gw-501516 and Insulin-Resistance

Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as 'exercise mimetics', have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this review, we highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We also discuss evidence from clinical trials using these compounds in human subjects to evaluate their efficacy in treating diabetes.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Diabetes Mellitus; Energy Metabolism; Exercise; Exercise Therapy; Fibroblast Growth Factors; Homeostasis; Humans; Insulin Resistance; Liver; Mitochondria; Muscle, Skeletal; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Sirtuins; Thiazoles

Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects.. This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).. ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

Topics: Acetates; Animals; Atherosclerosis; Chalcones; Cholesterol, HDL; Dyslipidemias; Fatty Liver; Fenofibrate; Humans; Insulin Resistance; Lipoproteins, HDL; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Propionates; Quinolines; Sulfonamides; Thiazoles; Triazoles; Triglycerides

Therapeutic strategies to alleviate the growing epidemic of insulin-resistant syndromes (obesity and type 2 diabetes) as well as the conferred cardiovascular disease risk remain sparse. The peroxisome proliferator-activated receptor δ (PPARδ) has emerged as a versatile regulator of lipid homeostasis and inflammatory signaling, making it an attractive therapeutic target for the treatment and prevention of type 2 diabetes and atherosclerosis.. PPARδ activation regulates lipid homeostasis and inflammatory signaling in a variety of cell types, conferring protection from metabolic disease and atherosclerosis. Specifically, PPARδ activation in the liver stimulates glucose utilization and inhibits gluconeogenesis, which improves insulin resistance and hyperglycemia. In macrophages, PPARδ-specific activation with synthetic agonists inhibits VLDL-induced triglyceride accumulation and inflammation. In mice, PPARδ agonists halt the progression of atherosclerosis and stabilize existing lesions by promoting an anti-inflammatory milieu within the diseased macrovasculature. In humans, PPARδ activation improves insulin sensitivity and reduces atherogenic dyslipidemia via a mechanism complementary to statin monotherapy.. Recent advances in the understanding of PPARδ reveal that activation of this receptor represents a multifaceted therapeutic strategy for the prevention and treatment of insulin-resistant syndromes and atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Clinical Trials as Topic; Dyslipidemias; Hepatocytes; Humans; Inflammation; Insulin Resistance; Liver; Macrophages; Mice; PPAR delta; Thiazoles

The identification of small molecule agonists for the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR-beta/delta, NR1C2) has enabled the characterization of this receptor's functions in preclinical models. Subsequently, a number of small molecule agonists of PPAR-beta/delta have been progressed into clinical trials.. This review will examine the major preclinical findings that underpin the hypothesis that PPAR-beta/delta agonists may be beneficial in treating dyslipidemia and Type 2 diabetes, as well as emerging clinical data with a variety of PPAR-beta/delta agonists.. The literature concerning preclinical experiments that combine in vivo and in vitro mechanistic studies are reviewed and compared with the results of the early clinical trials.. Thus far, the activities of the agonists seen in the clinic are broadly similar to those seen in preclinical models. However, it is still not known if PPAR-beta/delta agonists will truly be differentiated enough from current treatments to justify their use in treating dyslipidemia or Type 2 diabetes. Major challenges for the development of PPAR-beta/delta agonists exist and the path forward is as yet undefined.

Topics: Animals; Atherosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Humans; Insulin Resistance; Lipoproteins; PPAR delta; PPAR-beta; Propionates; Thiazoles

Topics: Animals; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Fatty Acids; Glucose Tolerance Test; Humans; Insulin Resistance; Kruppel-Like Transcription Factors; Life Style; Metabolic Syndrome; Mice; Mice, Transgenic; Multigene Family; Muscle, Skeletal; Nuclear Proteins; Oxidation-Reduction; Receptors, Cytoplasmic and Nuclear; Sterol Regulatory Element Binding Protein 1; Thiazoles; Transcription Factors; Transcription, Genetic

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors playing important regulatory functions in development and metabolism. PPARalpha and PPARgamma are the most extensively examined and characterized, mainly because they are activated by marketed hypolipidemic and insulin sensitizer compounds, such as fibrates and thiazolidinediones. It has been established that the third member of the family, PPARdelta is implicated in developmental regulations, but until recently, its role in metabolism remained unclear. The availability of specific PPARdelta agonists and of appropriate cellular and animal models revealed that PPARdelta plays a crucial role in fatty acid metabolism in several tissues. Treatment of obese animals with PPARdelta agonists results in normalization of metabolic parameters and reduction of adiposity. Activation of the nuclear receptor promotes fatty acid burning in skeletal muscle and adipose tissue by upregulation of fatty acid uptake, beta-oxidation and energy uncoupling. PPARdelta is also involved in the adaptive metabolic responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations strongly suggest that PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption and decreasing obesity.

Topics: Adipose Tissue; Animals; Fatty Acids; Insulin Resistance; Ligands; Macaca mulatta; Metabolic Syndrome; Muscle, Skeletal; Obesity; PPAR delta; Thiazoles

Previous reports have shown that PPARβ/δ agonists ameliorate insulin resistance associated with type 2 diabetes mellitus (T2DM). To determine the role of PPARβ/δ in tumor necrosis factor α (TNFα)-mediated insulin resistance, we investigated expression levels of adiponectin and insulin receptor (IR) in response to treatment with the PPARβ/δ agonist GW501516 with or without TNFα, a proinflammatory cytokine, in differentiated 3T3-L1 adipocytes. GW501516 induced adipocyte differentiation and the expression of adiponectin in a dose-dependent manner in differentiated adipocytes. TNFα treatment reduced adiponectin expression at the end of differentiation. This effect was reversed by GW501516 co-treatment with TNFα. TNFα treatment decreased adipogenic marker genes such as PPARγ, aP2, resistin, and GLUT4, and GW501516 reversed the effects of TNFα. GW501516 treatment increased the expression of insulin receptor and inhibited TNFα-mediated repression of insulin receptor. Our results showed that GW501516 abrogated TNFα-induced insulin resistance. In summary, our study demonstrated that the PPARβ/δ agonist, GW501516 reversed TNFα-induced decreases in adipocyte differentiation and adiponectin expression, and improved insulin sensitivity by increasing the expression of insulin receptor. Therefore, PPARδ may be a promising therapeutic target for treatment of insulin resistance in patients with T2DM.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Insulin Resistance; Mice; PPAR delta; PPAR-beta; Receptor, Insulin; Thiazoles; Tumor Necrosis Factor-alpha

Obesity-associated insulin resistance is a forerunner of type 2 diabetes. Macrophages reside within adipose tissue (ATMs) have been reported to regulate insulin sensitivity through secreting miRNAs containing exosomes. Here, we show that miR-29a is increased in obese ATMs derived exosomes (ATMs-Exos) and can be transferred into adipocytes, myocytes and hepatocytes causing insulin resistance in vitro and in vivo. Administration of obese ATMs-Exos impairs insulin sensitivity of lean mice. While knockdown miR-29a level in obese ATM-Exos blunts this effect. PPAR-δ is identified to function as downstream target of miR-29a in regulating insulin resistance. PPAR-δ agonist GW501516 partially rescued the insulin resistance induced by miR-29a. Taken together, these findings suggest that ATMs derived exosomal miR-29a could regulate obesity-associated insulin resistance, which may serve as a potential therapeutic target for obesity-associated type 2 diabetes.

Topics: Adipocytes; Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Exosomes; Gene Knockdown Techniques; Hepatocytes; In Vitro Techniques; Insulin Resistance; Macrophages; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Muscle Cells; Obesity; Receptors, Cytoplasmic and Nuclear; Thiazoles

Peroxisome proliferator-activated receptor (PPAR) δ plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPARδ are postulated, the specific molecular mechanisms whereby PPARδ controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPARδ results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPARδ with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPARδ with TCPTP45 blunted interleukin 6-induced insulin resistance, leading to retention of TCPTP45 in the nucleus, thereby facilitating deactivation of the signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3) signal. Finally, GW501516-activated PPARδ improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPARδ constitutes the most upstream component identified of the mechanism downregulating insulin signaling.

Topics: Active Transport, Cell Nucleus; Adipocytes, White; Alternative Splicing; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cells, Cultured; Glucose Intolerance; Hepatocytes; Humans; Insulin Resistance; Male; Mice, Inbred ICR; Muscle Fibers, Skeletal; Obesity; PPAR delta; Protein Multimerization; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Recombinant Fusion Proteins; RNA Interference; Specific Pathogen-Free Organisms; Thiazoles

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Topics: Adenosine; Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Adiponectin; Animals; Cell Line; Diabetes Mellitus, Experimental; Humans; Hypoglycemic Agents; Insulin Resistance; Ligands; Male; Mice; Mice, Inbred C57BL; Polypharmacology; PPAR delta; PPAR gamma; Receptor, Adenosine A3

We studied whether PPARβ/δ deficiency modifies the effects of high fructose intake (30% fructose in drinking water) on glucose tolerance and adipose tissue dysfunction, focusing on the CD36-dependent pathway that enhances adipose tissue inflammation and impairs insulin signaling. Fructose intake for 8 weeks significantly increased body and liver weight, and hepatic triglyceride accumulation in PPARβ/δ-deficient mice but not in wild-type mice. Feeding PPARβ/δ-deficient mice with fructose exacerbated glucose intolerance and led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the JNK pathway in white adipose tissue compared to those of water-fed PPARβ/δ-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPARβ/δ activator GW501516. Interestingly, the levels of the nuclear factor E2-related factor 2 (Nrf2), a transcription factor reported to up-regulate Cd36 expression and to impair insulin signaling, were increased in fructose-exposed adipocytes whereas co-incubation with GW501516 abolished this increase. In agreement with Nrf2 playing a role in the fructose-induced CD36 protein level increases, the Nrf2 inhibitor trigonelline prevented the increase and the reduction in insulin-stimulated AKT phosphorylation caused by fructose in adipocytes. Protein levels of the well-known Nrf2 target gene. quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPARβ/δ-null mice, suggesting that PPARβ/δ deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPARβ/δ-deficient mice. These findings indicate that the combination of high fructose intake and PPARβ/δ deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue.

Topics: 3T3-L1 Cells; Adipocytes; Alkaloids; Animals; CD36 Antigens; Cell Line; Cytokines; Fructose; Glucose Intolerance; Humans; Immunoblotting; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Lipoproteins, LDL; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; PPAR delta; PPAR-beta; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thiazoles

High activation of the angiotensin-converting enzyme (ACE)/(angiotensin-II type 1 receptor) AT1r axis is closely linked to pro-inflammatory effects and liver damage. The aim of this study was to evaluate the effects of the short-term administration of GW501516 on pro-inflammatory markers in white adipose tissue (WAT) and hepatic stellate cells (HSCs), lipogenesis and insulin resistance in the liver upon high-fructose diet (HFru)-induced ACE/AT1r axis activation. Three-month-old male C57Bl/6 mice were fed a standard chow diet or a HFru for 8 weeks. Then, the animals were separated randomly into four groups and treated with GW501516 for 3 weeks. Morphological variables, systolic blood pressure, and plasma determinations were analyzed. In the WAT, the ACE/AT1r axis and pro-inflammatory cytokines were assessed, and in the liver, the ACE/AT1r axis, HSCs, fatty acid oxidation, insulin resistance, and AMPK activation were evaluated. The HFru group displayed a high activation of the ACE/AT1r axis in both the WAT and liver; consequently, we detected inflammation and liver damage. Although GW501516 abolished the increased activation of the ACE/AT1r axis in the WAT, no differences were found in the liver. GW501516 blunted the inflammatory state in the WAT and reduced HSC activation in the liver. In addition, GW501516 alleviates damage in the liver by increasing the expression of the genes that regulate beta-oxidation and decreasing the expression of the genes and proteins that are involved in lipogenesis and gluconeogenesis. We conclude that GW501516 may serve as a therapeutic option for the treatment of a highly activated ACE/AT1r axis in WAT and liver.

Topics: Adipose Tissue, White; Animals; Fructose; Hepatic Stellate Cells; Inflammation; Insulin Resistance; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; PPAR delta; Renin-Angiotensin System; Thiazoles

The peroxisome proliferator-activated receptor (PPAR) δ regulates systemic lipid homeostasis and inflammation. However, the ability of PPARδ agonists to improve the pathology of pre-established lesions and whether PPARδ activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARδ agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis.. Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle α-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARδ-specific gene Adfp but not PPARα- or γ-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine Arg1, and attenuated the iNos/Arg1 ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress.. Intervention with a PPARδ agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Aortitis; Atherosclerosis; Biomarkers; Blood Glucose; Cholesterol, Dietary; Diet, High-Fat; Disease Models, Animal; Dyslipidemias; Inflammation Mediators; Insulin; Insulin Resistance; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR delta; Receptors, LDL; Signal Transduction; Thiazoles; Time Factors

Topics: Animals; Anti-Inflammatory Agents; Aortitis; Atherosclerosis; Insulin Resistance; Male; PPAR delta; Receptors, LDL; Thiazoles

IL-6 induces insulin resistance by activating signal transducer and activator of transcription 3 (STAT3) and upregulating the transcription of its target gene SOCS3. Here we examined whether the peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW501516 prevented activation of the IL-6-STAT3-suppressor of cytokine signalling 3 (SOCS3) pathway and insulin resistance in human hepatic HepG2 cells.. Studies were conducted with human HepG2 cells and livers from mice null for Pparβ/δ (also known as Ppard) and wild-type mice.. GW501516 prevented IL-6-dependent reduction in insulin-stimulated v-akt murine thymoma viral oncogene homologue 1 (AKT) phosphorylation and in IRS-1 and IRS-2 protein levels. In addition, treatment with this drug abolished IL-6-induced STAT3 phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ and prevented the increase in SOCS3 caused by this cytokine. Moreover, GW501516 prevented IL-6-dependent induction of extracellular-related kinase 1/2 (ERK1/2), a serine-threonine protein kinase involved in serine STAT3 phosphorylation; the livers of Pparβ/δ-null mice showed increased Tyr⁷⁰⁵- and Ser⁷²⁷-STAT3 as well as phospho-ERK1/2 levels. Furthermore, drug treatment prevented the IL-6-dependent reduction in phosphorylated AMP-activated protein kinase (AMPK), a kinase reported to inhibit STAT3 phosphorylation on Tyr⁷⁰⁵. In agreement with the recovery in phospho-AMPK levels observed following GW501516 treatment, this drug increased the AMP/ATP ratio and decreased the ATP/ADP ratio.. Overall, our findings show that the PPARβ/δ activator GW501516 prevents IL-6-induced STAT3 activation by inhibiting ERK1/2 phosphorylation and preventing the reduction in phospho-AMPK levels. These effects of GW501516 may contribute to the prevention of cytokine-induced insulin resistance in hepatic cells.

Topics: Animals; Cell Nucleus; Gene Expression Regulation; Hep G2 Cells; Hepatocytes; Humans; Insulin Resistance; Interleukin-6; Male; Mice; Mice, Knockout; Phosphorylation; PPAR delta; PPAR-beta; Protein Processing, Post-Translational; Protein Transport; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thiazoles

The peroxisome proliferator-activated receptor (PPAR)δ has been considered a therapeutic target for diabetes and obesity through enhancement of fatty acid oxidation. The present study aimed to characterize the effects of PPARδ agonists during insulin resistance of the whole body, muscle and liver.. Wistar rats and C57BL/J6 mice were fed a high fat diet (HF) and then treated with PPARδ agonists NNC61-5920 and GW501516. The effects on insulin resistance were evaluated by hyperinsulinaemic clamp or glucose tolerance tests combined with glucose tracers.. In HF rats, 3 weeks of treatment with NNC61-5920 reduced the glucose infusion rate (by 14%, P < 0.05) and glucose disposal into muscle (by 20-30%, P < 0.01) during hyperinsulinaemic clamp. Despite increased mRNA expression of carnitine palmitoyltransferase-1, pyruvate dehydrogenase kinase 4 and uncoupling protein 3 in muscle, plasma and muscle triglyceride levels were raised (P < 0.01). Similar metabolic effects were observed after extended treatment with NNC61-5920 and GW501516 to 6 weeks. However, HF mice treated with NNC61-5920 improved their plasma lipid profile, glucose tolerance and insulin action in muscle. In both HF rats and mice, NNC61-5920 treatment attenuated hepatic insulin resistance and decreased expression of stearoyl-CoA desaturase 1, fatty acid translocase protein CD36 and lipoprotein lipase in liver.. PPARδ agonists exacerbated insulin resistance in HF rats in contrast to their beneficial effects on metabolic syndrome in HF mice. These opposing metabolic consequences result from their different effects on lipid metabolism and insulin sensitivity in skeletal muscle of these two species.

Topics: Animals; Biomarkers; Dietary Fats; Glucose; Glucose Tolerance Test; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Organ Specificity; PPAR delta; Rats; Rats, Wistar; RNA, Messenger; Species Specificity; Thiazoles; Triglycerides

Peroxisome proliferator-activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity.. Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR. Donors' insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp.. Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0·0312 and P = 0·0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors' insulin sensitivity (P > 0·2, all). Treatment of myotubes with a selective high-affinity PPARδ agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13- and 16-fold, respectively (P < 0·0001, both). The individual PDK4 and ANGPTL4 expression levels reached upon GW501516 treatment were associated with donors' insulin sensitivity neither (P > 0·2, both). However, GW501516-mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARδ responsiveness, were positively associated with donors' insulin sensitivity derived from OGTT (P = 0·0182 and P = 0·0231, respectively) and hyperinsulinemic-euglycemic clamp (P = 0·0046 and P = 0·0258, respectively).. Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARδ, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity.

Topics: Blood Glucose; Body Mass Index; Cells, Cultured; Female; Gene Expression Regulation; Glucose Tolerance Test; Humans; Insulin Resistance; Lipid Metabolism; Male; Muscle Cells; Muscle Fibers, Skeletal; PPAR delta; Regression Analysis; RNA, Messenger; Thiazoles

Peroxisome proliferator activated receptors (PPARs) are nuclear receptors involved in glucose and lipid metabolism. Three isoforms of PPARs have been identified with different tissue distribution and biological functions. Although the pharmacology of each receptor is well studied, the physiological effect of simultaneous activation of PPARalpha, gamma and delta is only starting to emerge. We sought to determine the biological effects of a novel PPAR pan activator and elucidate the physiological mechanisms involved.. Ob/ob, diet-induced obese (DIO) or PPARalpha knockout mice were administered a novel agonist that activates all PPARs to various degrees to determine the effect on body weight, body composition, food intake and energy expenditure. In addition, serum parameters including glucose, insulin, triglycerides and ketone bodies as well as tissue acylcarnitine were evaluated. The effect of the novel agonist on liver and skeletal muscle histopathology was also studied.. We report that simultaneous activation of all PPARs resulted in substantial weight loss in ob/ob and DIO mice. Consistent with known PPAR pharmacology, we observed that agonist treatment increased lipid oxidation, although appetite suppression was mainly responsible for the weight loss. Agonist-induced weight loss was completely absent in PPARalpha knockout mice suggesting that PPARalpha pharmacology was the major contributor to weight regulation in mice.. Our work provides evidence that simultaneous activation of PPARalpha, gamma and delta decreases body weight by regulating appetite. These effects of the pan agonist were completely absent in PPARalpha knockout mice, suggesting that PPARalpha pharmacology was the major contributor to weight loss.

Topics: Animals; Appetite Depressants; Appetite Regulation; Energy Metabolism; Insulin Resistance; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; PPAR alpha; PPAR delta; PPAR gamma; Rosiglitazone; Thiazoles; Thiazolidinediones; Weight Loss

Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-kappaB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Ctheta (PKCtheta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPARdelta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARdelta agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser(307) and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPARdelta antagonist GSK0660. Treatment with the PPARdelta agonist enhanced the expression of two well known PPARdelta target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKCtheta activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPARdelta activation by GW501516 blocked palmitate-induced NF-kappaB DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPARdelta attenuates fatty acid-induced NF-kappaB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARdelta activation as a pharmacological target to prevent insulin resistance.

Topics: Analysis of Variance; Animals; Blotting, Western; Carnitine O-Palmitoyltransferase; Cell Line; Cell Nucleus; Electrophoretic Mobility Shift Assay; Epoxy Compounds; Fatty Acids; Humans; Insulin Resistance; Interleukin-6; Mice; Muscle, Skeletal; NF-kappa B; PPAR delta; Protein Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfones; Thiazoles; Thiophenes

Agonists targeting the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-delta may be potential therapeutic agents for insulin-resistant related conditions, as they may be able to stimulate fatty acid (FA) oxidation and attenuate the accumulation of harmful lipid species in skeletal muscle. Several reports have demonstrated that PPAR-delta agonists improve whole body insulin sensitivity. However, whether these agonists exert their direct effects on glucose and FA metabolism in skeletal muscle, and specifically with different fiber types, is unknown. This study was undertaken to determine the effects of oral treatment with the PPAR-delta agonist, GW 501516, in conjunction with the administration of a high-saturated-fat diet on insulin-stimulated glucose transport in isolated oxidative (soleus) and glycolytic (epitrochlearis) rodent skeletal muscle in vitro. High-fat feeding significantly decreased maximal insulin-stimulated glucose transport in soleus, but not epitrochlearis muscle, and was associated with increased skeletal muscle diacylglycerol and ceramide content. Unexpectedly, treatment with the PPAR-delta agonist significantly reduced insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, regardless of dietary fat content. The reduction in insulin-stimulated glucose transport induced by the agonist was associated with large increases in total muscle fatty acid translocase (FAT)/CD36protein content, but not diacylglycerol or ceramide contents. Agonist treatment did not alter the protein content of PPAR-delta, GLUT4, or insulin-signaling proteins (IRS-1, p85 PI3-K, Akt). Agonist treatment led to a small, but significant increase, in the oxidative capacity of glycolytic but not oxidative muscle. We propose that chronic treatment with the PPAR-delta agonist GW 501516 may induce or worsen insulin resistance in rodent skeletal muscle by increasing the capacity for FA transport across the sarcolemma without a sufficient compensatory increase in FA oxidation. However, an accumulation of diacylglycerol and ceramide, while associated with diet-induced insulin resistance, does not appear to be responsible for the agonist-induced reduction in insulin-stimulated glucose transport.

Topics: Administration, Oral; Animals; Biological Transport; Blood Glucose; CD36 Antigens; Ceramides; Dietary Fats; Diglycerides; Fatty Acid-Binding Proteins; Female; Glucose Transporter Type 4; Glycolysis; GTPase-Activating Proteins; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Muscle Fibers, Skeletal; Oxidation-Reduction; Phosphatidylinositol 3-Kinases; Phosphorylation; PPAR delta; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Thiazoles

We evaluated the effects of GW501516, a specific peroxisome proliferator-activated receptor beta/delta (PPARdelta) agonist in metabolic syndrome mice, obtained by perinatal injection of monosodium L-glutamate, to investigate the efficacy of GW501516 against metabolic syndrome and the effectiveness of PPARdelta activation as therapeutic target for metabolic syndrome. After 14 days treatment, GW501516 effectively improved the glucose intolerance, normalized the fasted blood glucose, and increased the serum high-density lipoprotein cholesterol (HDL-C) level. Postprandial blood glucose, serum insulin, leptin, free fatty acid (FFA) levels, and total cholesterol/HDL-C ratio were also significantly decreased. Moreover, semiquantitative reverse transcription-polymerase chain reaction results indicated that the above phenotypes might be due to (i) enhancement of fatty acid oxidation in muscle, adipose tissue and the liver; (ii) improvement of insulin-stimulated glucose transportation in skeletal muscle and adipose tissue; and (iii) reduced local glucocorticoid synthesis. Therefore, GW501516 could significantly ameliorate dyslipidaemia and insulin resistance in monosodium L-glutamate mice and activation of PPARdelta could be envisioned as a useful strategy against human metabolic syndrome and related diseases.

Topics: Animals; Animals, Newborn; Blood Glucose; Cholesterol, HDL; Dyslipidemias; Fatty Acids; Gene Expression; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Obese; Oxidation-Reduction; PPAR delta; Sodium Glutamate; Thiazoles

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.

Topics: Fluorescence Resonance Energy Transfer; Insulin Resistance; PPAR delta; Structure-Activity Relationship

Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.

Topics: Administration, Oral; Animals; Apolipoprotein A-I; Cell Line; Female; Humans; Hypolipidemic Agents; Insulin Resistance; Male; Mice; Mice, Obese; Mice, Transgenic; PPAR alpha; PPAR delta; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiadiazoles

In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid beta-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid beta-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARdelta is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Topics: Animals; Dimethyl Sulfoxide; Enzymes; Fatty Acids, Nonesterified; Insulin Resistance; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Oxidation-Reduction; Rats; Receptors, Cytoplasmic and Nuclear; Thiazoles; Transcription Factors

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the alpha (NR1C1) and gamma (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the delta (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARdelta agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARdelta agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Topics: Animals; Apolipoprotein A-I; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Biological Transport; Blood Glucose; Cell Line; Cholesterol; Cholesterol, HDL; Drug Design; Fasting; Fibroblasts; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Intestinal Mucosa; Intestines; Macaca mulatta; Macrophages; Male; Metabolic Diseases; Obesity; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Substrate Specificity; Thiazoles; Transcription Factors; Triglycerides