PPARα mRNA Expression Research Articles

Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression.

Microbiome is now considered as a significant metabolic organ with an immense potential to influence overall human health. A number of diseases that are associated with pharmacotherapy interventions was linked with altered gut microbiota. Moreover, it has been reported earlier that gut microbiome modulates the fate of more than 30 commonly used drugs and, vice versa, drugs have been shown to affect the composition of the gut microbiome. The molecular mechanisms of this mutual relationship, however, remain mostly elusive. Recent studies indicate an indirect effect of the gut microbiome through its metabolites on the expression of biotransformation enzymes in the liver. The aim of this study was to analyse the effect of gut microbiome on the fate of metronidazole in the mice through modulation of system of drug metabolizing enzymes, namely by alteration of the expression and activity of selected cytochromes P450 (CYPs). To assess the influence of gut microbiome, germ-free mice (GF) in comparison to control specific-pathogen-free (SPF) mice were used. First, it has been found that the absence of microbiota significantly affected plasma concentration of metronidazole, resulting in higher levels (by 30%) of the parent drug in murine plasma of GF mice. Further, the significant interaction between presence/absence of the gut microbiome and effect of metronidazole application, which together influence mRNA expression of CAR, PPARα, Cyp2b10 and Cyp2c38 was determined. Administration of metronidazole itself influenced significantly mRNA expression of Cyp1a2, Cyp2b10, Cyp2c38 and Cyp2d22. Finally, GF mice have shown lower level of enzyme activity of CYP2A and CYP3A than their SPF counterparts. The results hence have shown that, beside direct bacterial metabolism, different expression and enzyme activity of hepatic CYPs in the presence/absence of gut microbiota may be responsible for the altered metronidazole metabolism.

Dietary mulberry-leaf flavonoids supplementation improves liver lipid metabolism and ovarian function of aged breeder hens.

Mulberry-leaf flavonoids (MF), extracted from mulberry leaves, exert antioxidant and hypolipidemic effects. The purpose of this experimental study was to investigate the effects of dietary MF on the ovarian function and liver lipid metabolism of aged breeder hens. We used 270 (60-weeks-old) Qiling breeder hens randomly assigned in 3 treatments with supplemental dietary MF doses (0, 30, 60mg/kg). The results showed that dietary MF significantly improved the egg-laying rate, followed by the reduced feed conversion rate (FCR) (p<0.05). However, there is no obvious difference in hatchability and fertilised eggs hatchability among the three groups (p>0.05). The level of T-CHO, LDL-C and AKP in serum was reduced, and the HDL-C concentrations were increased by dietary MF (p<0.05). MF treatment also improved the antioxidant capacity and reduced the apoptotic index of the ovary (p<0.05). Additionally, dietary MF significantly increased the serum estradiol (E2) levels (p<0.05) and the transcription level of CYP19A1 and LHR in the ovary (p<0.05). Dietary MF enhanced fatty acid β-oxidation in the liver via up-regulating the mRNA expressions of PPARα and CPT-I (p<0.05). Moreover, the HMF group significantly decreased mRNA expressions of SREBP-1c (p<0.05) and increased mRNA expressions of ERα, VTG-Ⅱ and ApoB in the liver (p<0.05). In conclusion, dietary MF could improve the reproduction performance of aged breeder hens through improving ovary function and hepatic lipid metabolism.

Ventromedial Hypothalamus Activation Aggravates Hypertension Myocardial Remodeling Through the Sympathetic Nervous System.

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.

Simvastatin affects the PPARα signaling pathway and causes oxidative stress and embryonic development interference in Mugilogobius abei.

Simvastatin (SV) is a common hypolipidemic drug in clinical medicine that can reduce endogenous cholesterol biosynthesis by inhibiting hydroxyl-methyl-glutaryl coenzyme A reductase. SV took a large market share in the lipid-lowering drugs and it is frequently detected in various water bodies due to its increasing consumption in past years. In the present investigation, we selected a native fish species in the Pearl River Basin in China, Mugilogobius abei (M. abei), to study the effects of SV on non-target aquatic organisms. Results showed that a significant decrease in the volume of adipocytes under SV exposure were observed on oil red O section, and the expression of HMG-CoAR decreased significantly. The mRNA and protein expression of PPARα were significantly up-regulated, the expressions of other genes related to lipid metabolism were up-regulated to varying degrees as well. There was a positive correlation between the concentrations of SV and the protein expressions of plasma phospholipid transfer protein (PLTP) and cholesterolester transfer protein (CETP). In addition, the frozen sections showed that SV led to ROS accumulation in liver in a time and concentration dependent manner. The mRNA and protein expressions of Nrf2 were significantly up-regulated after 24 hours of SV exposure. Some biomarkers associated with antioxidant such as Trx2, TrxR and MDA content were positively correlated with the exposure concentration and time, while the content of GSH decreased sharply. It is noteworthy that the environmentally relevant concentration (0.5 μg/L) of SV exposure caused delayed embryonic development and deformations, decreased hatching rates. We conclude that SV promotes fat metabolism, gives rise to oxidative stress and has significant toxicity on embryo development in M. abei.

The effect of curculigo orchioides (Xianmao) on kidney energy metabolism and the related mechanism in rats based on metabolomics.

The Chinese materia medica Xianmao (XM) is widely used in Chinese clinics and the traditional Chinese medicine diets. Although XM is often used to study its kidney‐yang effect, the research on its effect on kidney energy metabolism and its mechanism is still relatively lacking. In this study, rats were given different doses of XM water extract for 4 weeks. Biochemical method was used to detect the content of serum biochemical indexes of liver and kidney function and blood lipid indicators, and HE staining method was used to observe the histopathological of liver and kidney in rats. The kidney Na+‐K+‐ATPase, Ca2+‐Mg2+‐ATPase, SDH (succinate dehydrogenase) enzyme activity, and the content of ATP in rats were measured. Metabolomics technology was used to analyze the potential biomarkers related to the effects of XM on kidney energy metabolism, and then, the metabolic pathways were analyzed. RT‐PCR was used to detect the expression of Ampk, Sirt1, Ppar‐α, and Pgc‐1α mRNA in kidney of rats. The results showed, compared with the blank control group, there was no significant effect on liver and kidney function in XMH, XMM, and XML groups. These significantly increased the kidney Na+‐K+‐ATPase, Ca2+‐Mg2+‐ATPase, SDH enzyme activity, and ATP content in XMH, XMM, and XML groups. Mitochondrial metabolic rate was inhibited in XMH group, but it was significantly increased in XMM and XML groups. The number of mitochondria was increased in XMH, XMM, and XML groups. Overall, these effects may be mediated by TCA cycle metabolism, butanoate metabolism, propanoate metabolism, alanine, aspartate, and glutamate metabolism, retinol metabolism, purine metabolism, pentose phosphate metabolism, aminoacyl‐tRNA biosynthesis, valine, leucine, and isoleucine biosynthesis, and degradation metabolism pathways, as well as by increasing expression of upstream genes Ampk, Sirt1, Ppar‐α, and Pgc‐1α mRNA.

Possible Synergistic Antidiabetic Effects of Quantified Artemisia judaica Extract and Glyburide in Streptozotocin-Induced Diabetic Rats via Restoration of PPAR-α mRNA Expression.

Simple SummaryA considerable number of diabetic patients are in favour of using oral antidiabetic drugs in combination with certain herbs instead of using oral antidiabetic drugs alone. Artemisia judaica (AJ) is one of the herbs documented to have antidiabetic effects. This study examined the effect of using combination of A. judaica extract (AJE) and the oral hypoglycemic drug glyburide (GLB, 5 mg/kg) on diabetic rats. Fasting blood glucose (FBG), insulin levels, glycated hemoglobin (HbA1c) percentage, serum lipid profile, and oxidative stress biomarkers were estimated. The histopathological examination of the pancreas and the immunohistochemical analysis of anti-insulin, anti-glucagon, and anti-somatostatin protein expressions were also performed. The analysis of the hepatic mRNA expression of peroxisome proliferator-activated receptor α (PPAR-α) and nuclear factor erythroid 2-related factor-2 (Nrf2) genes was performed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Combination of GLB and 500 mg/kg of AJE highly improved FBG, insulin levels, HbA1c, and lipid profile in blood when compared with GLB monotherapy. Furthermore, GLB plus 500 mg/kg of AJE combination was the most successful in restoring insulin content in the β-cells and diminished the levels of glucagon and somatostatin of the α- and δ-endocrine cells in the pancreatic islets, restoring PPAR-α and Nrf2 mRNA expression in the liver. In conclusion, these data indicate that GLB plus 500 mg/kg of AJE combination gives greater glycemic improvement than GLB monotherapy.Several members of the genus Artemisia are used in both Western and African traditional medicine for the control of diabetes. A considerable number of diabetic patients switch to using oral antidiabetic drugs in combination with certain herbs instead of using oral antidiabetic drugs alone. This study examined the effect of Artemisia judaica extract (AJE) on the antidiabetic activity of glyburide (GLB) in streptozotocin (STZ)-induced diabetes. Forty-two male Wistar rats were divided into seven equal groups. Normal rats of the first group were treated with the vehicle. The diabetic rats in the second–fifth groups received vehicle, GLB (5 mg/kg), AJE low dose (250 mg/kg), and AJE high dose (500 mg/kg), respectively. Groups sixth–seventh were treated with combinations of GLB plus the lower dose of AJE and GLB plus the higher dose of AJE, respectively. All administrations were done orally for eight weeks. Fasting blood glucose (FBG) and insulin levels, glycated hemoglobin (HbA1c) percentage, serum lipid profile, and biomarkers of oxidative stress were estimated. The histopathological examination of the pancreas and the immunohistochemical analysis of anti-insulin, anti-glucagon, and anti-somatostatin protein expressions were also performed. The analysis of the hepatic mRNA expression of PPAR-α and Nrf2 genes were performed using quantitative RT-PCR. All treatments significantly lowered FBG levels when compared with the STZ-control group with the highest percentage reduction exhibited by the GLB plus AJE high dose combination. This combination highly improved insulin levels, HbA1c, and lipid profile in blood of diabetic rats compared to GLB monotherapy. In addition, all medicaments restored insulin content in the β-cells and diminished the levels of glucagon and somatostatin of the α- and δ-endocrine cells in the pancreatic islets. Furthermore, the GLB plus AJE high dose combination was the most successful in restoring PPAR-α and Nrf2 mRNA expression in the liver. In conclusion, these data indicate that the GLB plus AJE high dose combination gives greater glycemic improvement in male Wistar rats than GLB monotherapy.

Anti-Obesity and Hypocholesterolemic Actions of Protamine-Derived Peptide RPR (Arg-Pro-Arg) and Protamine in High-Fat Diet-Induced C57BL/6J Mice.

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.

γ-Linolenic Acid Prevents Lipid Metabolism Disorder in Palmitic Acid-Treated Alpha Mouse Liver-12 Cells by Balancing Autophagy and Apoptosis via the LKB1-AMPK-mTOR Pathway.

Excessive fat deposition is the main character in nonalcoholic fatty liver disease (NAFLD), while γ-linolenic acid (GLA) is a polyunsaturated fatty acid that can reduce lipid deposition. This study investigated the effect and regulatory mechanism of GLA (100 μM) on lipid metabolism in alpha mouse liver 12 (AML-12) cells treated by 400 μM palmitic acid (PA). GLA reduced lipid content and increased fatty acid β oxidation, as indicated by decreasing triglyceride and cholesterol contents and increasing mRNA and protein expressions of CPT1α and PPARα. GLA relieved oxidative stress caused by PA, upregulated mRNA levels of superoxide dismutase and glutathione peroxidase, and decreased reactive oxygen species content. GLA reduced apoptosis, as indicated by decreases in the BAX/BCL2 expression level and apoptosis percentage. GLA activated autophagy, autophagosome-lysosome fusion, and LKB1-AMPK-mTOR signaling and upregulated mRNA and protein expressions of Beclin-1, autophagy-related 5, and liver kinase B1 (LKB1). These effects of GLA on lipid metabolism disorders of PA-treated hepatocytes were reversed by autophagy inhibitor 3MA and AMPK inhibitor compound C, confirming our conclusions. Overall, GLA can protect AML-12 cells from lipid metabolism disorder caused by PA via balancing autophagy and apoptosis mediated by the LKB1-AMPK-mTOR pathway. Consequently, GLA, as a dietary supplement, can help to prevent and treat NAFLD by regulating lipid metabolism and autophagy.

Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes.

Heart (right) failure is the most frequent cause of death in patients with pulmonary arterial hypertension. Although historically, increased right ventricular afterload has been considered the main contributor to right heart failure in such patients, recent evidence has suggested a potential role of load-independent factors. Here, we tested the hypothesis that resistin–like molecule α (RELMα), which has been implicated in the pathogenesis of vascular remodeling in pulmonary artery hypertension, also contributes to cardiac metabolic remodeling, leading to heart failure. Recombinant RELMα (rRELMα) was generated via a Tet-On expression system in the T-REx 293 cell line. Cultured neonatal rat cardiomyocytes were treated with purified rRELMα for 24 h at a dose of 50 nM. Treated cardiomyocytes exhibited decreased mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and transcription factors PPARα and ERRα, which regulate mitochondrial fatty acid metabolism, whereas genes that encode for glycolysis-related proteins were significantly upregulated. Cardiomyocytes treated with rRELMα also exhibited a decreased basal respiration, maximal respiration, spare respiratory capacity, ATP-linked OCR, and increased glycolysis, as assessed with a microplate-based cellular respirometry apparatus. Transmission electron microscopy revealed abnormal mitochondrial ultrastructure in cardiomyocytes treated with rRELMα. Our data indicate that RELMα affects cardiac energy metabolism and mitochondrial structure, biogenesis, and function by downregulating the expression of the PGC-1α/PPARα/ERRα axis.

Homeobox A5 and C10 genes modulate adaptation of brown adipose tissue during exercise training in juvenile rats.

What is the central question of this study? Exercise can stimulate brown adipose tissue (BAT) with subsequent increase in uncoupling protein 1 expression and mitochondrial biogenesis. In that case, do BAT-specific Hox genes modify BAT functioning and cause uncoupling protein expression changes due to exercise? What is the main finding and its importance? Exercise enhanced brown adipocyte markers, with significant upregulation of HoxA5 and downregulation of HoxC10 mRNA expression in rat BAT. HoxA5 and HoxC10 are thus likely to play distinct roles in exercise-induced changes in BAT markers during the early postnatal period. These findings provide new insight into the mechanisms underlying exercise-induced changes in BAT function. Brown adipose tissue (BAT) recruitment is involved in increased energy expenditure associated with cold exposure and exercise training. We explored whether exercise training induced changes in expression levels of brown adipocyte-selective factors and Homeobox (Hox) genes during the post-weaning growth period of male Wistar rats. Relative to total body weight, BAT weights alone were lower in exercise-trained (EX) rats compared to sedentary control (SED) rats. mRNA expression of HoxA5 was higher and that of HoxC10 was lower in EX rats than in SED rats, accompanied by both higher citrate synthase activity and protein expression levels for uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor (PPAR) α, and PPARγ-coactivator (PGC)-1α. HoxA5 knockdown with siRNA reduced the expression of PR-domain containing 16 (Prdm16), cell death-inducing DNA fragmentation factor-α-like effector A (Cidea) gene, type 2 deiodinase mRNA, and PRDM16 protein. Comparatively, HoxC10 knockdown with siRNA enhanced mRNA expression of Prdm16, Pparα and Pgc1α and protein expression of UCP1, PPARα and PGC1α in brown adipocytes. The stimulation of brown adipocytes with isoproterenol, a β-adrenoceptor agonist, caused a phenomenon similar to the effect of exercise training on the genes tested: upregulation of HoxA5 mRNA, downregulation of HoxC10 mRNA, and increased protein expression for UCP1 and PGC1α. Collectively, HoxA5 and HoxC10 may have unique functions that contribute to modulating the expression of BAT-selective markers in BAT of juvenile rats during exercise training. The study findings regarding activation and recruitment of BAT during exercise training have implications for anti-obesity management.

Pueraria lobata root polysaccharide alleviates glucose and lipid metabolic dysfunction in diabetic db/db mice

Context Pueraria lobata (Willd.) Ohwi (Fabaceae) root extract can lower blood glucose levels; however, whether Pueraria lobata root polysaccharide (PLP) possesses these effects is still unknown. Objective This study evaluates the therapeutic effect of PLP on diabetic metabolic syndrome. Materials and methods The db/m mice were assigned to normal control group (NC), db/db mice were divided into four groups randomly (n = 8). The db/db mice received rosiglitazone (10 mg/kg BW) or PLP (100 or 200 mg/kg BW) via oral gavage for 6 weeks. Afterward, blood glucose, insulin, and glycogen content were assayed, and insulin tolerance test (ITT), oral glucose tolerance test (OGTT) were performed. Glucose and lipid metabolism-related parameters and gene expression levels were assayed by ELISA and RT-PCR, respectively. Results After treatment with HPLP, the values of body weight, epididymal fat, subcutaneous fat, fasting blood glucose, insulin, and HOMA-IR decreased to 45.89 ± 1.66 g, 1.65 ± 0.14 g, 1.97 ± 0.16 g, 14.84 ± 1.52 mM, 9.35 ± 0.98 mU/L, and 5.56 ± 1.26, respectively; the levels of TG, TC, LDL-C, and FFA decreased to 1.67 ± 0.11 mmol/L, 6.23 ± 0.76 mmol/L, 1.29 ± 0.07 mmol/L, and 1.71 ± 0.16 mmol/L, respectively. HPLP down-regulated PEPCK, G6PC, FOXO1, SREBP-1, and ACC mRNA expression (p < 0.01), and up-regulated GS, Akt2, PI3K, GLUT2, PPARα, and LDLR mRNA expression in the liver (p < 0.01). Discussion and conclusion PLP exerts antidiabetic effects via activating the PI3K/AKT signalling pathway, thus improving insulin resistance, glucose, and lipid metabolism in db/db mice. Thus, PLP may be considered as a potential antidiabetic agent in clinical therapy.

Honokiol Alleviates Methionine-Choline Deficient Diet-Induced Hepatic Steatosis and Oxidative Stress in C57BL/6 Mice by Regulating CFLAR-JNK Pathway.

Background Honokiol (HNK) has been reported to possess various beneficial effects in the context of metabolic disorders, including fatty liver, insulin resistance, and oxidative stress which are closely related to nonalcoholic steatohepatitis (NASH), however with no particular reference to CFLAR or JNK. Methods C57BL/6 mice were fed methionine-choline-deficient (MCD) diet and administered simultaneously with HNK (10 and 20 mg/kg once a day, ig) for 6 weeks, and NCTC1469 cells were pretreated, respectively, by oleic acid (OA, 0.5 mmol/L) plus palmitic acid (PA, 0.25 mmol/L) for 24 h, and adenovirus-down Cflar for 24 h, then exposed to HNK (10 and 20 μmol/L) for 24 h. Commercial kits, H&E, MT, ORO staining, RT-qPCR, and Western blotting were used to detect the biomarkers, hepatic histological changes, and the expression of key genes involved in NASH. Results The in vivo results showed that HNK suppressed the phosphorylation of JNK (pJNK) by activating CFLAR; enhanced the mRNA expression of lipid metabolism-related genes Acox, Cpt1α, Fabp5, Gpat, Mttp, Pparα, and Scd-1; and decreased the levels of hepatic TG, TC, and MDA, as well as the levels of serum ALT and AST. Additionally, HNK enhanced the protein expression of oxidative stress-related key regulatory gene NRF2 and the activities of antioxidases HO-1, CAT, and GSH-Px and decreased the protein levels of prooxidases CYP4A and CYP2E1. The in vivo effects of HNK on the expression of CLFAR, pJNK, and NRF2 were proved by the in vitro experiments. Moreover, HNK promoted the phosphorylation of IRS1 (pIRS1) in both tested cells and increased the uptake of fluorescent glucose 2-NBDG in OA- and PA-pretreated cells. Conclusions HNK ameliorated NASH mainly by activating the CFLAR-JNK pathway, which not only alleviated fat deposition by promoting the efflux and β-oxidation of fatty acids in the liver but also attenuated hepatic oxidative damage and insulin resistance by upregulating the expression of NRF2 and pIRS1.

L-carnitine exerts a nutrigenomic effect via direct modulation of nuclear receptor signaling in adipocytes, hepatocytes and SKMC, demonstrating its nutritional impact

L-carnitine is an indispensable metabolite facilitating the transport of fatty acids into the mitochondrial matrix and has been previously postulated to exert a nutrigenomic effect. However, the underlying molecular mechanisms remain mostly unclear. We hypothesized that L-carnitine interacts with nuclear receptors involved in metabolic regulation, thereby modulating downstream targets of cellular metabolism. Therefore, we investigated the effect of L-carnitine supplementation on protein activity, mRNA expression, and binding affinities of nuclear receptors as well as mRNA expression of downstream targets in skeletal muscle cells, hepatocytes, and differentiated adipocytes. L-carnitine supplementation to hepatocytes increased the protein activity of multiple nuclear receptors (RAR, RXR, VDR, PPAR, HNF4, ER, LXR). Diverging effects on the mRNA expression of PPAR-α, PPAR-δ, PPAR-γ, RAR-β, LXR-α, and RXR-α were observed in adipocytes, hepatocytes, and skeletal muscle cells. mRNA levels of PPAR-α, a key regulator of lipolysis and β-oxidation, were significantly upregulated, emphasizing a role of L-carnitine as a promoter of lipid catabolism. L-carnitine administration to hepatocytes modulated the transcription of key nuclear receptor target genes, including ALDH1A1, a promoter of adipogenesis, and OGT, a contributor to insulin resistance. Electrophoretic mobility shift assays proved L-carnitine to increase binding affinities of nuclear receptors to their promoter target sequences, suggesting a molecular mechanism for the observed transcriptional modulation. Overall, these findings indicate that L-carnitine modulates the activity and expression of nuclear receptors, thereby promoting lipolytic gene expression and decreasing transcription of target genes linked to adipogenesis and insulin resistance.

Effect of Lactobacillus plantarum KFY02 isolated from naturally fermented yogurt on the weight loss in mice with high-fat diet-induced obesity via PPAR-α/γ signaling pathway

• Lactobacillus plantarum KFY02 was newly isolated from the naturally fermented milk yogurt in Korla of Xinjiang. • The study used a high-fat diet (HFD) to induce obese mice. The normal group was fed 10% fat diet, and the other groups were fed 45% HFD. • Observation of pathological changes showed that LP-KFY02 could alleviate the damage caused by obesity on the tissue samples from the liver of mice and reduce the expansion of fat cells. • The results of qPCR and western blot experiments further showed that LP-KFY02 could effectively up-regulate the mRNA and protein expression of LPL, PPAR-α, CYP7A1 and CPT1A in the liver and epididymal adipose tissues, as well as cut down the mRNA and protein expression of PPAR-γ and C/EBP-α. • LP-KFY02 could effectively treat obesity arose from HFD, and its effect is comparable to commercially available L-carnitine, and superior to the Lactobacillus delbruechii subsp. bulgaricus commonly used in industry. In this study, an in vivo lipid-lowering animal experiment was performed on Lactobacillus plantarum KFY02 (LP-KFY02) newly isolated from Xinjiang fermented yogurt. The study used a high-fat diet (HFD) to induce obese mice. Serum and tissue samples from mice were examined by molecular biological detection. The results indicated that LP-KFY02 could inhibit increases in various organ indexes of mice caused by HFD. LP-KFY02 could reduce the levels of alkaline phosphatase (AKP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c) in the serum and liver of obese mice with HFD and improve high-density lipoprotein cholesterol (HDL-C) levels. Observation of pathological changes also showed that LP-KFY02 could alleviate the damage caused by obesity on the tissue samples from the liver of mice and reduce the expansion of fat cells. The results of qPCR experiments further showed that LP-KFY02 could effectively up-regulate the mRNA expression of lipoprotein lipase (LPL), peroxisome proliferative-activating receptor α (PPAR-α), cholesterol 7α-hydroxylase (CYP7A1), and carnitine palmitoyltransferase 1A (CPT1A) in the liver and epididymal adipose tissues, as well as cut down the mRNA expression of peroxisome proliferative-activating receptor γ (PPAR-γ) and CCAAT enhancer-binding proteins (C/EBP-α). Furthermore, ELISA results showed LP-KFY02 obviously decreased the level of pro-inflammatory factors interleukin (IL)-6, TNF-α, IL-1β and IFN-γ in serum, but increased the anti-inflammatory factors IL-4 and IL-10 content. LP-KFY02 could effectively treat obesity arose from HFD, and its effect is comparable to commercially available L-carnitine, and superior to the Lactobacillus delbruechii subsp . bulgaricus commonly used in industry. LP-KFY02 is a health beneficial strain with probiotic potential.

Protective effect of Yi-Qi-Huo-Xue Decoction against ischemic heart disease by regulating cardiac lipid metabolism.

Yi-Qi-Huo-Xue Decoction (YQHX) is the recombination of Dang-Gui-Bu-Xue Decoction (DBD), which is one of the well-known traditional Chinese Medicine (TCM) prescription, and has long been shown to have significant protective effects against myocardial ischemic injury. In previous studies, we found that YQHX could regulate lipid and glucose metabolism, promote angiogenesis, attenuate inflammatory response, and ameliorate left ventricular function in myocardial ischemia rat models. However, the underlying mechanism of how YQHX involves in lipid metabolism remains unclear so far. In this study, the underlying mechanism of YQHX in lipid metabolism disorders was elucidated in a myocardial ischemia rat model and a hypoxia-induced H9c2 cell injury model. YQHX (8.2 g·kg-1) and positive-control drug trimetazidine (10 mg·kg-1) were administered daily on the second day after left anterior descending (LAD) operation. At 7 days and 28 days after surgery, changes of cardiac morphology, structure, and function were evaluated by H&E staining and echocardiography, respectively. The plasma lipid levels and mitochondrial ATP content were also evaluated. Western blot and RT-PCR were used to determine the protein and mRNA expressions of AMPK, PGC-1α, CPT-1α, and PPARα. YQHX improved cardiac function and ameliorated lipid metabolism disorders. Furthermore, YQHX increased the expression of p-AMPK, PGC-1α, and CPT-1α without changing PPARα in ischemic rat myocardium. In vitro, YQHX activated the protein and mRNA expression of PGC-1α, CPT-1α, and PPARα in hypoxia-induced H9c2 cells injury, whereas AMPK inhibitor Compound c blocked the effects of YQHX. Taken together, the results suggest that YQHX reduces lipid metabolism disorders in myocardial ischemia via the AMPK-dependent signaling pathway.

Malus hupehensis leaves extract attenuates obesity, inflammation, and dyslipidemia by modulating lipid metabolism and oxidative stress in high‐fat diet‐induced obese mice

Malus hupehensis leaves (MHL) are used to make traditional Chinese tea. In this study, MHL extract was shown to improve metabolic disorders and inflammatory response in high-fat diet-induced obese mice. MHL extract could reduce body weight, and significantly alleviate liver damage and fat accumulation. MHL extract caused a decrease in the levels of ALT, AST, AKP, TC, TG, LDL-C, and an increase in the level of HDL-C. It also caused a decrease in inflammatory cytokines, including TNF-α, IFN-γ, IL-1β, IL-6, and an increase in the anti-inflammatory cytokine IL-10 and IL-4. MHL extract could upregulate mRNA expression of PPAR-α, LPL, CPT1, CYP7A1, SOD1, SOD2, CAT, GSH1, and GSH-Px and downregulate that of PPAR-γ and C/EBP-α in the liver of obese mice. In conclusion, our work represents the first study demonstrating that MHL extract possesses an anti-obesity effect and alleviates obesity-related symptoms, including dyslipidemia, chronic low-grade inflammatory, and liver damage. PRACTICAL APPLICATIONS: The research may contribute to the development and application of MHL as functional foods or dietary supplement to fight against obesity.

Network pharmacology analysis and experimental validation to explore the mechanism of sea buckthorn flavonoids on hyperlipidemia

Ethnopharmacological relevanceSea buckthorn is popularly used as a herbal medicine and food additive in the world. Sea buckthorn flavonoids (SF) is reported to have an ameliorative effect on obesity and hyperlipidemia (HLP). AimTo identify the major bioactive compounds and the lipid-lowering mechanism of SF. MethodsWe used network pharmacology analysis and in vitro experiments to identify the major bioactive compounds and the lipid-lowering mechanism of SF. ResultsA total of 12 bioactive compounds, 60 targets related to SF and HLP were identified, and a component-target-disease network was constructed. The KEGG analysis revealed that SF regulated cholesterol metabolism, fat digestion and absorption, and PPAR signaling pathways in HLP. The experimental validation indicated that sea buckthorn flavonoids extract (SFE) and 4 bioactive compounds reduced lipid droplet accumulation, up-regulated the mRNA expression of PPAR-γ, PPAR-α, ABCA1 and CPT1A, etc, down-regulated SREBP-2 and its target gene LDLR, which are closely related to cholesterol conversion into bile acids, de novo synthesis and fatty acids oxidation. The major bioactive flavonoid isorhamnetin (ISOR) also increased the protein expression of PPAR-γ, LXRα and CYP7A1. ConclusionSF might promote cholesterol transformation into bile acids and cholesterol efflux, inhibit cholesterol de novo synthesis and accelerate fatty acids oxidation for ameliorating HLP.

Anti-Diabetic Effects of Curcumin-Magnesium Oxide Nanoparticles Conjugate in Type 2 Diabetic Rats

Diabetes is a disorder that impairs the ability of the body to process blood glucose. Diabetes is either due to the pancreas produces insufficient amount of insulin or the cells of the body do not react with the insulin produced. Type 2 diabetes (diabetes mellitus) is the most common type of diabetes and grows in prevalence worldwide. The aim of our study was to investigate the anti-diabetic impact with emphasis on hepatic lipid metabolism and spleen histopathology effect of curcumin-magnesium oxide nanoparticles conjugate (Cur-MgO NPs conjugate) in nicotinamide (NA)-streptozotocin (STZ) induced type 2 diabetic rats. This study included three groups: Group 1 (control group), Group 2 (STZ induced type 2 diabetic rats) and Group 3 (type 2 diabetic rats were orally administered Cur-MgO NPs conjugate (10 mg/Kg BW/day for 45 days)). The levels of plasma glucose, serum insulin, lipid profile and hepatic expression of lipogenic enzymes Malonyl-CoA decarboxylase (MCD), Peroxisome proliferator-activated receptor alpha (Ppar α) were measured. Moreover, histopathological examination of spleen was carried out. The assessment of Insulin Resistance (HOMA-IR), a significant reduction in serum insulin level and HOMA of β-cell function (HOMA β). Also, reduction in hepatic mRNA expression of MCD and Ppar-α and an altered lipid profile were noticed in diabetic group in comparison with the control group. Oral administration of Cur-MgO NPs conjugate restored glucose (102.73±2.16), TC (139.80±3.61) and LDL-c (87.56±3.72) to their physiological levels in the control group (108.29±2.45, 150.27±2.56 and 94.43±2.75 respectively). Histopathological examination of the spleen showed damage of lymphoid cells in type 2 diabetes (T2D), while in treated group showed moderate improvement in spleen tissue and cells are rescued from apoptosis. The outcome of present study revealed that Cur-MgO NP conjugate has potential ameliorative effect on the hematologic, immunologic and hepatic metabolic alterations in type 2 diabetic rats.

Skeletal Muscle Angiopoietin-Like Protein 4 and Glucose Metabolism in Older Adults after Exercise and Weight Loss.

Angiopoietin-like protein 4 (ANGPTL4) is an adipokine that plays an important role in energy homoeostasis and lipid and lipoprotein metabolism. This study was designed to determine the effect of an exercise plus weight loss intervention on ANGPTL4 expression and its relationship with metabolic health. Thirty-five obese sedentary men (n = 18) and postmenopausal women (n = 17), (X ± SEM, age: 61 ± 1 years, BMI: 31.3 ± 0.7 kg/m2, VO2max: 21.7 ± 0.9 L/kg/min) completed a 6 month program of 3×/week aerobic exercise and 1×/week dietary instruction to induce weight loss (AEX + WL). Participants underwent vastus lateralis muscle biopsies, a hyperinsulinemic–euglycemic clamp, oral glucose tolerance tests and body composition testing. Basal skeletal muscle ANGPTL4 mRNA was lower in men than women (p < 0.01). Peroxisome proliferator-activated receptor (PPAR) alpha (PPARα) mRNA expression was higher in men than women (p < 0.05). There were no significance changes in serum or skeletal muscle ANGPTL4 (basal or insulin-stimulated) or muscle PPARα mRNA expression after AEX + WL. Muscle mRNA ANGPTL4 is correlated with serum ANGPTL4 (r = 0.41, p < 0.05), body fat (r = 0.64, p < 0.0001), and glucose utilization (r = 0.38, p < 0.05). AEX + WL does not change basal or insulin-stimulated skeletal muscle ANGPTL4 mRNA expression, suggesting other factors contribute to improved insulin sensitivity after the loss of body fat and improved fitness.

Aurantio-obtusin improves obesity and insulin resistance induced by high-fat diet in obese mice.

Aurantio-obtusin (AUR) is the main bioactive compound among the anthraquinones, from Cassia seed extract. This study was conducted to identify whether AUR could improve obesity and insulin resistance, induced by a high-fat diet in obese mice. Mice were fed a high-fat diet for 6 weeks and were then assigned to the high-fat diet (HFD) control group, the AUR 5 mg/kg group, or the AUR 10 mg/kg group. AUR improves glucose by activating the expression of PI3K, Akt and GLUT4, GLUT2. AUR altered the expression levels of several lipid metabolism-related and adipokine genes. AUR decreased the mRNA expression of PPAR-γ, FAS and increased the mRNA expression of PPAR-α in liver. AUR lowered SREBP-1c, FAS, SCD-1, inflammatory cytokines, and increased the expression of PPAR-γ, PPAR-α, CPT-1, and adiponectin in white adipose tissue (WAT). AUR docking with the insulin receptor showed that the residues of the insulin receptor, ectodomain, were the same as those around the emodin. The effect of AUR may be elicited by regulating the activity of the insulin signaling pathway, expression of lipid metabolism-related genes, and expression of inflammatory cytokine markers to improve adiposity, insulin resistance, and dyslipidemia.