted fatty acid uptake and esterification, and failed to reduce fatty acid oxidation. In contracting obese rat muscle, the increases in fatty acid uptake and esterification and FABPpm translocation were normal, but FAT/CD36 translocation was impaired and fatty acid oxidation was blunted. There was no relationship between plasmalemmal fatty acid transporters and palmitate partitioning. In conclusion, fatty acid metabolism is impaired at several levels in muscles of obese Zucker rats; specifically, they are 1) insulin resistant with respect to FAT/CD36 translocation and fatty acid uptake, esterification, and oxidation and 2) contraction resistant with respect to fatty acid oxidation and FAT/CD36 translocation, but, conversely, 3) obese muscles are neither insulin nor contraction resistant at the level of FABPpm. Finally, 4) there is no evidence that plasmalemmal fatty acid transporters contribute to the channeling of fatty acids to specific metabolic destinations within the muscle. [ABSTRACT FROM AUTHOR]

The effect of conjugated linoleic acid (CLA), a popular weight-loss supplement, on insulin sensitivity in humans is controversial and has notbeen extensively studied. To date no studies have examined the effects of CLA supplementation on human skeletal muscle metabolism or lipid content. It is also unknown whether CLA accumulates in human skeletal muscle with supplementation. In the present study, 9 overweight, non-diabetic individuals received 4 g/d of mixed CLA isomers in the form of 1 g supplements, for 12 weeks. CLA isomers significantly increased in both plasma and skeletal muscle following supplementation. Skeletal muscle ceramide content was also significantly increased, although there was no consistent change in muscle diacylglycerol or triacylglycerol content. Insulin sensitivity was significantly decreased (p ≤ 0.05) following CLA supplementation, with a significant increase in glucose and insulin area under the curve during an oral glucose tolerance test (p ≤ 0.005). The protein content of PPARα, for which CLA is a potent ligand, was unchanged following supplementation. Accordingly, there was no change in markers of muscle oxidative capacity. In conclusion, mixed-isomer CLA supplementation in overweight non-diabetic humans results in the accumulation of CLA and ceramide in skeletal muscle, and decreases insulin sensitivity. [ABSTRACT FROM AUTHOR]

An increased rate of fatty acid transport into skeletal muscle has been has been linked to the accumulation of intramuscular lipids and insulin resistance, and red muscles are more susceptible than white muscles in developing fatty acid-mediated insulin resistance. Therefore, we examined in Zucker diabetic fatty (ZDF) rats, relative to lean rats, 1) whether rates of fatty acid transport and transporters (FAT/CD36 and FABPpm) were upregulated in skeletal muscle during the transition from insulin resistance (week 6) to type 2 diabetes (weeks 12 and 24), 2) whether such changes occurred primarily in red skeletal muscle, and 3) whether changes in FAT/CD36 and GLUT4 were correlated. In red muscles of ZDF compared with lean rats, the rates of fatty acid transport were upregulated (+66%) early in life (week 6). Compared with the increase in fatty acid transport in lean red muscle from weeks 12–24 (+57%), the increase in fatty acid transport rate in ZDF red muscle was 50% greater during this same period. In contrast, no differences in fatty acid transport rates were observed in the white muscles of lean and ZDF rats at any time (weeks 6–24). In red muscle only, there was an inverse relationship between FAT/CD36 and GLUT4 protein expression as well as their plasmalemmal content. These studies have shown that, 1) before the onset of diabetes, as well as during diabetes, fatty acid transport and FAT/CD36 expression and plasmalemmal content are upregulated in ZDF rats, but importantly, 2) these changes occurred only in red, not white, muscles of ZDF rats. [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]

Chabowski, Adrian, Susan L. M. Coort, Jorge Calles-Escandon, Narendra N. Tandon, Jan F. C. Glatz, Joost J. F. P. Luiken, and Arend Bonen. Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. Am J Physiol Endocrinol Metab 287:E781-E789, 2004. First published May 27, 2004; 10.1152/ajpendo.00573.2003.—Because insulin has been shown to stimulate long-chain fatty acid (LCFA) esterification in skeletal muscle and cardiac myocytes, we investigated whether insulin increased the rate of LCFA transport by altering the expression and the subcellular distribution of the fatty acid transporters FAT/CD36 and FABPpm. In cardiac myocytes, insulin very rapidly increased the expression of FAT/CD36 protein in a time- and dose-dependent manner. During a 2-h period, insulin (10 nM) increased cardiac myocyte FAT/CD36 protein by 25% after 60 min and attained a maximum after 90–120 min (+40–50%). There was a dose-dependent relationship between insulin (10-12 to 10-7 M) and FAT/CD36 expression. The half-maximal increase in FAT/CD36 protein occurred at 0.5 × 10-9 M insulin, and the maximal increase occurred at 10-9 to 10-8 M insulin (+40–50%). There were similar insulin-induced increments in FAT/CD36 protein in cardiac myocytes (+43%) and in Langendorff-perfused hearts (+32%). In contrast to FAT/CD36, insulin did not alter the expression of FABPpm protein in either cardiac myocytes or the perfused heart. By use of specific inhibitors of insulin-signaling pathways, it was shown that insulin-induced expression of FAT/CD36 occurred via the PI 3-kinase/Akt insulin-signaling pathway. Subcellular fractionation of cardiac myocytes revealed that insulin not only increased the expression of FAT/CD36, but this hormone also targeted some of the FAT/CD36 to the plasma mem- brane while concomitantly lowering the intracellular depot of FAT/ CD36. At the functional level, the insulin-induced increase in FAT/ CD36 protein resulted in an increased rate of palmitate transport into giant vesicles (+34%), which paralleled the increase in plasmalemmal FAT/CD36 (+29%). The present studies have shown that insulin regulates protein expression of FAT/CD36, but not FABPpm, via the PI 3-kinase/Akt insulin-signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] Adipose derived mesenchymal stem cells (ADMSCs) are a component of adipose tissue that in recent years has gained on importance. The progenitor cells serve as an essentially unlimited source of new adipocytes and therefore are considered to be an important determinant of the tissue's physiology. In this paper we investigated mature adipocytes differentiated from ADMSCs obtained from subcutaneous/visceral fat of patients with different metabolic status (lean, obese without and with metabolic syndrome). We focused our interests on the sphingolipid signaling pathway, i.e. a signal transduction system indispensable for cells functioning, but also implicated in the development of medical conditions associated with obesity. We observed that the cells derived from visceral tissue had significantly greater levels of almost all the examined sphingolipids (especially Cer, dhCer, SM). Moreover, obesity and metabolic syndrome present in donor patients was associated with an increased level of sphingosine kinase (SPHK) and the product of its reaction sphingosine-1-phosphate (S1P). Moreover, the condition appeared to display a tissue specific pattern. Namely, the adipocytes of subcutaneous provenance had an increased activation of ceramide de novo synthesis pathway when the donors of ADMSCs had metabolic syndrome. The above translated into greater accumulation of ceramide in the cells. To our knowledge this is the first study that demonstrated altered sphingolipid profile in the mature adipocytes differentiated from ADMSCs with respect to the stem cells tissue of origin and the donor patient metabolic status. [ABSTRACT FROM AUTHOR]

Summary: Obesity is a critical risk factor for the development of metabolic diseases, and its prevalence is increasing worldwide. Stem cell‐based therapies have become a promising tool for therapeutic intervention. Among them are adipose‐derived mesenchymal stem cells (ADMSCs), secreting numerous bioactive molecules, like growth factors, cytokines, and chemokines. Their unique features, including immunosuppressive and immunomodulatory properties, make them an ideal candidates for clinical applications. Numerous experimental studies have shown that ADMSCs can improve pancreatic islet cell viability and function, ameliorate hyperglycemia, improve insulin sensitivity, restore liver function, counteract dyslipidemia, lower pro‐inflammatory cytokines, and reduce oxidative stress in the animal models. These results prompted scientists to use ADMSCs clinically. However, up to date, there have been few clinical studies or ongoing trails using ADMSCs to treat metabolic disorders such as type 2 diabetes mellitus (T2DM) or liver cirrhosis. Most human studies have implemented autologous ADMSCs with minimal risk of cellular rejection. Because the functionality of ADMSCs is significantly reduced in subjects with obesity and/or metabolic syndrome, their efficacy is questioned. ADMSCs transplantation may offer a potential therapeutic approach for the treatment of metabolic complications of obesity, but randomized controlled trials are required to establish their safety and efficacy in humans prior to routine clinical use. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by excessive lipid deposition. Lipid metabolism disturbances are possibly associated with hepatocyte inflammation development and oxidative balance impairment. The aim of our experiment was to examine the first moment when changes in plasma and liver arachidonic acid (AA) levels as a pro-inflammatory precursor may occur during high-fat diet (HFD)-induced NAFLD development. Wistar rats were fed a diet rich in fat for five weeks, and after each week, inflammation and redox balance parameters were evaluated in the liver. The AA contents in lipid fractions were assessed by gas–liquid chromatography (GLC). Protein expression relevant to inflammatory and lipogenesis pathways was determined by immunoblotting. The oxidative system indicators were determined with assay kits. Our results revealed that a high-fat diet promoted an increase in AA levels, especially in the phospholipid (PL) fraction. Importantly, rapid inflammation development via increased inflammatory enzyme expression, elevated lipid peroxidation product content and oxidative system impairment was caused by the HFD as early as the first week of the experiment. Based on these results, we may postulate that changes in AA content may be an early indicator of inflammation and irreversible changes in NAFLD progression. [ABSTRACT FROM AUTHOR]

Dexamethasone (DEX) is a synthetic glucocorticoid with anti-inflammatory properties. We evaluated a potentially protective dexamethasone influence on hepatocellular lipid metabolism and fatty acid (FA) transporters expression. The HepG2 cells were incubated with palmitic acid (PA) and/or dexamethasone in two different time expositions (16 h and 40 h). Intracellular and extracellular lipid and sphingolipid concentrations were estimated by the gas-liquid chromatography and high-performance liquid chromatography, respectively. The protein expression involved in FA uptake and lipid metabolism was determined by immunoblotting. The treatment of HepG2 with dexamethasone and palmitate enhanced lipid transport to the cell via increased especially FABPpm expression and resulted in the increased triacylglycerol (TAG), diacylglycerol (DAG) and ceramide deposition. Dexamethasone with palmitate treatment altered FA composition resulting in the elevated n-3 polyunsaturated fatty acid (PUFA) activity in DAG and TAG and the diminished n-6 PUFA activity in DAG after prolonged exposure. We may speculate that although protective lipid secretion into media and decrease in inflammatory FA precursors dexamethasone treatment exacerbated lipotoxicity in HepG2 cells. • GCs exposure increased lipotoxicity by exacerbated lipid transport into the cell. • DEX enhanced protective lipid secretion into media. • GCs inhibit the inflammation protecting against NAFLD progression to NASH. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, complex, immunological disorder, which may lead to many different systemic complications. Sphingolipids, including ceramide, are bioactive lipids, which take part in the regulation of immune reactions, cell growth, and apoptosis. Twenty psoriatic patients and twenty-eight control subjects were included in the study. Skin (both lesional and non-lesional) and serum samples were collected from both the control group and the psoriatic patients. The levels of sphingosine (SFO), sphingosine-1-phosphate (S1P), sphingomyelin, sphinganine (SFA), sphinganine-1-phosphate (SFA1P), and ceramide (CER) were assessed in both tissue (t) and serum (s) samples using high-performance liquid chromatography (HPLC). We identified elevated serum levels of SFO, S1P, SFA, and SFA1P in psoriatic patients when compared to healthy individuals. As far as the lesional skin and serum of psoriatic patients are concerned, we demonstrated positive associations between CER_t and CER_s, SFA_t and CER_s, and SFO_t and CER_s. Additionally, we found negative correlations in the non-lesional skin and serum of psoriatic patients, including SFO_t vs. SFO_s, CER_t vs. SFA_s, CER_t vs. SFO_s, and SFO_t vs. SFA_s. Finally, we observed a positive correlation between S1P and SFA1P in both the serum samples of psoriatic patients and the serum samples of the control group. In this study, we did not observe any correlations between psoriasis area and severity index (PASI) scores and sphingolipid levels. In conclusion, our findings indicate an interplay between skin and serum lipids in psoriatic patients, which is not observed in healthy individuals. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a consequence of liver injuries, in which the overproduction and progressive accumulation of extracellular matrix (ECM) components with the simultaneous failure of matrix turnover mechanisms are observed. The aim of this study was to investigate the concentration-dependent influence of cannabigerol (CBG, Cannabis sativa L. component) on ECM composition with respect to transforming growth factor beta 1 (TGF-β1) changes in primary hepatocytes with fibrotic changes induced by palmitate and fructose media. Cells were isolated from male Wistar rats' livers in accordance with the two-step collagenase perfusion technique. This was followed by hepatocytes incubation with the presence or absence of palmitate with fructose and/or cannabigerol (at concentrations of 1, 5, 10, 15, 25, 30 µM) for 48 h. The expression of ECM mRNA genes and proteins was determined using PCR and Western blot, respectively, whereas media ECM level was evaluated using ELISA. Our results indicated that selected low concentrations of CBG caused a reduction in TGF-β1 mRNA expression and secretion into media. Hepatocyte exposure to cannabigerol at low concentrations attenuated collagen 1 and 3 deposition. The protein and/or mRNA expressions and MMP-2 and MMP-9 secretion were augmented using CBG. Considering the mentioned results, low concentrations of cannabigerol treatment might expedite fibrosis regression and promote regeneration. [ABSTRACT FROM AUTHOR]

Endothelial (EL) and lipoprotein (LPL) lipases are enzymes involved in lipoproteins metabolism and formation of atherosclerosis, a pathological feature of coronary artery disease (CAD). This paper examines the role of the lipases in the right atrial appendage (RAA) and coronary perivascular adipose tissue (PVAT) of patients with CAD alone or with accompanying diabetes. Additionally, correlation analysis for plasma concentration of the lipases, apolipoproteins (ApoA-ApoJ) and blood lipids (Chol, HDL-C, LDL-C, TAG) was performed. We observed that CAD had little effect on the lipases gene/protein levels in the RAA, while their transcript content was elevated in the PVAT of diabetic CAD patients. Interestingly, the RAA was characterized by higher expression of EL/LPL (EL: +1-fold for mRNA, +5-fold for protein; LPL: +2.8-fold for mRNA, +12-fold for protein) compared to PVAT. Furthermore, ApoA1 plasma concentration was decreased, whereas ApoC1 and ApoH were increased in the patients with CAD and/or diabetes. The concentrations of ApoC3 and ApoD were strongly positively correlated with TAG content in the blood, and the same was true for ApoB with respect to LDL-C and total cholesterol. Although plasma concentrations of EL/LPL were elevated in the patients with diabetes, CAD alone had little effect on blood, myocardial and perivascular fat expression of the lipases. [ABSTRACT FROM AUTHOR]

Pyrroloquinoline quinone (PQQ) acts as a powerful modulator of PGC‐1α activation and therefore regulates multiple pathways involved in cellular energy homeostasis. In the present study, we assessed the effects of L6 myotubes incubation with 0.5, 1, and 3 μM PQQ solution for 2 and 24 hr with respect to the cells' lipid metabolism. We demonstrated that PQQ significantly elevates PGC‐1α content in a dose‐ and time‐dependent manner with the highest efficiency for 0.5 and 1 µM. The level of free fatty acids was diminished (24 hr: −66%), while an increase in triacylglycerol (TAG) amount was most pronounced after 0.5 μM (2 hr: +93%, 24 hr: +139%) treatment. Ceramide (CER) content was elevated after 2 hr incubation with 0.5 µM and after prolonged exposure to all PQQ concentrations. The cells treated with PQQ for 2 hr exhibited decreased sphinganine (SFA) and sphinganine‐1‐phosphate (SFA1P) level, while 24 hr incubation resulted in an elevated sphingosine (SFO) amount. In summary, PGC‐1α activation promotes TAG and CER synthesis. Pyrroloquinoline quinone (PQQ) acts as a powerful modulator of PGC‐1α activation and therefore regulates multiple pathways involved in cellular energy homeostasis. Data reported herein reinforce a role for PQQ/PGC‐1α in lipid storage into ceramide (CER) and triacylglycerol (TAG) lipid pools, in addition to an increment of cellular oxidative potential. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex chronic immunologically mediated disease that may involve skin, nails, and joints. It is characterized by hyperproliferation, deregulated differentiation, and impaired apoptosis of keratinocytes. Sphingolipids, namely ceramide, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate, are signal molecules that may regulate cell growth, immune reactions, and apoptosis. Fifteen patients with psoriasis and seventeen healthy persons were enrolled in the study. Skin samples were taken from psoriatic lesions and non-lesional areas. Tissue concentration of ceramides, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate was measured by liquid chromatography. We assessed that all levels of ceramides, sphingosine-1-phosphate, sphingosine, sphingomyelin, and sphinganine-1-phosphate were higher in lesioned psoriatic skin than in non-affected skin. The profile of bioactive lipids in the lesional skin of patients with psoriasis differed significantly from non-involved psoriatic skin and skin in healthy subjects. [ABSTRACT FROM AUTHOR]

Impaired heart function can develop in individuals with diabetes in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined whether dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)–induced cardiac abnormalities. Male C57Bl/6N mice were fed a low-fat diet (LFD), HFD, or HFD+Nitrate (4 mmol/L sodium nitrate) for 8 weeks. HFD-fed mice presented with pathological left ventricle (LV) hypertrophy, reduced stroke volume, and increased end-diastolic pressure, in association with increased myocardial fibrosis, glucose intolerance, adipose inflammation, serum lipids, LV mitochondrial reactive oxygen species (ROS), and gut dysbiosis. In contrast, dietary nitrate attenuated these detriments. In HFD-fed mice, FMT from HFD+Nitrate donors did not influence serum nitrate, blood pressure, adipose inflammation, or myocardial fibrosis. However, microbiota from HFD+Nitrate mice decreased serum lipids, LV ROS, and similar to FMT from LFD donors, prevented glucose intolerance and cardiac morphology changes. Therefore, the cardioprotective effects of nitrate are not dependent on reducing blood pressure, but rather mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis. Article Highlights: Identifying therapeutic approaches that prevent cardiometabolic diseases are clearly important, and nitrate represents one such potential compound given its multifactorial metabolic effects. We aimed to determine whether nitrate could prevent high-fat diet (HFD)–induced cardiac abnormalities and whether this was dependent on the gut microbiome. Dietary nitrate attenuated HFD-induced pathological changes in cardiac remodelling, left ventricle reactive oxygen species, adipose inflammation, lipid homeostasis, glucose intolerance, and gut dysbiosis. Fecal microbial transplantation from nitrate-fed mice also prevented serum dyslipidemia, left ventricle reactive oxygen species, glucose intolerance, and cardiac dysfunction. Therefore, the cardioprotective effects of nitrate are related to mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis. [ABSTRACT FROM AUTHOR]

Background/Aims: Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid that is found in high concentration in plasma. The majority of plasma S1P is transported bound to HDL and albumin. Although the major sources of circulating S1P have been identified, it remains obscure what is the contribution of different organs/tissues to S1P homeostasis in plasma. Answering this question was the major aim of the present study. Methods: The experiment was performed on male Wistar rats from whom blood samples were taken from either: 1) femoral vein, right ventricle of the heart, and abdominal aorta (n=15) or 2) hepatic vein, portal vein, and abdominal aorta (n=11). Plasma was fractionated by sequential flotation ultracentrifugation and sphingolipids were quantified by a HPLC method. Results: Compared to the mixed venous blood sampled from the right ventricle, total plasma and lipoprotein-depleted plasma (LPDP) concentration of S1P in the arterial blood was lower. On the other hand, the level of S1P increased across the leg both in plasma and LPDP. The concentration of S1P, sphingosine, and sphinganine in the plasma, HDL, and LPDP isolated from the blood taken from the hepatic vein was markedly higher compared to both arterial and portal blood. Conclusions: We conclude that, in contrast to HDL-bound S1P, albumin-associated S1P is very labile in the circulation. It is degraded in the pulmonary, and to a lesser extent, gastrointestinal circulation, and released across the liver and skeletal muscle. We also conclude that liver is an important source of HDL-bound S1P and circulating free sphingoid bases. [ABSTRACT FROM AUTHOR]

Aims There is significant evidence that the endocannabinoid system (ECS) takes part in the regulation of the cardiovascular system in hypertension. It is quite well established that hypertension causes several changes in the heart metabolism, but it is still unknown whether the ECS affects this process. Therefore, we investigated the influence of prolonged ECS activation on myocardial lipid metabolism in deoxycorticosterone acetate (DOCA)-salt hypertensive rats by chronic fatty acid amide hydrolase (FAAH) inhibition. Materials and methods We examined the uptake and oxidation of palmitic acid during the heart perfusion as well as intramyocardial and plasma lipid contents using gas liquid chromatography. Total, plasmalemmal and intracellular expressions of selected proteins were estimated by the Western blot technique. Moreover, the left ventricle's morphology, including myocardial vessels density, was measured using immunohistochemistry. Key findings We demonstrated that hypertension induced cardiomyocytes and myocardial blood vessels hypertrophy, followed by a reduction in myocardial palmitate oxidation. Interestingly, prolonged activation of the ECS in the normotensive rats induced cardiomyocyte enlargement and intensified fatty acids metabolism. We have also shown that FAAH inhibition improved morphology of coronary blood vessels and only partially maintained its effect on lipid metabolism in the DOCA-salt hearts (i.e. elevated plasma and intramyocardial TAG contents as well as plasmalemmal FAT/CD36 and total FATP1 expressions). Significance This study revealed that chronic FAAH inhibition has no protective effects on the heart lipid metabolism in hypertension. [ABSTRACT FROM AUTHOR]

Arachidonic acid (AA) is a key precursor for proinflammatory and anti-inflammatory derivatives that regulate the inflammatory response. The modulation of AA metabolism is a target for searching a therapeutic agent with potent anti-inflammatory action in cardiovascular disorders. Therefore, our study aims to determine the potential preventive impact of N-acetylcysteine (NAC) supplementation on myocardial inflammation and the occurrence of oxidative stress in obesity induced by high-fat feeding. The experiment was conducted for eight weeks on male Wistar rats fed a standard chow or a high-fat diet (HFD) with intragastric NAC supplementation. The Gas-Liquid Chromatography (GLC) method was used to quantify the plasma and myocardial AA levels in the selected lipid fraction. The expression of proteins included in the inflammation pathway was measured by the Western blot technique. The concentrations of arachidonic acid derivatives, cytokines and chemokines, and oxidative stress parameters were determined by the ELISA, colorimetric, and multiplex immunoassay kits. We established that in the left ventricle tissue NAC reduced AA concentration, especially in the phospholipid fraction. NAC administration ameliorated the COX-2 and 5-LOX expression, leading to a decrease in the PGE2 and LTC4 contents, respectively, and augmented the 12/15-LOX expression, increasing the LXA4 content. In obese rats, NAC ameliorated NF-κB expression, inhibiting the secretion of proinflammatory cytokines. NAC also affected the antioxidant levels in HFD rats through an increase in GSH and CAT contents with a simultaneous decrease in the levels of 4-HNE and MDA. We concluded that NAC treatment weakens the NF-κB signaling pathway, limiting the development of myocardial low-grade inflammation, and increasing the antioxidant content that may protect against the development of oxidative stress in rats with obesity induced by an HFD. [ABSTRACT FROM AUTHOR]

Obesity is one of the principal public health concerns leading to disturbances in glucose and lipid metabolism, which is a risk factor for several chronic diseases, including insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. In recent years, it turned out that cannabidiol (CBD) is a potential therapeutic agent in the treatment of obesity and its complications. Therefore, in the present study, we used CBD therapy (intraperitoneal injections in a dose of 10 mg/kg of body mass for 14 days) in a rat model of obesity induced by a high-fat diet (HFD). Gas–liquid chromatography and Western blotting were applied in order to determine the intramuscular lipid content and total expression of selected proteins in the white and red gastrocnemius muscle, respectively. Based on fatty acid composition, we calculated de novo lipogenesis ratio (16:0/18:2n-6), desaturation ratio (18:1n-9/18:0), and elongation ratios (18:0/16:0, 20:0/18:0, 22:0/20:0 and 24:0/22:0), in the selected lipid fractions. Two-week CBD administration significantly reduced the intramuscular fatty acids (FAs) accumulation and inhibited de novo lipogenesis in different lipid pools (in the free fatty acid, diacylglycerol, and triacylglycerol fractions) in both muscle types, which coincided with a decrease in the expression of membrane fatty acid transporters (fatty acid translocase, membrane-associated fatty acid binding protein, and fatty acid transport proteins 1 and 4). Moreover, CBD application profoundly improved the elongation and desaturation ratios, which was in line with downregulated expression of enzymes from the family of elongases and desaturases regardless of the metabolism presented by the muscle type. To our knowledge, this study is the first that outlines the novel effects of CBD action on skeletal muscle with different types of metabolism (oxidative vs. glycolytic). [ABSTRACT FROM AUTHOR]

Delta-6 desaturase (D6D), encoded by the Fads2 gene, catalyzes the first step in the conversion of a-linolenic acid to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The ablation of D6D in whole body Fads2-/- knockout (KO) mice results in an inability to endogenously produce EPA and DHA. Evidence supports a beneficial role for EPA and DHA on insulin-stimulated glucose disposal in skeletal muscle in the context of a metabolic challenge; however, it is unknown how low EPA and DHA levels impact skeletal muscle fatty acid composition and insulin signaling in a healthy context. The objective of this study was to examine the impact of ablating the endogenous production of EPA and DHA on skeletal muscle fatty acid composition, whole body glucose and insulin tolerance, and a key marker of skeletal muscle insulin signaling (pAkt). Male C57BL/6J wild-type (WT), Fads2+/- heterozygous, and Fads2-/- KO mice were fed a low-fat diet (16% kcal from fat) modified to contain either 7% w/w lard or 7% w/w flaxseed for 21 wk. No differences in total phospholipid (PL), triacylglycerol, or reactive lipid content were observed between genotypes. As expected, KO mice on both diets had significantly less DHA content in skeletal muscle PL. Despite this, KO mice did not have significantly different glucose or insulin tolerance compared with WT mice on either diet. Basal pAktSer473 was not significantly different between the genotypes within each diet. Ultimately, this study shows for the first time, to our knowledge, that the reduction of DHA in skeletal muscle is not necessarily detrimental to glucose homeostasis in otherwise healthy animals. NEW & NOTEWORTHY Skeletal muscle is the primary location of insulin-stimulated glucose uptake. EPA and DHA supplementation has been observed to improve skeletal muscle insulin-stimulated glucose uptake in models of metabolic dysfunction. Fads2-/- knockout mice cannot endogenously produce long-chain n-3 polyunsaturated fatty acids. Our results show that the absence of DHA in skeletal muscle is not detrimental to whole body glucose homeostasis in healthy mice. [ABSTRACT FROM AUTHOR]

Synthetic and natural glucocorticoids are able to highly modify liver lipid metabolism, which is possibly associated with nonalcoholic fatty liver disease development. We have assessed the changes in lipid and sphingolipid contents in hepatocytes, lipid composition and saturation status as well as the expression of proteins involved in fatty acid transport after both dexamethasone and palmitate treatments. The experiments were conducted on primary rat hepatocytes, incubated with dexamethasone and/or palmitic acid during short (16 h) and prolonged (40 h) exposure. Intracellular and extracellular lipid and sphingolipid contents were assessed by gas liquid chromatography and high-performance liquid chromatography, respectively. The expression of selected proteins was estimated by Western blotting. Short and prolonged exposure to dexamethasone combined with palmitic acid resulted in increased expression of fatty acid transporters, which was subsequently reflected by excessive intracellular accumulation of triacylglycerols and ceramide. The expression of microsomal transfer protein and cassette transporter was also significantly increased after dexamethasone and palmitate treatment, which was in accordance with elevated extracellular lipid and sphingolipid contents. Our data showed additive effects of dexamethasone and palmitate on protein-dependent fatty acid uptake in primary hepatocytes, resulting in the increased accumulation of triacylglycerols and sphingolipids. Moreover, the combined treatment altered fatty acid composition and diminished triacylglycerols desaturation index. Importantly, we observed that additive effects on both increased microsomal transport protein expression as well as elevated export of triacylglycerols, which may be relevant as a liver protective mechanism. [ABSTRACT FROM AUTHOR]

Coumestrol is a phytoestrogen found in various plant foods. Increasing evidence ascertained its robust anti-inflammatory, anti-oxidative properties likewise ability to mitigate insulin resistance. Thus, it may be a potential medicine in the treatment of many metabolic disorders, including obesity, type 2 diabetes (T2D) as well as non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to shed some light on its influence on the accumulation of certain lipid fractions and the expression of pro-inflammatory proteins in primary rat hepatocytes during the lipid-overload state. The cells were isolated from the male Wistar rat's liver with the use of collagenase perfusion. It was followed by incubation of the cells with the presence or absence of palmitic acid and/or coumestrol. The accumulation of lipid fractions was assessed by gas-liquid chromatography (GLC) whereas the expression of the proteins was evaluated by the Western blot technique. Treatment with coumestrol in the state of increased fatty acids availability led to the deposition of triacylglycerols rather than diacylglycerols, significantly decreased expression of proinflammatory and profibrotic cytokines, especially interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as well as transforming growth factor β (TGF-β), and nuclear factor κ β (NF-κβ). Also, we observed a substantial diminution in proinflammatory enzymes expression. Taking into consideration the direction of the aforementioned changes, we may assume that coumestrol can ameliorate the array of factors leading to the development of steatosis, likewise counteracting progression to steatohepatitis, thus it may be a step forward to the long-awaited breakthrough in the treatment of NAFLD. • Coumestrol increased deposition of EPA and DHA in lipid overloaded conditions. • Coumestrol decresed excessive diacylglycerol accumulation. • Coumestrol in lipid overloaded conditions exerted an anti-inflammatory effect on proteins levels. • Coumestrol affected hepatic intracellular lipids composition. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea syndrome (OSAS) is a common but underdiagnosed condition with significant health and economic implications for society. Inflammatory mediators are proposed to be associated with the presence and severity of OSAS and contribute to morbidity and mortality. This paper details a prospective non-randomized case control study of a cohort of subjects, who underwent surgical treatment of OSAS and were enrolled to assess the sleep parameters and blood levels of selected inflammatory markers at pre-operative and post-operative time points, also comparing them to the levels in a control group. A total of 25 study subjects and 18 control subjects were enrolled. Median values and interquartile range (IQR) of the apnea–hypopnea index (AHI) in the study group pre-operatively and post-operatively were 34 (18.5–45.5) and 13.3 (7.5–27.3), while in the control group 1.4 (1.0–2.1) per hour. The mean (IQR) hs-CRP levels (mg/L) were 1.782 (0.941–5.594) and 1.980 (0.990–5.445) in the study group, pre-operatively and post-operatively, respectively, while 0.891 (0.767–1.436) in the control group. The mean (IQR) TNF-α levels (pg/mL) were 7.999 (6.137–9.216) and 6.614 (5.534–7.460) pre-and post-operatively, respectively, and were 6.000 (5.026–6.823) in the control group. Results demonstrated that both inflammatory markers, hs-CRP and TNF-α, are higher in subjects with OSAS compared to the controls, and their levels decrease, but are still higher than the controls, after successful surgical treatment. Further analysis including the body mass index and age demonstrated that these changes were significant for TNF-α, but not hs-CRP. [ABSTRACT FROM AUTHOR]

Lipid mediators derived from arachidonic acid (AA) are implicated with the occurrence of inflammation and oxidative stress. The current knowledge of AA metabolism focuses on searching for the therapeutic strategy to subvert affected AA metabolism. The aim of our study was to evaluate the potential protective effect of chronic α-lipoic acid (α-LA) supplementation on myocardial inflammation state and oxidative stress in obesity-related cardiovascular dysfunction. The experiment was carried out on male Wistar rats receiving a standard or a high-fat diets with intragastric α-LA administration for 8 weeks. Plasma and myocardial AA concentrations were determined using the gas-liquid chromatography (GLC). The Western blot technique was used to examine the expression of proteins from the inflammatory pathway. The content of selected cytokines, inflammatory mediators, and oxidative stress indicators was detected by the ELISA, colorimetric, and multiplex assay kits. Our results revealed that α-LA caused a notable reduction in AA content, mainly in the phospholipid fraction with a simultaneous diminishment in the synthesis of pro-inflammatory mediators, i.e., prostaglandin E2, leukotrienes B4 and C4 by decreasing the expression of COX-2 and 5-LOX. α-LA also augmented the level of antioxidative SOD2 and GSH and decreased the level of lipid peroxidation products, which improved oxidative system impairment in the left ventricle tissue. The data clearly showed that α-lipoic acid has a significant role in inflammation and oxidative stress development ameliorating the risk of cardiac obesity induced by high-fat feeding. • α-LA supplementation rate-limits synthesis of PGE2 and also LTB4 and LTC4. • α-lipoic acid increased in SOD2 and GSH levels. • α-LA impacts on inflammation by a decrease in arachidonic acid content. [ABSTRACT FROM AUTHOR]

Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of matrix molecules and inflammatory processes lead to progressive fibrosis, cirrhosis, and ultimately liver failure. In addition, increased accumulation of sphingolipids accompanied by increased expression of pro-inflammatory cytokines in the ECM is closely related to lipogenesis, MAFLD development, and its progression to fibrosis. In our work, we will summarize all information regarding the role of sphingolipids e.g., ceramide and S1P in MAFLD development. These sphingolipids seem to have the most significant effect on macrophages and, consequently, HSCs which trigger the entire cascade of overproduction matrix molecules, especially type I and III collagen, proteoglycans, elastin, and also tissue inhibitors of metalloproteinases, which as a result cause the development of liver fibrosis. [ABSTRACT FROM AUTHOR]

Cryoablation is a recommended, modern and well-tolerated method of treating atrial fibrillation (AF). The study evaluates plasma biomarkers related to AF and the effectiveness of its treatment – cryoablation. Heart- and adipocyte-type fatty acid binding proteins (H-FABP and A-FABP, respectively) as well as fatty acids (FAs) were assessed in patients that underwent cryoballoon ablation (CBA) for AF. Concentrations of plasma FABPs and FAs were measured in 33 AF patients on admission and 24 ​h after CBA (enzyme-linked immunoassay and gas liquid chromatography, respectively). The control group consisted of 20 volunteers. We showed that plasma H-FABP and A-FABP concentrations were significantly higher in the patients with AF than in the control group (1135 ​pg/mL vs 836 ​pg/mL, and 34.29 ​ng/mL vs 15.14 ​ng/mL, respectively; p ​< ​0.05). After CBA, H-FABP plasma concentration increased even further (1574 ​pg/mL vs 1135 ​pg/mL; p ​< ​0.05) and FAs levels decreased concomitantly. AF recurred in 8 patients (24.25%) after 3 months and in 13 patients (39.4%) after 6 months. Initially higher concentration of oleic acid (680.24 ​± ​189.768 vs 567.04 ​± ​70.002; p ​< ​0.05) correlated substantially with lower AF relapse rate in 6 months follow-up. The patients with AF showed increased concentration of H-FABP, whereas CBA triggered further elevation of H-FABP with a simultaneous decline in the total plasma FAs concentration. H-FABP and A-FABP could not be confirmed as new biomarkers of cryoablation efficiency, but this requires further investigation due to the limitations of the study. [ABSTRACT FROM AUTHOR]

Autoimmune diabetes (AD) in adults includes both the classical form of type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). LADA shares clinical and metabolic features with type 1 and type 2 diabetes mellitus (T2DM). Ceramide (Cer) levels negatively correlate with insulin sensitivity in humans and animal models. However, only a few studies have focused on other sphingolipids, including sphingomyelin (SM). Therefore, we determined sphingolipids in patients with newly diagnosed diabetes as possible diagnostic biomarkers. We evaluated sphingolipids in a cohort of 59 adults with newly diagnosed diabetes without prior hypoglycemic pharmacotherapy to distinguish diabetes mellitus types and for precise LADA definition. All patients with newly diagnosed diabetes were tested for the concentrations of individual Cer and SM species by gas-liquid chromatography. The study included healthy controls and patients with T1DM, T2DM and LADA. SM species were significantly altered in patients with newly diagnosed diabetes compared to healthy controls. SM-C16:0, C16:1, -C18:0, -C18:1, -C18:2, -C18:3, -C20:4, and -C22:6 species were found to be significantly elevated in LADA patients. In contrast, significant differences were observed for Cer species with saturated acyl chains, especially Cer-C14:0, -C16:0, -C18:0 (AD and T2DM), -C22:0, and -C24:0 (T1DM). Following ROC analysis, SM-C16:0, and particularly -C18:1, and -C20:4 may be supportive diagnostic markers for LADA. SM profiling in patients with newly diagnosed diabetes could be potentially helpful for differential diagnosis of LADA, T1DM, and T2DM in more challenging cases. [ABSTRACT FROM AUTHOR]

Adipose tissue's (AT) structural changes accompanying obesity may alter lipid transport protein expression and, thus, the fatty acids (FAs) transport and lipid balance of the body. Metabolic abnormalities within AT contribute to the elevated production of reactive oxygen species and increased oxidative/nitrosative stress. Although compounds such as N-acetylcysteine (NAC) and α-lipoic acid (ALA), which restore redox homeostasis, may improve lipid metabolism in AT, the mechanism of action of these antioxidants on lipid metabolism in AT is still unknown. This study aimed to examine the impact of NAC and ALA on the level and FA composition of the lipid fractions, and the expression of FA transporters in the visceral and subcutaneous AT of high-fat diet-fed rats. Male Wistar rats were randomly divided into four groups. The mRNA levels and protein expression of FA transporters were assessed using real-time PCR and Western Blot analyses. The collected samples were subjected to histological evaluation. The level of lipids (FFA, DAG, and TAG) was measured using gas-liquid chromatography. We found that antioxidants affect FA transporter expressions at both the transcript and protein levels, and, therefore, they promote changes in AT's lipid pools. One of the most remarkable findings of our research is that different antioxidant molecules may have a varying impact on AT phenotype. NAC and ALA exert different influences on AT, which is reflected in histopathological images, FA transport proteins expression patterns, or even the lipid storage capacity of adipocytes. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a non-homogenous malignancy. High-grade serous carcinoma (HGSC) is the most common subtype, and its drug resistance mechanisms remain unclear. Despite the advantages of modern pharmacotherapy, high-grade ovarian cancer is associated with a poor prognosis and research into targeted therapies is in progress. The aim of the study was to assess the dominant energy substrate transport mechanism in ovarian cancer cells and to verify whether genomic aberrations could predict clinical outcomes using the Cancer Genome Atlas (TCGA) dataset. Total RNA was extracted from HGSC frozen tissues, and the expression of selected genes was compared to respective controls. GLUT1, FABPpm, MCT4 and SNAT1 genes were significantly overexpressed in carcinomas compared with controls, while expression of CD36/SR-B2, FATP1, FABP4, GLUT4, ASCT2 and LPL was decreased. No differences were found in FATP4, LAT1, MCT1 and FASN. The transcript content of mitochondrial genes such as PGC-1α, TFAM and COX4/1 was similar between groups, while the β-HAD level declined in ovarian cancer. Additionally, the MCT4 level was reduced and PGC-1α was elevated in cancer tissue from patients with 'small' primary tumor and omental invasion accompanied by ascites as compared to patients that exhibited greater tendencies to metastasize to lymph nodes with clear omentum. Based on TCGA, higher FABP4 and LPL and lower TFAM expression indicated poorer overall survival in patients with ovarian cancer. In conclusion, the presented data show that there is no exclusive energy substrate in HGSC. However, this study indicates the advantage of glucose and lactate transport over fatty acids, thereby suggesting potential therapeutic intervention targets to impede ovarian cancer growth. [ABSTRACT FROM AUTHOR]

While the cause of Type 2 diabetes remains poorly defined, the accumulation of reactive lipids within white adipose tissue, skeletal muscle, and liver have been repeatedly implicated as underlying mechanisms. The ability of polyunsaturated fatty acids (PUFAs) to prevent the development of insulin resistance has gained considerable interest in recent years; however, the mechanisms- of-action remain poorly described. Therefore, we determined the efficacy of diets supplemented with either linoleic acid (LA) or α-linolenic acid (ALA) in preventing insulin resistance and reactive lipid accumulation in key metabolic tissues of the obese Zucker rat. Obese Zucker rats displayed impaired glucose homeostasis and reduced n-3 and n-6 PUFA content in the liver and epididymal white adipose tissue (EWAT). After the 12-wk feeding intervention, both LA- and ALA-supplemented diets prevented whole body glucose and insulin intolerance; however, ALA had a more pronounced effect. These changes occurred in association with n-3 and n-6 accumulation in all tissues studied, albeit to different extents (EWAT > liver > muscle). Triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and sphingolipid accumulation were not attenuated in obese animals supplemented with either LA or ALA, suggesting that preservation of glucose homeostasis occurred independent of changes in reactive lipid content. However, PUFA-supplemented diets differentially altered the fatty acid composition of TAGs, DAGs, and PLs in a tissue-specific manner, suggesting essential fatty acid metabolism differs between tissues. Together, our results indicate that remodeling of the fatty acid composition of various lipid fractions may contribute to the improved glucose tolerance observed in obese rats fed PUFA-supplemented diets. [ABSTRACT FROM AUTHOR]

Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases - hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described. [ABSTRACT FROM AUTHOR]

Available data suggest that cannabidiol (CBD) may ameliorate symptoms of insulin resistance by modulating the sphingolipid concentrations in particular organs. However, it is not entirely clear whether its beneficial actions also involve adipose tissues in a state of overnutrition. The aim of the study was to evaluate the effect of CBD on sphingolipid metabolism pathways and, as a result, on the development of insulin resistance in subcutaneous (SAT) and visceral (VAT) adipose tissues of an animal model of HFD-induced insulin resistance. Our experiment was performed on Wistar rats that were fed with a high-fat diet and/or received intraperitoneal CBD injections. We showed that CBD significantly lowered the ceramide content in VAT by reducing its de novo synthesis and increasing its catabolism. However, in SAT, CBD decreased the ceramide level through the inhibition of salvage and de novo synthesis pathways. All of these changes restored adipose tissues' sensitivity to insulin. Our study showed that CBD sensitized adipose tissue to insulin by influencing the metabolism of sphingolipids under the conditions of increased availability of fatty acids in the diet. Therefore, we believe that CBD use may be considered as a potential therapeutic strategy for treating or reducing insulin resistance, T2DM, and metabolic syndrome. [ABSTRACT FROM AUTHOR]

Simple Summary: The most common malignancy diagnosed in childhood is acute lymphoblastic leukemia (ALL). With significant advances in ALL treatment and excellent supportive care, overall survival is now up to 90%, depending on the risk group. As a result, the survivor population is growing significantly. At the same time, it is observed that survivors experience many health problems that substantially reduce their quality of life. Emerging evidence suggests that the increased susceptibility to multiple disorders related to accelerated aging in CCS may be attributed to chronic inflammation. Therefore, this study aimed to investigate whether asymptomatic survivors of ALL have a biological phenotype of accelerated cellular senescence early in life. For this purpose, a broad panel of 51 cytokines was tested. We show that survivors after ALL treatment have an inflammatory profile associated with premature cellular aging. Factors that increase the risk of immunological alterations include younger age at diagnosis, high-risk protocols, and radiation therapy. Childhood acute lymphoblastic leukemia (ALL) survivors are at higher risk of developing many late effects later in life. They experience multiple health problems that have significant public health implications, such as frailty, premature onset of lifestyle diseases, and second tumors. There is some evidence that chronic inflammation causes accelerated aging in childhood cancer survivors; however, the available data are very limited. The aim of the study was to evaluate the broad panel of cytokines among asymptomatic ALL survivors after anticancer treatment. The study included 56 subjects with a mean age of 16.11 ± 3.98 years. The commercially available Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay and Bio-Plex TGF-β Assay were used for simultaneous determination of 48 cytokines and 3 isoforms of TGF-β. Among 51 tested cytokines, the levels of 33 were statistically significantly higher in ALL survivors than in the control group (p < 0.05). Increased levels of pro-inflammatory cytokines, including the IL-1 family (IL-1 β, IL-1Ra; p < 0.0001), IL-6 (p < 0.001), IL-17 (p < 0.001), IL-18 (p < 0.05), TNFα (p < 0.01), IFNα2 (p < 0.05), and IFNγ (p < 0.01), were found elevated in the entire study group, compared with the controls. Subjects treated previously according to the high-risk protocol had higher IL-18 levels than low- and intermediate-risk groups (p < 0.05). Elevated levels of IL-1ra, IL-6, IL-12 (p70), IL-17, LIF, M-CSF, CSF, and VEGF were found in ALL survivors treated before the age of 5, compared with subjects treated over 5 years of age (p < 0.05). Moreover, individuals who received radiotherapy presented elevated levels of both IL-18 (p < 0.05) and MIG (p < 0.05). In conclusion, we found that young asymptomatic survivors after ALL treatment demonstrated a biological profile of complex low-grade chronic inflammation. [ABSTRACT FROM AUTHOR]

Adipose tissue is an abundant source of mesenchymal stem cells (ADMSCs). Evidence has suggested that depot-specific ADMSCs (obtained from subcutaneous or visceral adipose tissue–subADMSCs or visADMSCs, respectively) account for differential responses of each depot to metabolic challenges. However, little is known about the phenotype and changes in metabolism of the adipocytes derived from ADMSCs of obese individuals. Therefore, we investigated the phenotypic and metabolic characteristics, particularly the lipid profile, of fully differentiated adipocytes derived from ADMSCs of lean and obese (with/without metabolic syndrome) postmenopausal women. We observed a depot-specific pattern, with more pronounced changes present in the adipocytes obtained from subADMSCs. Namely, chronic oversupply of fatty acids (present in morbid obesity) triggered an increase in CD36/SR-B2 and FATP4 protein content (total and cell surface), which translated to an increased LCFA influx (3H-palmitate uptake). This was associated with the accumulation of TAG and DAG in these cells. Furthermore, we observed that the adipocytes of visADMSCs origin were larger and showed smaller granularity than their counterparts of subADMSCs descent. Although ADMSCs were cultured in vitro, in a fatty acids-deprived environment, obesity significantly influenced the functionality of the progenitor adipocytes, suggesting the existence of a memory effect. [ABSTRACT FROM AUTHOR]

Background/Aims: Correlation between type 2 diabetes and other abnormalities such as obesity with redox balance disturbance was analyzed in many reports. Nonetheless, antioxidants impact on parameters accompanying these conditions is still unknown. Currently the role of redox imbalance in the adipose tissue has gained a lot of attention. Methods: We investigated the impact of α-lipoic acid (ALA) on plasma glucose and insulin concentrations, oxidative stress and inflammation parameters in the subcutaneous (SAT) and visceral (VAT) adipose tissue of high fat diet-fed (HFD) rats. Male Wistar rats were randomly divided into three groups (n = 6) -- control diet (CTRL), HFD and HFD with α-lipoic acid (HFD+ALA). Results: HFD increased body weight, plasma insulin and glucose as well as leads to oxidative stress parameters in the adipose tissue. ALA supplementation reduced body weight and oxidative stress parameters more effectively in the visceral than subcutaneous adipose tissue of insulin resistant rats. Conclusion: Insulin resistance led to increased enzymatic and nonenzymatic antioxidant systems, protein and lipid glycoxidation, nitrosative stress, and selected inflammatory parameters more in VAT than in SAT of insulin resistant rats. Moreover, ALA inhibited HFD consequences mainly in VAT mostly through glutathione (GSH) biosynthesis. [ABSTRACT FROM AUTHOR]