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Accumulation of acylcarnitines is a characteristic feature of various metabolic disorders affecting fatty acid metabolism. Despite extensive research, no specific molecules have been identified to induce ferroptosis through the regulation of acylcarnitine metabolism. In this study, acylcarnitine accumulation was identified based on cell metabolomics study after the treatment with Stemona alkaloid derivative (SA-11), which was proved to induce ferroptosis in our previous research. Furthermore, the CPT-1 level was proved to significantly increase, while the CPT-2 level indicated no significant difference, which resulted in the accumulation of acylcarnitine. Besides, the ferroptosis-inducing ability of SA-11 was significantly enhanced by the addition of exogenous acylcarnitine, presumably due to the production of additional ROS. This hypothesis was corroborated by the observation of increased ROS levels in HCT-116 cells treated with SA-11 compared to the control group. These findings suggest that targeting acylcarnitine metabolism, particularly through CPT-1, may offer a novel therapeutic strategy for cancer treatment by enhancing ferroptosis induction. [ABSTRACT FROM AUTHOR]

Accumulation of acylcarnitines is a characteristic feature of various metabolic disorders affecting fatty acid metabolism. Despite extensive research, no specific molecules have been identified to induce ferroptosis through the regulation of acylcarnitine metabolism. In this study, acylcarnitine accumulation was identified based on cell metabolomics study after the treatment with Stemona alkaloid derivative (SA-11), which was proved to induce ferroptosis in our previous research. Furthermore, the CPT-1 level was proved to significantly increase, while the CPT-2 level indicated no significant difference, which resulted in the accumulation of acylcarnitine. Besides, the ferroptosis-inducing ability of SA-11 was significantly enhanced by the addition of exogenous acylcarnitine, presumably due to the production of additional ROS. This hypothesis was corroborated by the observation of increased ROS levels in HCT-116 cells treated with SA-11 compared to the control group. These findings suggest that targeting acylcarnitine metabolism, particularly through CPT-1, may offer a novel therapeutic strategy for cancer treatment by enhancing ferroptosis induction.

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles. [ABSTRACT FROM AUTHOR]

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disorder. The naturally occurring phytosterol; β-sitosterol has antiobesogenic and anti-diabetic properties. The purpose of this study was to explore the role of β-sitosterol in preventing hepatic steatosis induced by a high-fat diet (HFD) in rats. In the current study, to induce NAFLD in the female Wister rats, an HFD was administered to them for 8 weeks. The pathogenic severity of steatosis in rats receiving an HFD diet was dramatically decreased by oral administration of β-sitosterol. After administering β-sitosterol to HFD-induced steatosis for three weeks, several oxidative stress-related markers were then assessed. We showed that β-sitosterol reduced steatosis and the serum levels of triglycerides, transaminases (ALT and AST) and inflammatory markers (IL-1β and iNOS) compared to HFD-fed rats. Additionally, β-sitosterol reduced endoplasmic reticulum stress by preventing the overexpression of inositol-requiring enzyme-1 (IRE-1α), X-box binding protein 1(sXBP1) and C/EBP homologous protein (CHOP) genes which, showing a function in the homeostatic regulation of protein folding. Also, it was found that the expression of the lipogenic factors; peroxisome proliferator-activated receptor (PPAR-α), sterol regulatory element binding protein (SREBP-1c) and carnitine palmitoyltransferase-1(CPT-1), which are involved in the regulation of the fatty acid oxidation process, may be regulated by β-sitosterol. It can be concluded that β-sitosterol may prevent NAFLD by reducing oxidative stress, endoplasmic reticulum stress and inflammatory responses, which supports the possibility of using β-sitosterol as an alternative therapy for NAFLD. Together, β-sitosterol may be an option for NAFLD prevention. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the protective effects of PPARγ/CPT-1 regulation on cisplatin-induced cochlear hair cell injury. The viability, apoptosis and mitochondrial membrane potential of cisplatin-induced HEI-OC1 cells were determined by CCK-8 assay, TUNEL and JC-1 staining, respectively. The oxidative stress and lipid metabolism were detected by the assay kits of MDA, ROS, SOD, CAT, TG and FFA. The transfection efficiency of overexpression (OV)-PPARG and OV-CPT1A was examined by RT-qPCR and the expressions of apoptosis- and lipid metabolism-related proteins were detected by western blot. As a result, cisplatin with varying concentrations (5, 10, 30 μM) suppressed the viability, promoted the apoptosis and hindered the mitochondrial function of HEI-OC1 cells, accompanied with up-regulated expressions of Bax and cleaved caspase-3 and down-regulated expression of Bcl-2. The oxidative stress was aggravated and lipid metabolism was inhibited by cisplatin (5, 10, 30 μM) induction, evidenced by the increased levels of MDA, ROS, TG, FFA and the decreased levels of SOD and CAT. Overexpression of PPARG or CPT1A could improve the viability, mitochondrial function, lipid metabolism and suppress the oxidative stress and apoptosis of cisplatin-induced HEI-OC1 cells. In conclusion, up-regulation of PPARG or CPT1A ameliorated cochlear hair cell injury by improving cellular lipid metabolism and inhibiting oxidative stress. [ABSTRACT FROM AUTHOR]

Long-chain fatty acid (LCFA) oxidation has been shown to play an important role in interleukin-4 (IL-4)-mediated macrophage polarization (M(IL-4)). However, many of these conclusions are based on the inhibition of carnitine palmitoyltransferase-1 with high concentrations of etomoxir that far exceed what is required to inhibit enzyme activity (EC90 < 3 μM). We employ genetic and pharmacologic models to demonstrate that LCFA oxidation is largely dispensable for IL-4-driven polarization. Unexpectedly, high concentrations of etomoxir retained the ability to disrupt M(IL-4) polarization in the absence of Cpt1a or Cpt2 expression. Although excess etomoxir inhibits the adenine nucleotide translocase, oxidative phosphorylation is surprisingly dispensable for M(IL-4). Instead, the block in polarization was traced to depletion of intracellular free coenzyme A (CoA), likely resulting from conversion of the pro-drug etomoxir into active etomoxiryl CoA. These studies help explain the effect(s) of excess etomoxir on immune cells and reveal an unappreciated role for CoA metabolism in macrophage polarization.

Purpose: In gestational diabetes (GDM), abnormalities occur not only in glucose metabolism, but also in lipid metabolism. Adiponectin (ADPN) plays an important role in the regulation of lipid metabolism. In this paper, the role and mechanism of ADPN in GDM are discussed. Methods: GDM model was formed in pregnant mice induced by high-fat diet and streptozotocin, and blood glucose level was detected after ADPN treatment. The levels of TG, TC, HDL-C, and LDL-C in blood lipid of mice were detected by biochemical apparatus. HE staining was used to detect the placenta damage in mice. The expression of oxidative stress-related indexes in placental tissues was also detected by ELISA. Placental iron deposition was detected by Prussian blue staining. Redox capacity of placental tissue was detected by ELISA. Western blot was used to detect the expression of ferroptosis-related proteins in placental tissues. The expression of ADPN in placenta and peripheral blood was detected by ELISA, and the expression of ADPNR, downstream CPT-1, and GLUT4 of placenta were detected by RT-qPCR and western blot. Subsequently, trophoblast cells were induced by palmitic acid and glucose, and the cell activity was detected by CCK-8. The results in animal experiments were verified in cell experiments by RT-qPCR, western blot, and fluorescence labeling of iron ions. Finally, ADPN and CPT-1 inhibitor PM were given to trophoblast cells to further explore the mechanism. Results: ADPN inhibited blood glucose and lipid levels in GDM mice. ADPN inhibited oxidation/peroxide imbalance-induced ferroptosis in placental tissues of GDM mice. ADPN inhibited the expression of CPT-1 and GLUT4 in placental tissues of GDM mice. This result was also confirmed in cell experiments, and this process may be achieved by regulating CPT-1. Conclusions: ADPN ameliorated placental injury in GDM by correcting fatty acid oxidation/peroxide imbalance-induced ferroptosis via restoration of CPT-1 activity. [ABSTRACT FROM AUTHOR]

Abstract Aim Antioxidant therapy for with vitamin E appears to be effective for the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanism of action and optimal therapeutic dosage is unclear. The present study was undertaken to examine whether the effects of α‐tocopherol (α‐Toc) on NAFLD are dose‐dependent in a diet‐induced obese model. Methods Male mice were fed standard chow, high‐fat (HF) diet, HF diet with low‐dose, or with high dose of α‐Toc supplementation. Histological findings, triglyceride content, and the levels of protein expression related to fatty acid synthesis/oxidation such as carnitine palmitoyltransferase I (CPT‐1) of liver were evaluated. In addition, 2‐tetradecylglycidic acid (TDGA), a CPT‐1 inhibitor, was administered to mice fed HF diet with low‐dose of α‐Toc. Finally, HepG2 cells in fat‐loaded environment were treated with 0–50 μM α‐Toc. Results Treatment of low‐dose of α‐Toc decreased HF‐induced hepatic fat accumulation, but this finding was not observed in treatment of high dose of α‐Toc. HF‐induced reduction of CPT‐1 was attenuated with low‐dose of α‐Toc but not with high dose of α‐Toc. TDGA suppressed the improvement of histological findings in liver induced by low‐dose of α‐Toc treatment. CPT‐1 expression in HepG2 cells increased in response to low‐dose of α‐Toc, but not in high dose. Conclusions Dual action of α‐Toc on CPT‐1 protein levels was observed. The effect of vitamin E on NAFLD may be not be dose‐dependent.

An increasing number of studies indicate that dietary polyphenols are beneficial to non-alcoholic fatty liver (NAFL) disease. However, the published reports about marine polyphenols are still limited. In this work, the ameliorative effect of polyphenols from Laminaria (L.) japonica on NAFL was investigated in vivo. According to the spectral analyses, dieckol was identified from L. japonica. After NAFL was induced by a high-fat diet, the ICR mice were administered dieckol-enriched extract (DEE) (50 mg/kg/day) for 4 weeks. Compared with the normal diet (ND) group, significant (P

Abstract Objective To emphasize the mechanism of concurrent exercise effect on lipid disorders in insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Materials and methods Twenty male ApoE knockout mice were randomly divided into two groups: HFD group (n = 10) fed a high fat diet, and HFDE group (n = 10) with high-fat diet intervention for 12 weeks and swimming exercise. Other ten healthy male C57BL/6 J mice were fed a normal diet, and included as control group. Retro-orbital blood samples were collected for biochemical analysis. Oil red O staining of liver tissues was performed to confirm the exercise effect. Western blotting was performed to evaluate the expressions of PPAR-γ, CPT-1, MCAD. Results The levels of TG, TC, LDL, FFA, FIN, FPG and Homa-IRI in the HFD group were significantly higher than ND group, while these were markedly decreased in the HFDE group compared with HFD group. The Oil Red O staining of liver samples further confirmed the exercise effect on the change of lipid deposition in the liver. Western blotting showed increased expressions of PPAR-γ, CPT-1, MCAD induced by high fat diet were significantly downregulated by exercise. Conclusion A concurrent 12-week exercise protocol alleviated the lipid metabolism disorders of IR and NAFLD, probably via PPAR-γ/CPT-1/MCAD signaling.

Inhibition of lipid accumulation is the key step to prevent nonalcoholic fatty liver (NAFL) progressing to nonalcoholic steatohepatitis. We aimed to study the effect of low-molecular-weight citrus pectin (LCP) against lipid accumulation and the underlying mechanism. Oleic acid (OA)-induced lipid deposition in HepG2 cells was applied to mimic in vitro model of lipid accumulation. Oil Red O (ORO) stain result showed lipid accumulation was significantly reduced, and levels of adipose triglyceride lipase (ATGL) and carnitine palmitoyltransferase-1 (CPT-1), involved in triacylglycerol catabolism and fatty acid β-oxidation, detected by RT-qPCR were increased after OA-stimulated HepG2 cells treated with LCP. RNA sequencing analysis identified 740 differentially expressed genes (DEGs) in OA-stimulated HepG2 cells treated with the LCP group (OA+LCP group), and bioinformatics analysis indicated that some DEGs were enriched in lipid metabolism-related processes and pathways. The expression of the top 8 known DEGs in the OA+LCP group was then verified by RT-qPCR, which showed that fold change (abs) of METTL7B was the highest among the 8 candidates. In addition, overexpression of METTL7B in HepG2 cells significantly inhibited the lipid accumulation and enhanced levels of ATGL and CPT-1. In conclusion, LCP inhibited lipid accumulation through the upregulation of METTL7B, and further enhancement of ATGL and CPT-1 levels. LCP is expected to develop as a promising agent to ameliorate fat accumulation in NAFL. [ABSTRACT FROM AUTHOR]

Aim: Antioxidant therapy for with vitamin E appears to be effective for the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanism of action and optimal therapeutic dosage is unclear. The present study was undertaken to examine whether the effects of α‐tocopherol (α‐Toc) on NAFLD are dose‐dependent in a diet‐induced obese model. Methods: Male mice were fed standard chow, high‐fat (HF) diet, HF diet with low‐dose, or with high dose of α‐Toc supplementation. Histological findings, triglyceride content, and the levels of protein expression related to fatty acid synthesis/oxidation such as carnitine palmitoyltransferase I (CPT‐1) of liver were evaluated. In addition, 2‐tetradecylglycidic acid (TDGA), a CPT‐1 inhibitor, was administered to mice fed HF diet with low‐dose of α‐Toc. Finally, HepG2 cells in fat‐loaded environment were treated with 0–50 μM α‐Toc. Results: Treatment of low‐dose of α‐Toc decreased HF‐induced hepatic fat accumulation, but this finding was not observed in treatment of high dose of α‐Toc. HF‐induced reduction of CPT‐1 was attenuated with low‐dose of α‐Toc but not with high dose of α‐Toc. TDGA suppressed the improvement of histological findings in liver induced by low‐dose of α‐Toc treatment. CPT‐1 expression in HepG2 cells increased in response to low‐dose of α‐Toc, but not in high dose. Conclusions: Dual action of α‐Toc on CPT‐1 protein levels was observed. The effect of vitamin E on NAFLD may be not be dose‐dependent. [ABSTRACT FROM AUTHOR]

Background/Aims: Fisetin is a naturally abundant flavonoid isolated from various fruits and vegetables that was recently identified to have potential biological functions in improving allergic airway inflammation, as well as anti-oxidative and anti-tumor properties. Fisetin has also been demonstrated to have anti-obesity properties in mice. However, the effect of fisetin on nonalcoholic fatty liver disease (NAFLD) is still elusive. Thus, the present study evaluated whether fisetin improves hepatic steatosis in high-fat diet (HFD)-induced obese mice and regulates lipid metabolism of FL83B hepatocytes in vitro. Methods: NAFLD was induced by HFD in male C57BL/6 mice. The mice were then injected intraperitoneally with fisetin for 10 weeks. In another experiment, FL83B cells were challenged with oleic acid to induce lipid accumulation and treated with various concentrations of fisetin. Results: NAFLD mice treated with fisetin had decreased body weight and epididymal adipose tissue weight compared to NAFLD mice. Fisetin treatment also reduced liver lipid droplet and hepatocyte steatosis, alleviated serum free fatty acid, and leptin concentrations, significantly decreased fatty acid synthase, and significantly increased phosphorylation of AMPKα and the production of sirt-1 and carnitine palmitoyltransferase I in the liver tissue. In vitro, fisetin decreased lipid accumulation and increased lipolysis and β-oxidation in hepatocytes. Conclusion: This study suggests that fisetin is a potential novel treatment for alleviating hepatic lipid metabolism and improving NAFLD in mice via activation of the sirt1/AMPK and β-oxidation pathway.

Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (KATP)-dependent Ca2+ signalling and KATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin secretion (GSIS), are well established. A proposed model included a key role for a metabolic partitioning 'switch', the acetyl-CoA carboxylase (ACC)/malonyl-CoA/carnitine palmitoyltransferase-1 (CPT-1) axis, in beta cell glucose and fatty acid signalling for insulin secretion. This model has gained overwhelming support from a number of studies in recent years and is now refined through its link to the glycerolipid/NEFA cycle that provides lipid signals through its lipolysis arm. Furthermore, acetyl-CoA carboxylase may also control beta cell growth. Here we review the evidence supporting a role for the ACC/malonyl-CoA/CPT-1 axis in the control of GSIS and its particular importance under conditions of elevated fatty acids (e.g. fasting, excess nutrients, hyperlipidaemia and diabetes). We also document how it is linked to a more global lipid signalling system that includes the glycerolipid/NEFA cycle. [ABSTRACT FROM AUTHOR]

In Western societies where food is abundant, these excess nutrients are stored as fats mainly in adipose tissue. Fats are stored in structures known as lipid droplets, and a genome-wide screen performed in Drosophila cells has identified several genes that are important for the formation of these droplets. One group of genes found during this screen included those that regulate mRNA splicing. Previous work from our lab has identified some splicing factors that play a role in regulating fat storage; however, the full complement of splicing proteins that regulate lipid metabolism is still unknown. In this study, the levels of a number of serine-arginine (SR) domain containing splicing factors (RSF1, RBP1, RBP1-like, SF2 and Srp-54) were decreased using RNAi in the adult fat body to assess their role in the control of Drosophila metabolism. Decreasing SF2 and RBP1 showed increased triglycerides, while inducing RNAi towards RSF1, RBP1-Like and Srp-54 had no effect on triglycerides. Interestingly, the increased triglyceride phenotype in the SF2-RNAi flies was due to an increase in the amount of fat stored per cell while the RBP1-RNAi flies have more fat cells. In addition, the splicing of the β-oxidation enzyme, CPT1, was altered in the SF2-RNAi flies potentially promoting the increased triglycerides in these animals. Together, this study identifies novel splicing factors responsible for the regulation of lipid storage in the Drosophila fat body and contributes to our understanding of the mechanisms, which influence the regulation of fat storage in adipose-like cells. • SR proteins control mRNA splicing, but have unknown metabolic functions. • SF2 and RBP1 affect triglyceride storage in the Drosophila fat body. • Decreasing RBP1 in the fat body increases the number of fat body cells. • Decreasing SF2 in the fat body increases the amount of fat stored per cell. • SF2 alters fat body CPT1 splicing. [ABSTRACT FROM AUTHOR]

• Dieckol is one of the main polyphenol component in Laminaria japonica. • Polyphenols from Laminaria japonica can accelerate the recovery of non-alcoholic fatty liver. • Polyphenols from Laminaria japonica improving hepatic steatosis through stimulating hepatic fatty acid β-oxidation. An increasing number of studies indicate that dietary polyphenols are beneficial to non-alcoholic fatty liver (NAFL) disease. However, the published reports about marine polyphenols are still limited. In this work, the ameliorative effect of polyphenols from Laminaria (L.) japonica on NAFL was investigated in vivo. According to the spectral analyses, dieckol was identified from L. japonica. After NAFL was induced by a high-fat diet, the ICR mice were administered dieckol-enriched extract (DEE) (50 mg/kg/day) for 4 weeks. Compared with the normal diet (ND) group, significant (P < 0.05) improvements in body weight gain, liver index, visceral fat index, plasma lipid profiles, and hepatic fat deposition were observed in ND + DEE group. Moreover, DEE supplementation selectively ameliorated levels of phosphorylated-AMP-activated protein kinase, carnitine palmitoyltransferase-1, and peroxisome proliferator-activated receptor-α in liver. Therefore, polyphenols from L. japonica might have potential ameliorative effect on hepatic steatosis via stimulating hepatic fatty acid β-oxidation. [ABSTRACT FROM AUTHOR]

Lipids as a fuel source for energy supply during submaximal exercise originate from subcutaneous adipose tissue derived fatty acids (FA), intramuscular triacylglycerides (IMTG), cholesterol and dietary fat. These sources of fat contribute to fatty acid oxidation (FAox) in various ways. The regulation and utilization of FAs in a maximal capacity occur primarily at exercise intensities between 45 and 65% VO2max, is known as maximal fat oxidation (MFO), and is measured in g/min. Fatty acid oxidation occurs during submaximal exercise intensities, but is also complimentary to carbohydrate oxidation (CHOox). Due to limitations within FA transport across the cell and mitochondrial membranes, FAox is limited at higher exercise intensities. The point at which FAox reaches maximum and begins to decline is referred to as the crossover point. Exercise intensities that exceed the crossover point (~65% VO2max) utilize CHO as the predominant fuel source for energy supply. Training status, exercise intensity, exercise duration, sex differences, and nutrition have all been shown to affect cellular expression responsible for FAox rate. Each stimulus affects the process of FAox differently, resulting in specific adaptions that influence endurance exercise performance. Endurance training, specifically long duration (>2 h) facilitate adaptations that alter both the origin of FAs and FAox rate. Additionally, the influence of sex and nutrition on FAox are discussed. Finally, the role of FAox in the improvement of performance during endurance training is discussed. [ABSTRACT FROM AUTHOR]

Interest in low-carbohydrate, high-fat (LCHF) diets has increased over recent decades given the theorized benefit of associated intramuscular adaptations and shifts in fuel utilization on endurance exercise performance. Consuming a LCHF diet during exercise training increases the availability of fat (i.e., intramuscular triglyceride stores; plasma free fatty acids) and decreases muscle glycogen stores. These changes in substrate availability increase reliance on fat oxidation for energy production while simultaneously decreasing reliance on carbohydrate oxidation for fuel during submaximal exercise. LCHF diet-mediated changes in substrate oxidation remain even after endogenous or exogenous carbohydrate availability is increased, suggesting that the adaptive response driving changes in fat and carbohydrate oxidation lies within the muscle and persists even when the macronutrient content of the diet is altered. This narrative review explores the intramuscular adaptations underlying increases in fat oxidation and decreases in carbohydrate oxidation with LCHF feeding. The possible effects of LCHF diets on protein metabolism and post-exercise muscle remodeling are also considered.

Lipids as a fuel source for energy supply during submaximal exercise originate from subcutaneous adipose tissue derived fatty acids (FA), intramuscular triacylglycerides (IMTG), cholesterol and dietary fat. These sources of fat contribute to fatty acid oxidation (FAox) in various ways. The regulation and utilization of FAs in a maximal capacity occur primarily at exercise intensities between 45 and 65% VO2max, is known as maximal fat oxidation (MFO), and is measured in g/min. Fatty acid oxidation occurs during submaximal exercise intensities, but is also complimentary to carbohydrate oxidation (CHOox). Due to limitations within FA transport across the cell and mitochondrial membranes, FAox is limited at higher exercise intensities. The point at which FAox reaches maximum and begins to decline is referred to as the crossover point. Exercise intensities that exceed the crossover point (~65% VO2max) utilize CHO as the predominant fuel source for energy supply. Training status, exercise intensity, exercise duration, sex differences, and nutrition have all been shown to affect cellular expression responsible for FAox rate. Each stimulus affects the process of FAox differently, resulting in specific adaptions that influence endurance exercise performance. Endurance training, specifically long duration (>2 h) facilitate adaptations that alter both the origin of FAs and FAox rate. Additionally, the influence of sex and nutrition on FAox are discussed. Finally, the role of FAox in the improvement of performance during endurance training is discussed.

Background/Aims: Fisetin is a naturally abundant flavonoid isolated from various fruits and vegetables that was recently identified to have potential biological functions in improving allergic airway inflammation, as well as anti-oxidative and anti-tumor properties. Fisetin has also been demonstrated to have anti-obesity properties in mice. However, the effect of fisetin on nonalcoholic fatty liver disease (NAFLD) is still elusive. Thus, the present study evaluated whether fisetin improves hepatic steatosis in high-fat diet (HFD)-induced obese mice and regulates lipid metabolism of FL83B hepatocytes in vitro. Methods: NAFLD was induced by HFD in male C57BL/6 mice. The mice were then injected intraperitoneally with fisetin for 10 weeks. In another experiment, FL83B cells were challenged with oleic acid to induce lipid accumulation and treated with various concentrations of fisetin. Results: NAFLD mice treated with fisetin had decreased body weight and epididymal adipose tissue weight compared to NAFLD mice. Fisetin treatment also reduced liver lipid droplet and hepatocyte steatosis, alleviated serum free fatty acid, and leptin concentrations, significantly decreased fatty acid synthase, and significantly increased phosphorylation of AMPKα and the production of sirt-1 and carnitine palmitoyltransferase I in the liver tissue. In vitro, fisetin decreased lipid accumulation and increased lipolysis and β-oxidation in hepatocytes. Conclusion: This study suggests that fisetin is a potential novel treatment for alleviating hepatic lipid metabolism and improving NAFLD in mice via activation of the sirt1/AMPK and β-oxidation pathway. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti-HCV activity of l-carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH-1 or HCV replicon-transfected Huh7.5.1 cells were treated with or without l-carnitine to examine its anti-HCV effects. The effects of l-carnitine on HCV entry, HCV-induced adipogenesis and lipid droplet formation, and HCV-induced oxidative stress were examined. Treatment of JFH-1-infected cells with l-carnitine inhibited HCV propagation in a concentration-dependent manner. In contrast, l-carnitine had no anti-HCV activity in the HCV replicon system, which is lacking viral assembly. In addition, l-carnitine did not affect HCV entry. However, l-carnitine treatment decreased intracellular lipid droplets, which are crucial for HCV assembly in JFH-1-infected cells. The expression level of CPT-1 was decreased in JFH-1-infected cells, and l-carnitine treatment restored this expression. HCV-infected cells exhibited increased production of reactive oxygen species and glutathione oxidation. l-carnitine decreased oxidative stress induced by JFH-1-infection, as shown by glutathione/glutathione disulfide assays and MitoSOX staining. l-carnitine exhibited anti-HCV activity, possibly by inhibiting HCV assembly and through its anti-adipogenic activity in HCV-infected cells. Moreover, l-carnitine has antioxidant properties in HCV-infected hepatocytes. Overall, these results indicated that l-carnitine may be an effective adjunctive agent in antiviral therapies to treat chronic hepatitis C. J. Med. Virol. 89:857-866, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Hovenia dulcis Thunb. (HDT) was known to have anti-fatigue, anti-diabetes, neuroprotective, and hepatoprotective effects. In the present study, the anti-fatty liver mechanism of HDT was elucidated in oleic acid (OA)-treated Hep G2 cells and acute hyperlipidemia mouse model using Triton WR-1339. Here, HDT activated p-AMP-activated protein kinase (p-AMPK), proliferator activated receptor-α, carnitine palmitoyltransferase and also inhibited the expression of lipogenesis and cholesterol synthesis proteins, such as 3-hydroxy-3-methylglutaryl-CoA reductase, sterol regulatory element binding protein-1c, SREBP-2, and fatty acid synthase in OA-treated Hep G2 cells. Conversely, AMPK inhibitor compound C blocked the anti-fatty liver effect of HDT to induce AMPK phosphorylation and decrease 3-hydroxy-3-methylglutaryl-CoA reductase and lipid accumulation by oil red O staining in OA-treated Hep G2 cells. Additionally, HDT pretreatment protected against the increase of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol and phospholipid in an acute hyperlipidemia mouse model with enhancement of glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase activities. Taken together, HDT inhibits OA-induced hepatic lipid accumulation via activation of AMPK and proliferator activated receptor-α/carnitine palmitoyltransferase signaling and enhancement of antioxidant activity as a potent candidate for nonalcoholic fatty liver disease and hyperlipidemia. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Fatty acids cause endothelial dysfunction involving increased ROS (reactive oxygen species) and reduced NO (nitric oxide) bioavailability. We show that in MAECs (mouse aortic endothelial cells), the PPARβ/δ (peroxisomeproliferator- activated receptor β/δ) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser1177 and increased intracellular ROS levels caused by exposure to palmitate in vitro. The impaired endothelium-dependent relaxation to acetylcholine in mouse aorta induced by palmitate was restored by GW0742. In vivo, GW0742 treatment prevented the reduced aortic relaxation, phosphorylation of eNOS at Ser1177, and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPARβ/δ antagonist GSK0660 abolished all of these protective effects induced by GW0742. This agonist enhanced the expression of CPT (carnitine palmitoyltransferase)-1. The effects of GW0742 on acetylcholineinduced relaxation in aorta and on NO and ROS production in MAECs exposed to palmitate were abolished by the CPT-1 inhibitor etomoxir or by siRNA targeting CPT-1. GW0742 also inhibited the increase in DAG (diacylglycerol), PKCα/βII (protein kinase Cα/βII) activation, and phosphorylation of eNOS at Thr495 induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPARβ/δ activation restored the lipid-induced endothelial dysfunction by up-regulation of CPT-1, thus reducing DAG accumulation and the subsequent PKC-mediated ROS production and eNOS inhibition. [ABSTRACT FROM AUTHOR]

It is known that fatty acids (FA) regulate lipid metabolism by modulating the expression of numerous genes. In order to gain a better understanding of the effect of individual FA on lipid metabolism related genes in rainbow trout ( Oncorhynchus mykiss), an in vitro time-course study was implemented where twelve individual FA (butyric 4:0; caprylic 8:0; palmitic (PAM) 16:0; stearic (STA) 18:0; palmitoleic16:1n-7; oleic 18:1n-9; 11- cis-eicosenoic 20:1n-9; linoleic (LNA) 18:2n-6; α-linolenic (ALA) 18:3n-3; eicosapentenoic (EPA) 20:5n-3; docosahexaenoic (DHA) 22:6n-3; arachidonic (ARA) 20:4n-6) were incubated in rainbow trout liver slices. The effect of FA administration over time was evaluated on the expression of leptin, PPARα and CPT-1 (lipid oxidative related genes). Leptin mRNA expression was down regulated by saturated fatty acids (SFA) and LNA, and was up regulated by monounsaturated fatty acids (MUFA) and long chain PUFA, whilst STA and ALA had no effect. PPARα and CPT-1mRNA expression were up regulated by SFA, MUFA, ALA, ARA and DHA; and down regulated by LNA and EPA. These results suggest that there are individual and specific FA induced modifications of leptin, PPARα and CPT-1 gene expression in rainbow trout, and it is envisaged that such results may provide highly valuable information for future practical applications in fish nutrition. [ABSTRACT FROM AUTHOR]

The article discusses carnitine palmitoyltransferase-1A deficiency (CPT-1A) which is a rare fatty acid metabolism defect presenting as autosomal recessive inheritance. It mentions the clinical presentation of the disease which includes hypoglycemia for infants, lethargy and seizures in children that might become fatal. It also mentions that its effects are outgrown and decreases around the age of 5. Included in the article are the etiology, diagnosis and treatment.

Background: Naringenin, a flavonoid present in grapefruit, has recently been shown to exert hypolipidemic and hypocholesterolemic effects, which has a particular importance for protecting against chronic diseases. However, the lipid-lowering potential of naringenin at the concentrations in the dietary range and its underlying mechanisms have yet to be fully elucidated. Aim: The aim of the present study was (1) to investigate the effects of dietary naringenin on plasma and hepatic triglyceride and cholesterol levels and on adipose deposition in rat and (2) to determine the contribution of hepatic peroxisome proliferators-activated receptor α (PPARα) expression to fatty acid oxidation. Methods: Male Long-Evans hooded rats were fed a diet supplemented with naringenin (0.003, 0.006, and 0.012%) for 6 weeks. We analyzed plasma and hepatic lipid contents and determined the protein expression of PPARα, carnitine-palmitoyl transferase 1L (CPT-1), and uncoupling protein 2 (UCP2), all of which are critical genes for fatty acid oxidation. Results: Naringenin supplementation caused a significant reduction in the amount of total triglyceride and cholesterol in plasma and liver. In addition, naringenin supplementation lowered adiposity and triglyceride contents in parametrial adipose tissue. Naringenin-fed animals showed a significant increase in PPARα protein expression in the liver. Furthermore, expression of CPT-1 and UCP2, both of which are known to be regulated by PPARα, was markedly enhanced by naringenin treatment. Conclusions: Our results indicate that the activation of PPARα transcription factor and upregulation of its fatty acid oxidation target genes by dietary naringenin may contribute to the hypolipidemic and anti-adiposity effects in vivo. [ABSTRACT FROM AUTHOR]

Abstract: The polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduces proliferation of several cell types, including colon tumor cells, and regulates gene expression in a cell- and gene-selective manner. In hepatocytes, the fatty acid synthase (FAS) gene is down-regulated by DHA whereas the carnitine palmitoyltransferase-1 (CPT-1) gene is up-regulated. In adipocytes but not in hepatocytes, the expression of the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) gene is stimulated by unsaturated FA, including DHA. We monitored the expression of the FAS, CPT-1 and PEPCK-C genes in rat and human colon and in colonic tumors from humans. The ratio of PEPCK-C to FAS transcripts was in favor of PEPCK-C in human and rat colon, whereas the opposite occurred in Caco2 tumoral cells. FAS gene expression declined from proliferative to differentiated Caco2 cells, while in contrast the expression of PEPCK-C and CPT-1 genes increased. DHA strongly induced expression of the PEPCK-C and CPT-1 genes, in correlation with decreased cell growth, while, as expected, it reduced FAS mRNA. We assessed the relative expression of PEPCK-C, CPT-1 and FAS genes in fragments of colonic tumors and adjacent non-tumoral tissue from a series of 10 patients. PEPCK-C and CPT-1 mRNAs are more abundant in non-tumoral tissues than in the tumoral counterpart, whereas the opposite occurred for the FAS gene. Therefore, the PEPCK-C gene can be defined as a new negative marker for colonic tumors and a target for the anti-tumorigenic action of omega-3 PUFAs. [ABSTRACT FROM AUTHOR]

Abstract: We previously demonstrated that adiponectin has anti-fibrogenic and anti-inflammatory effects in the liver of mouse models of various liver diseases. However, its role in liver regeneration remains unclear. The aim of this study was to determine the role of adiponectin in liver regeneration. We assessed liver regeneration after partial hepatectomy in wild-type (WT) and adiponectin knockout (KO) mice. We analyzed DNA replication and various signaling pathways involved in cell proliferation and metabolism. Adiponectin KO mice exhibited delayed DNA replication and increased lipid accumulation in the regenerating liver. The expression levels of peroxisome proliferator-activated receptor (PPAR) α and carnitine palmitoyltransferase-1 (CPT-1), a key enzyme in mitochondrial fatty acid oxidation, were decreased in adiponectin KO mice, suggesting possible contribution of altered fat metabolism to these phenomena. Collectively, the present results highlight a new role for adiponectin in the process of liver regeneration. [Copyright &y& Elsevier]

Objective:Nutrition during critical periods in early life may increase the subsequent risk of obesity, hypertension and metabolic diseases in adulthood. Few studies have focused on the long-term consequences of poor nutrition during the suckling period on the susceptibility to developing obesity when exposed to a palatable cafeteria-style high-fat diet (CD) after weaning.Design:This study examined the impact of early undernutrition, followed by CD exposure, on blood pressure, hormones and genes important for insulin sensitivity and metabolism and skeletal muscle mRNA expression of adiponectin receptor 1 (AdipoR1), carnitine palmitoyl-transferase I (CPT-1), cytochrome c oxidase 4 (COX4) and peroxisome proliferator-activated receptor α (PPARα). Following normal gestation, Sprague–Dawley rat litters were adjusted to 18 (undernourished) or 12 (control) pups. Rats were weaned (day 21) onto either palatable CD or standard chow.Results:Early undernourished rats were significantly lighter than control by 17 days, persisting into adulthood only when animals were fed chow after weaning. Regardless of litter size, rats fed CD had doubled fat mass at 15 weeks of age, and significant elevations in plasma leptin, insulin and adiponectin. Importantly, undernutrition confined to the suckling period, elevated circulating adiponectin regardless of post-weaning diet. Blood pressure was reduced in early undernourished rats fed chow, and increased by CD. Early undernutrition was associated with long-term elevations in the expression of AdipoR1, CPT-1, COX4 and PPARα in skeletal muscle.Conclusion:This study demonstrates the important role of early nutrition on body weight and metabolism, suggesting early undernourishment enhances insulin sensitivity and fatty-acid oxidation. The long-term potential benefit of limiting nutrition in the early postnatal period warrants further investigation.International Journal of Obesity (2008) 32, 1585–1594; doi:10.1038/ijo.2008.141; published online 26 August 2008 [ABSTRACT FROM AUTHOR]

Abstract: Backgrounds and aims: Non-alcoholic-steatohepatitis (NASH) is closely related to insulin resistance, but it is unknown whether insulin resistance may be localized in hepatocytes. This study investigates insulin signalling in liver tissue from NASH, and the molecular mechanisms by which insulin-resistance could lead to liver damage (apoptosis). Moreover, to investigate the mechanisms of lipid overload we studied key enzymes in hepatocytes lipid metabolism. Methods and Results: In liver specimens from 11 patients with NASH and 7 histological normal livers, we measured total and phosphorylated Akt (active form), Bax and Bcl-2 by Western-blot analysis. In addition, we studied AMP-activated protein Kinase and Carnitine-Palmitoyl-Transferase-1 gene expression, key regulators of non-esterified fatty acid synthesis and oxidation, by reverse transcription polymerase chain reaction. In NASH, phosphorylated Akt was impaired (104.3±10.6 vs 152.6±22.4 AU, p <0.002) and correlated with necroinflammatory score (r =−0.62; p <0.05). Bax/Bcl-2 ratio was increased in NASH. Moreover, we observed a decrease of AMP-activated protein Kinase (10.74±6 vs 144.7±41.6 AU, p <0.0001) and Carnitine-Palmitoyl-Transferase-1 gene expression (38.7±14.6 vs 192.1±26.2 AU, p <0.0001), and both were correlated with steatosis score (r =−0.56, p <0.05, r =−0.87, p <0.05 respectively). Conclusions: Akt, a key molecule of insulin signalling and cell apoptosis is impaired in NASH, suggesting an important role of hepatic insulin resistance in liver failure. Moreover, decreased non-esterified fatty acid oxidation may cause hepatic lipid overload. [Copyright &y& Elsevier]

Objective:Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short- and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators.Methods:Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured.Results:Caloric intake of the palatable HFD group was 2–3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks.Conclusion:Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD.International Journal of Obesity (2008) 32, 249–258; doi:10.1038/sj.ijo.0803716; published online 4 September 2007 [ABSTRACT FROM AUTHOR]

Abstract: Prostacyclin (PGI2) and its analogues exert cardioprotective effects via the rhodopsin type membrane PGI2 receptor, IP. Peroxisome proliferator-activated receptor (PPAR) δ is a nuclear receptor abundantly expressed in cardiomyocytes and plays a pivotal role in maintaining constitutive mitochondrial fatty acid β-oxidation (FAO). Recently, a novel signaling pathway of PGI2 via PPARδ has been demonstrated in non-cardiac tissues. We therefore examined whether carbacyclin (cPGI2), a PGI2 analogue, up-regulates transcriptional expression of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme in mitochondrial FAO, via PPARδ in cardiomyocytes. Intraperitoneal injection of cPGI2 increased CPT-1 mRNA expression in murine hearts. Transcriptional activity was evaluated by PPAR responsive element (PPRE)-luciferase reporter gene assay in cultured neonatal rat cardiomyocytes. CPT-1 mRNA expression and PPRE promoter activity were significantly increased by cPGI2 in a concentration-dependent manner, where PPRE has been mapped to the promoter region of the CPT-1 gene. Moreover, the elevation of CPT-1 mRNA expression and PPRE promoter activity by cPGI2 was not abolished by H-89, a potent protein kinase A inhibitor, but was significantly inhibited in cardiomyocytes over-expressing a dominant-negative type of PPARδ. Furthermore, electrophoretic mobility shift assays demonstrated that binding of PPARδ to PPRE in the CPT-1 gene promoter is enhanced in response to cPGI2 stimulation. In addition, down-regulation of CPT-1 mRNA expression in cardiomyocytes subjected to hypoxia was attenuated by cPGI2. These results indicate that cPGI2 induces CPT-1 mRNA expression through PPARδ, independent of the IP receptor signaling pathway, suggesting a possibility that cPGI2 modulates cardiac energy metabolism by activating FAO via PPARδ. [Copyright &y& Elsevier]

Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as an anti-anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen-sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions. [ABSTRACT FROM AUTHOR]

Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement ofß-oxidation flux by labeled palmitate demonstrates that tBid inhibitsß-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid onß-oxidation. The unexpected role of tBid in the regulation of lipidß-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.Cell Death and Differentiation (2005) 12, 603-613. doi:10.1038/sj.cdd.4401636 Published online 22 April 2005 [ABSTRACT FROM AUTHOR]

Skeletal muscle contains two populations of mitochondria that appear to be differentially affected by disease and exercise training. It remains unclear how these mitochondrial subpopulations contribute to fiber type-related and/or training- induced changes in fatty acid oxidation and regulation of carnitine palmitoyltransferase-1β (CPT1β), the enzyme that controls mitochondrial fatty acid uptake in skeletal muscle. To this end, we found that fatty acid oxidation rates were 8.9-fold higher in subsarcolemmal mitochondria (SS) and 5.3-fold higher in intermyofibrillar mitochondria (IMF) that were isolated from red gastrocnemius (RG) compared with white gastrocnemius (WG) muscle, respectively. Malonyl-CoA (10 µM), a potent inhibitor of CPT 113, completely abolished fatty acid oxidation in SS and IMF mitochondria from WG, whereas oxidation rates in the corresponding fractions from RG were inhibited only 89% and 60%, respectively. Endurance training also elicited mitochondrial adaptations that resulted in enhanced fatty acid oxidation capacity. Ten weeks of treadmill running differentially increased palmitate oxidation rates 100% and 46% in SS and IMF mitochondria, respectively. In SS mitochondria, elevated fatty acid oxidation rates were accompanied by a 48% increase in citrate synthase activity but no change in CPT1 activity. Nonlinear regression analyses of mitochondrial fatty acid oxidation rates in the presence of 0-100 µM malonyl-CoA indicated that IC50 values were neither dependent on mitochondrial subpopulation nor affected by exercise training. However, in IMF mitochondria, training reduced the Hill coefficient (P < 0.05), suggesting altered CPT1β kinetics. These results demonstrate that endurance exercise provokes subpopulation-specific changes in mitochondrial function that are characterized by enhanced fatty acid oxidation and modified CPT 1β-malonyl-CoA dynamics. [ABSTRACT FROM AUTHOR]

We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP-activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that this cycle requires both PI3K and AMPK signaling. This substrate cycling linking glucose and lipid metabolism to thermogenesis provides a novel thermogenic mechanism by which leptin protects skeletal muscle from excessive fat storage and lipotoxicity. [Copyright &y& Elsevier]

Background: The ventromedial hypothalamus (VMH) is an important nuclei in responding to emotional stress, and emotional stress is a risk factor for cardiovascular diseases. However, the role of the VMH in cardiovascular diseases remains unknown. This study aimed to investigate the effects and underlying mechanisms of VMH activation on hypertension related cardiac remodeling in two-kidney-one-clip (2K1C) hypertension (HTN) rats. Methods: Eighteen male Sprague-Dawley rats were injected with AAV-hSyn-hM3D(Gq) into the VMH at 0 weeks and then randomly divided into three groups: (1) sham group (sham 2K1C + saline i.p. injection); (2) HTN group (2K1C + saline i.p. injection); (3) HTN+VMH activation group (2K1C + clozapine-N-oxide i.p. injection). One week later, rats were subjected to a sham or 2K1C operation, and 2 weeks later rats were injected with clozapine-N-oxide or saline for 2 weeks. Results: In the HTN+VMH activation group, FosB expression was significantly increased in VMH sections compared with those of the other two groups. Compared to the HTN group, the HTN+VMH activation group showed significant: (1) increases in systolic blood pressure (SBP); (2) exacerbation of cardiac remodeling; and (3) increases in serum norepinephrine levels and sympathetic indices of heart rate variability. Additionally, myocardial RNA-sequencing analysis showed that VMH activation might regulate the HIF-1 and PPAR signal pathway and fatty acid metabolism. qPCR results confirmed that the relative mRNA expression of HIF-1α was increased and the PPARα and CPT-1 mRNA expression were decreased in the HTN+VMH activation group compared to the HTN group. Conclusions: VMH activation could increase SBP and aggravate cardiac remodeling possibly by sympathetic nerve activation and the HIF-1α/PPARα/CPT-1 signaling pathway might be the underlying mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Liu, Liu, Zhou, Xu, Li, Chen, Wang, Zhou, Wang, Lai, Zhou, Zhou and Jiang.)

With increased breeding density, the possibility of hypoxia increases. This study simulated the hypoxic environment (1.2 ± 0.2 mg / L) that may occur within 24 h of aquaculture to stress largemouth bass (Micropterus salmoides). The effects of this environment on related enzymes and genes were examined to explore the effects of hypoxia on lipid metabolism in the liver. Hypoxic stress increased liver triglyceride and non-esterified fatty acid content, and increased lipase (LPS) and lipoprotein lipase (LPL) activities related to fat mobilization. Hypoxia stress also significantly increased the expression levels of genes involved in fatty acid activation and fatty acid transport, including hormone-sensitive triglyceride lipase (HSL), solute carrier family member 27 member 6 (SLC27A6), peroxisomal proliferation activated receptor alpha (PPARA,) and acyl-CoA synthase long-chain family 4 (ACSL4). However, hypoxia stress significantly reduced the expression level of the carnitine palmitoyltransferase 1 (CPT-1) gene, with a downward trend of enzyme activity. The decreased level of CPT-1 was explained by negative regulation by miR-124 and miR-205, as measured by quantitative polymerase chain reaction and dual-luciferase reporter assays. Overall, acute hypoxic stress enhanced lipid mobilization, fatty acid activation, and fatty acid transport, but inhibited fatty acid oxidation by miR-124 and miR-205 down-regulation of CPT-1 expression. These findings provide new insights into the regulation of lipid metabolism in fish under hypoxic stress. Note: Red: up-regulation; Blue: down-regulation; Italics: genes; Non-italics: enzymes. Unlabelled Image • Anaerobic glycolysis was enhanced under acute hypoxia. • Fatty mobilization and fatty acid transport were enhanced under acute hypoxia. • MiR125 and miR-205 down-regulated the CPT-1 to inhibit β -oxidation under acute hypoxia. [ABSTRACT FROM AUTHOR]

Interest in low-carbohydrate, high-fat (LCHF) diets has increased over recent decades given the theorized benefit of associated intramuscular adaptations and shifts in fuel utilization on endurance exercise performance. Consuming a LCHF diet during exercise training increases the availability of fat (i.e., intramuscular triglyceride stores; plasma free fatty acids) and decreases muscle glycogen stores. These changes in substrate availability increase reliance on fat oxidation for energy production while simultaneously decreasing reliance on carbohydrate oxidation for fuel during submaximal exercise. LCHF diet-mediated changes in substrate oxidation remain even after endogenous or exogenous carbohydrate availability is increased, suggesting that the adaptive response driving changes in fat and carbohydrate oxidation lies within the muscle and persists even when the macronutrient content of the diet is altered. This narrative review explores the intramuscular adaptations underlying increases in fat oxidation and decreases in carbohydrate oxidation with LCHF feeding. The possible effects of LCHF diets on protein metabolism and post-exercise muscle remodeling are also considered. [ABSTRACT FROM AUTHOR]

Occurrence of obesity and its associated metabolic disorders continues to escalate. The present study evaluates the anti-obesity effects of ethanolic fruit extract of Terminalia chebula (EETC) on high fat diet induced obese mice. The bioactive compounds present in the EETC is evaluated by Fourier-transform infrared (FT-IR), Gas chromatography-mass spectrometry (GC-MS), and Liquid chromatography-mass spectrometry (LC-MS) analysis. The effects of EETC on energy intake, glucose tolerance, and various biochemical parameters were analyzed using laboratory mice. Relative gene expression of Fatty acid synthase (FAS), Peroxisome proliferator-activated receptors α (PPARα), Carnitine palmitoyltransferase-1 (CPT-1), Tumor necrosis factor alpha (TNF-α) as well as Interleukin 6 (IL-6) were analyzed in liver and adipose tissues. The findings reveal the hypolipidemic and anti-obesity potential of EETC on high fat fed obese mice. EETC exerts its anti-obesity effects by suppressing lipogenesis through reduction in lipogenic enzyme (FAS) expression, increased fatty acid oxidation via PPARα and CPT-1 and by triggering the anti-inflammatory responses. To our knowledge, this is the first report of the effect of EETC on PPARα and CPT-1 in in vivo., (© 2021 Wiley-VCH GmbH.)