Regulator Peroxisome Proliferator-activated Receptor Research Articles

Fucoxanthin ameliorates hyperglycemia, hyperlipidemia and insulin resistance in diabetic mice partially through IRS-1/PI3K/Akt and AMPK pathways

Fucoxanthin has potential anti-diabetic activities, but its precise effects and underlying mechanisms remain unclear. In this study, C57BL/KsJ-db/db mice were fed diets containing fucoxanthin (0.2% and 0.4%, w/w) for 6 weeks. Results showed dietary fucoxanthin significantly improved glucose/lipid metabolism and insulin resistance, and prevented pancreatic histological changes in db/db mice. Moreover, fucoxanthin markedly lowered blood glucose by regulating glucokinase and phosphoenolpyruvate carboxykinase mRNA expressions in liver, promoted glycogen synthesis by regulating glucose transporter 4, glycogen synthase and glycogen synthase kinase-3 beta protein expressions in skeletal muscle, and lowered blood lipid levels by regulating peroxisome proliferator-activated receptor alpha, p-acetyl CoA carboxylase, carnitine palmitoyltransferase 1 and fatty acid synthetase protein expressions in liver. Mechanistic studies indicated that fucoxanthin effectively regulates the expression of IRS-1/PI3K/AKT and AMPK signaling proteins in liver and skeletal muscle. All results suggested that fucoxanthin is a potential functional food or effective drug for type 2 diabetes mellitus.

Mechanistic Insights Into the Interaction Between Transcription Factors and Epigenetic Modifications and the Contribution to the Development of Obesity

Objective: The development of obesity is inseparable from genetic and epigenetic factors, and transcription factors (TFs) play an essential role in these two mechanisms. This review analyzes the interaction of TFs with epigenetic modifications and the epigenetic mechanisms underlying peroxisome proliferator-activated receptor (PPAR)γ, an important transcription factor, in the development of obesity.Methods: We describe the relationship between TFs and different epigenetic modifications and illustrate the several mechanisms described. Next, we summarize the epigenetic mechanisms of PPARs, an important class of transcription factors involved in obesity, that induce obesity with different triggering factors. Finally, we discuss the mechanisms of epigenetic modification of PPAR-related ligands in lipid metabolism and propose future avenues of research.Results: TFs participate in epigenetic modifications in different forms, causing changes in gene expression. The interactions between the different epigenetic modifications and PPARs are important biological developments that affect fat tissue differentiation, lipogenesis, and lipid metabolism, thereby inducing or inhibiting the development of obesity. We then highlight the need for more research to understand the role of epigenetic modifications and PPARs.Conclusions: Epigenetic mechanisms involved in the regulation of PPARs may be excellent therapeutic targets for obesity treatment. However, there is a need for a deeper understanding of how PPARs and other obesity-related transcription factors interact with epigenetic modifications.

Functional Regulation of PPARs through Post-Translational Modifications.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug development for the management of metabolic disorders. The function of PPARs is mainly regulated through ligand binding, which induces structural changes, further affecting the interactions with co-activators or co-repressors to stimulate or inhibit their functions. In addition, PPAR functions are also regulated by various Post-translational modifications (PTMs). These PTMs include phosphorylation, SUMOylation, ubiquitination, acetylation, and O-GlcNAcylation, which are found at numerous modification sites. The addition of these PTMs has a wide spectrum of consequences on protein stability, transactivation function, and co-factor interaction. Moreover, certain PTMs in PPAR proteins have been associated with the status of metabolic diseases. In this review, we summarize the PTMs found on the three PPAR isoforms PPARα, PPARβ/δ, and PPARγ, and their corresponding modifying enzymes. We also discuss the functional roles of these PTMs in regulating metabolic homeostasis and provide a perspective for future research in this intriguing field.

Development of a novel monoclonal antibody against 4-hydroxy-2E,6Z-dodecadienal (4-HDDE)-protein adducts: Immunochemical application in quantitative and qualitative analyses of lipid peroxidation in vitro and ex vivo

Non-enzymatic peroxidation of polyunsaturated fatty acids (PUFA) results in the formation of various α,β-unsaturated aldehydes, of which 4-hydroxyalkenals are abundant. The propensity of n-6 PUFA, such as linoleic acid, γ-linolenic acid and arachidonic acid, to undergo radical-induced peroxidation and generate 4-hydroxy-2E-nonenal (4-HNE) has been widely demonstrated. The ability of the latter to form covalent adducts with macromolecules and modify cellular functions has been linked to numerous pathological processes. Concomitantly, evidence has accumulated on specific signaling properties of low concentrations of 4-HNE that may induce hormetic and protective responses to peroxidation stress in cells. It has long been known that peroxidation of PUFA, and particularly arachidonic acid, also give rise to 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), which is more chemically reactive than 4-HNE. Few studies on 4-HDDE revealed its ability to avidly interact covalently with electronegative moieties in macromolecules and to its ability to selectively activate the transcriptional regulator Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ. The research on 4-HDDE has been impeded due to the lack of available pure 4-HDDE and antibodies that recognize 4-HDDE-modified epitopes in proteins. The purpose of this study was to employ an established procedure to synthesize 4-HDDE and use it to create and characterize a monoclonal antibody against 4-HDDE-modified proteins and establish its application for ELISA and immunohistochemical analysis of cells and tissues and further expand lipid peroxidation research.

NADPH Oxidases and Mitochondria in Vascular Senescence.

Aging is the major risk factor in the development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and myocardial infarction. Oxidative stress caused by overproduction of reactive oxygen species (ROS) and/or by reduced expression of antioxidant enzymes is a major contributor to the progression of vascular senescence, pathologic remodeling of the vascular wall, and disease. Both oxidative stress and inflammation promote the development of senescence, a process by which cells stop proliferating and become dysfunctional. This review focuses on the role of the mitochondria and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases Nox1 and Nox4 in vascular senescence, and their contribution to the development of atherosclerosis. Recent findings are reviewed, supporting a critical role of the mitochondrial regulator peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α), the inflammatory gene nuclear factor κB (NF-κB), zinc, the zinc transporters (ZnTs) ZnT3 and ZnT10, and angiotensin II (Ang II) in mitochondrial function, and their role in telomere stability, which provides new mechanistic insights into a previously proposed unified theory of aging.

Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia

GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and −12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor α (PPARα) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57Bl/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart.

RSjP40 protein promotes PPARγ expression in LX-2 cells through microRNA-27b.

miR-27b is reported to participate in the proliferation and differentiation of hepatic stellate cells (HSCs) and to regulate fat metabolism of rat HSCs by targeting retinoid X receptor α. Our previous study also indicated that the recombinant P40 protein from Schistosoma japonicum (rSjP40) inhibited the activation of HSCs. In this study, we observed the expression of miR-27b in rSjP40-treated LX-2 cells and explored its potential mechanisms. Quantitative real-time PCR showed that rSjP40 inhibits the expression of miR-27b in LX-2 cells. Further results obtained by Western blot and dual-luciferase reporter assay confirmed that miR-27b regulates peroxisome proliferator-activated receptor γ (PPARγ) expression in rSjP40-treated LX-2 cells by targeting the 3'-UTR of PPARγ. 5-AZA-2'-deoxycytidine (5-AZA-dC), which inhibits methylation of HSCs, partially reversed rSjP40-induced down-regulation expression of miR-27b in LX-2 cells. 5-AZA-dC also partially reversed rSjP40-induced up-regulation expression of PPARγ in LX-2 cells. The increased expression of PPARγ in rSjP40-treated LX-2 cells may be partially due to miR-27b methylation. Therefore, our study provides further insight into the mechanism by which rSjP40 inhibits HSC activation and provides a basis for future study of the blocking effect of rSjP40 in liver fibrosis.-Zhu, D., Lyu, L., Shen, P., Wang, J., Chen, J., Sun, X., Chen, L., Zhang, L., Zhou, Q., Duan, Y. rSjP40 protein promotes PPARγ expression in LX-2 cells through microRNA-27b.

Erratum for Salma et al., "Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor γ2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice".

Erratum for Salma et al., "Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor γ2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice".

The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPAR\u03b3

Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.

Effect of regulating peroxisome proliferator-activated receptor γ on soluble endoglin expression in first-trimester trophoblasts

Objective To investigate the effect of regulating peroxisome proliferator-activated receptor γ (PPARγ) on soluble endoglin (sEng) expression in first-trimester trophoblasts via an in vitro study. Methods Chorionic villus were collected from 20 samples of first-trimester artificial abortion in Peking University First Hospital from July 1st to 31st, 2016. Primary culture of trophoblast cells was performed. Trophoblast cells from each sample were divided into three groups, which were PPARγ antagonist group, PPARγ antagonist and PPARγ agonist group, and control group. Supernatant sEng level was detected in each group by enzyme linked immunosorbent assay (ELISA). Paired-sample t test was used for statistical analysis. Results Compared with the control group, trophoblast cells in the PPARγ antagonist group grew slower and were reduced in number. No significant difference in growth or morphology of trophoblast cells was observed between the PPARγ antagonist and PPARγ agonist group and the control group. Supernatant sEng level was elevated in the PPARγ antagonist group, but was not significantly changed in the PPARγ antagonist and PPARγ agonist group as compared with that in the control group [(124.1±23.8) vs (94.0±12.7) pg/ml, t=4.31, P<0.05; (87.1±10.6) vs (94.0±12.7) pg/ml, t=1.62, P=0.12). Conclusions Suppression of PPARγ promotes sEng expression in trophoblast cells and that can be reversed by PPARγ agonist. Key words: Pregnancy trimester, first; Trophoblasts; PPARγ; Antigens, CD; Receptors, cell surface; Pre-eclampsia

Small heterodimer partner (SHP) deficiency protects myocardia from lipid accumulation in high fat diet-fed mice.

The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. We investigated the effect of SHP expression on myocardia assessing not only heart structure and function but also lipid metabolism and related gene expression in a SHP deletion animal model. Transcriptional profiling with a microarray revealed that genes participating in cell growth, cytokine signalling, phospholipid metabolism, and extracellular matrix are up-regulated in the myocardia of SHP knockout (KO) mice compared to those of wild-type (WT) mice (nominal p value < 0.05). Consistent with these gene expression changes, the left ventricular masses of SHP KO mice were significantly higher than WT mice (76.8 ± 20.5 mg vs. 52.8 ± 6.8 mg, P = 0.0093). After 12 weeks of high fat diet (HFD), SHP KO mice gained less weight and exhibited less elevation in serum-free fatty acid and less ectopic lipid accumulation in the myocardium than WT mice. According to microarray analysis, genes regulated by PPARγ1 and PPARα were down-regulated in myocardia of SHP KO mice compared to their expression in WT mice after HFD, suggesting that the reduction in lipid accumulation in the myocardium resulted from a decrease in lipogenesis regulated by PPARγ. We confirmed the reduced expression of PPARγ1 and PPARα target genes such as CD36, medium-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase by SHP KO after HFD.

Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling

The prevalence of cardiomyopathy from metabolic stress has increased dramatically; however, its molecular mechanisms remain elusive. Here, we show that extracellular signal-regulated protein kinase 5 (Erk5) is lost in the hearts of obese/diabetic animal models and that cardiac-specific deletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractility and mitochondrial abnormalities with repressed fuel oxidation and oxidative damage upon high fat diet (HFD). Erk5 regulation of peroxisome proliferator-activated receptor γ co-activator-1α (Pgc-1α) is critical for cardiac mitochondrial functions. More specifically, we show that Gp91phox activation of calpain-1 degrades Erk5 in free fatty acid (FFA)-stressed cardiomyocytes, whereas the prevention of Erk5 loss by blocking Gp91phox or calpain-1 rescues mitochondrial functions. Similarly, adeno-associated virus 9 (AAV9)-mediated restoration of Erk5 expression in Erk5-CKO hearts prevents cardiomyopathy. These findings suggest that maintaining Erk5 integrity has therapeutic potential for treating metabolic stress-induced cardiomyopathy.

Differential tissue regulation of peroxisome proliferator-activated receptor α (PPARα) and cannabinoid receptor 1 (CB1) gene transcription pathways by diethylene glycol dibenzoate (DEGB): preliminary observations in a seabream (Sparus aurata) in vivo model

Today a variety of endocrine disrupting chemicals (EDCs) are recognized in the group of metabolic disruptors, a wide range of environmental contaminants that alter energy balance regulation by affecting the peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) pathway. Herein, we investigated the effect of diethylene glycol dibenzoate (DEGB), a dibenzoate-based plasticizer used as alternative to phthalates, on the expression of key genes involved in lipid metabolism and energy balance by using Sparus aurata juveniles as models. We also evaluated the correlation between cannabinoid receptor 1 (CB1) and PPARα transcriptional patterns in both liver and brain tissues. Exposure to the highest DEGB concentration differentially modulated PPARα/CB1 transcriptional pathways in liver/brain tissues of seabream. We hypothesize that, at peripheral level (i.e. liver), DEGB acts as PPARα agonist resulting in a potential stimulation of key lipolytic genes and a concomitant down-regulation of endocannabinoid metabolic enzyme genes.

Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor γ2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice.

Members of the MiT transcription factor family are pivotal regulators of several lineage-selective differentiation programs. We show that two of these, Tfeb and Tfe3, control the regulator of adipogenesis, peroxisome proliferator-activated receptor γ2 (Pparγ2). Knockdown of Tfeb or Tfe3 expression during in vitro adipogenesis causes dramatic downregulation of Pparγ2 expression as well as adipogenesis. Additionally, we found that these factors regulate Pparγ2 in mature adipocytes. Next, we demonstrated that Tfeb and Tfe3 act directly by binding to consensus E-boxes within the Pparγ transcriptional regulatory region. This transcriptional control also exists in vivo, as we discovered that wild-type mice in the fed state increased their expression of Tfe3, Tf3b, and Pparγ in white adipose tissue. Furthermore, Tfe3 knockout (Tfe3KO) mice in the fed state failed to upregulate Pparγ and the adiponectin gene, a Pparγ-dependent gene, confirming the in vivo role for Tfe3. Lastly, we found that blood glucose is elevated and serum adiponectin levels are suppressed in the Tfe3KO mice, indicating that the Tfe3/Tfeb/Pparγ2 axis may contribute to whole-body energy balance. Thus, we offer new insights into the upstream regulation of Pparγ by Tfe3/Tf3b and propose that targeting these transcription factors may offer opportunities to complement existing approaches for the treatment of diseases that have dysregulated energy metabolism.

Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice

ObjectiveWe have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis. MethodsTo test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding. ResultsIn contrast to wild-type (WT) controls, β-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, β-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of β-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and β-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed β-less mice. ConclusionsThe response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms.

Comparison of Sirtuin 3 Levels in ALS and Huntington's Disease-Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models.

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers.

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs' expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.

Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1α gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. The epidermal growth factor receptor (EGFR) inhibitor erlotinib blocked ERK1/2 phosphorylation and increased PGC-1α gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1α and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the down-regulation of PGC-1α and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/FOXO3a/1/PGC-1α, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1α and subsequently decreasing MB.

Hypoglycaemic activity of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione in streptozotocin-induced diabetic mice through ameliorating metabolic function and regulating peroxisome proliferator-activated receptor γ.

IntroductionDiabetes mellitus is characterized by hyperglycaemia causing changes in plasma lipoproteins, which leads to insulin resistance, secretion defects or both. The present study aimed to evaluate the ability of 2-dodecyl-6-methoxy-cyclohexa-2,5-diene-1,4-dione (DMDD) isolated from Averrhoa carambola L. roots to lower hyperglycaemia and to investigate its potential mechanism in diabetic mice.Material and methodsDMDD was isolated using a column chromatographic technique. Experimental mice were fed with a high-fat diet for a month and were intravenously injected with streptozotocin (80 mg/kg, single dose). Diabetic mice were orally administered DMDD (12.5, 25, 50 mg/kg) and 50 mg/kg pioglitazone for 15 days. Fasting blood glucose (FBG), fasting blood insulin (FINS), pancreatic insulin content, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), as well as serum total cholesterol (TC), triglyceride (TG) and free fatty acid (FFA) were determined. Adipose tissue was assessed by histological examination, immunohistochemistry, western blot and reverse transcription-polymerase chain reaction methods.ResultsDMDD significantly increased the insulin level (all p < 0.05). In contrast, FBG, IL-6, TNF-α, TC, TG and FFA were significantly decreased (all p < 0.05). However, DMDD induced the activation of adipocyte peroxisome proliferator-activated receptor γ (PPAR-γ), confirmed by increased protein and mRNA expression of PPAR-γ.ConclusionsDMDD possessed hypoglycaemic activity due to its potential mechanism involving PPARγ-mediated adipocyte endocrine regulation.

Activation of peroxisome proliferator-activated receptor-γ by a 12/15-lipoxygenase product of arachidonic acid: a possible neuroprotective effect in the brain after experimental intracerebral hemorrhage.

OBJECTIVE In this study, the authors investigated the involvement of 15( S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in the regulation of peroxisome proliferator-activated receptor-γ (PPARγ) after intracerebral hemorrhage (ICH) and its effects on hemorrhage-induced inflammatory response and oxidative stress in an experimental rodent model. METHODS To simulate ICH in a rat model, the authors injected autologous whole blood into the right striatum of male Sprague-Dawley rats. The distribution and expression of 12/15-lipoxygenase (12/15-LOX) were determined by immunohistochemistry and Western blot analysis, respectively. Immunofluorescent double labeling was used to study the cellular localization of 12/15-LOX, and 15(S)-HETE was measured with a 15(S)-HETE enzyme immunoassay kit. Neurological deficits in the animals were assessed through behavioral testing, and apoptotic cell death was determined with terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling. RESULTS Rats with ICH had increased expression of 12/15-LOX predominantly in neurons and also in oligodendrocytes, astrocytes, and microglia. Moreover, ICH elevated production of 15(S)-HETE in the brain area ipsilateral to the blood injection. The PPARγ agonist, exogenous 15(S)-HETE, significantly increased PPARγ protein levels and increased PPARγ-regulated gene (i.e., catalase) expression in the ICH rats. Reduced expression of the gene for the proinflammatory protein nuclear factor κB coincided with decreased neuron damage and improved functional recovery from ICH. A PPARγ antagonist, GW9662, reversed the effects of exogenous 15(S)-HETE on the PPARγ-regulated genes. CONCLUSIONS The induction of 15(S)-HETE during simulated ICH suggests generation of endogenous signals of neuroprotection. The effects of exogenous 15(S)-HETE on brain hemorrhage-induced inflammatory responses and oxidative stress might be mediated via PPARγ.