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Ppar Alpha Diabetes

A Novel Peroxisome Proliferator-activated Receptor (ppar)α Agonist And Pparγ Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity And Metabolic Disorders In Mice*

A Novel Peroxisome Proliferator-activated Receptor (ppar)α Agonist And Pparγ Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity And Metabolic Disorders In Mice*

Abstract A novel peroxisome proliferator-activated receptor (PPAR) modulator, Z-551, having both PPARα agonistic and PPARγ antagonistic activities, has been developed for the treatment of obesity and obesity-related metabolic disorders. We examined the effects of Z-551 on obesity and the metabolic disorders in wild-type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed body weight gain and ameliorated insulin resistance and abnormal glucose and lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte hypertrophy, and reduced molecules involved in fatty acid uptake and synthesis, macrophage infiltration, and inflammation in adipose tissue. Z-551 increased molecules involved in fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of glucose, triglyceride, free fatty acid, insulin, and leptin. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPARα-deficient mice and those of a synthetic PPARγ antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on body weight, insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma triglyceride and free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced obesity, insulin resistance, and impairment of glucose and lipid metabolisms by PPARα agonistic and PPARγ antagonistic activities, and therefore, might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and dyslipidemia. Continue reading >>

Therapeutic Roles Of Peroxisome Proliferator–activated Receptor Agonists

Therapeutic Roles Of Peroxisome Proliferator–activated Receptor Agonists

Peroxisome proliferator–activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPARα and -γ are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPARα. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPARγ, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPARγ agonists are therefore used to treat type 2 diabetes. PPARα and -γ agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPARα/γ agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPARδ, and its potential as a therapeutic target are currently under investigation. The three peroxisome proliferator–activated receptor (PPAR) isoforms PPARα, -γ, and -δ are nuclear receptors activated by fatty acids and fatty acid–derived eicosanoids. PPARα is expressed mainly in tissues where active fatty acid catabolism occurs (e.g., liver, brown fat, kidney, heart, and skeletal muscle), and PPARγ is restricted largely to white and brown adipose tissue, with lower leve Continue reading >>

Peroxisome Proliferator-activated Receptor (ppar)-α Activation Prevents Diabetes In Oletf Rats

Peroxisome Proliferator-activated Receptor (ppar)-α Activation Prevents Diabetes In Oletf Rats

Comparison With PPAR-γ Activation Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ stimulation on the development of diabetes in obese diabetes-prone OLETF rats. Chronic administration of a PPAR-α agonist (0.5% [wt/wt] fenofibrate) or a PPAR-γ agonist (3 mg · kg−1 · day−1 rosiglitazone) completely prevented the development of glycosuria. Pancreatic islets from untreated OLETF rats underwent sequential hypertrophy and atrophy, which was completely prevented by chronic fenofibrate treatment. In contrast, rosiglitazone treatment did not affect islet hypertrophy at earlier stages but prevented β-cell atrophy at later stages. Fenofibrate treatment decreased body weight and visceral fat, whereas rosiglitazone treatment increased body weight. Despite the opposite effects on adiposity, both drugs were equally effective in improving insulin actions in skeletal muscle. Furthermore, both drugs significantly decreased the triglyceride content in the soleus muscle and pancreatic islets. The present study demonstrates that the PPAR-α agonist fenofibrate prevents the development of diabetes in OLETF rats by reducing adiposity, improving peripheral insulin action, and exerting beneficial effects on pancreatic β-cells. Increasing evidence suggests that lipid accumulation in nonadipose tissues, such as skeletal muscle and pancreatic islet, is causally related to the development of type 2 diabetes in obese individuals (1,2). Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear transcription factors that regulate lipid metabolism (3). Thiazolidinedione (TZD), a Continue reading >>

In Vivo Actions Of Peroxisome Proliferator–activated Receptors

In Vivo Actions Of Peroxisome Proliferator–activated Receptors

Peroxisome proliferator–activated receptors (PPARs) form a family of nuclear hormone receptors involved in energy hemostasis and lipid metabolism (1,2) and include three isotypes encoded by different genes: PPARα (chromosome 22q12–13.1), PPARβ/δ (chromosome 6p21.2–21.1), and PPARγ (chromosome 3p25). PPARα was the first discovered and causes cellular peroxisome proliferation in rodent livers (3), giving this receptor family its name. Upon activation, PPARs interact with retinoid X receptor to create heterodimers, which bind to a specific DNA sequence motif termed peroxisome proliferator response element (4). Peroxisome proliferator response element usually appears in promoter regions and is constructed from repeats of nucleotide sequence AGGTCA separated by a single nucleotide. PPARα is widely expressed in tissues with high fatty acid catabolic activity: brown fat, heart, liver, kidney, and intestine (5). Upon activation by endogenous fatty acids and their derivatives, PPARα mediates fatty acid catabolism, gluconeogenesis, and ketone body synthesis, mainly in liver (6–9). In rodents, PPARα activation also influences immune modulation (10,11) and amino acid metabolism (12), reduces plasma triglyceride, reduces muscle and liver steatosis, and ameliorates insulin resistance (IR) (13,14). Pharmacologic PPARα activation is achieved by fibrates (7) and results in reduced (30–50%) triglyceride and VLDL levels by increasing lipid uptake, lipoprotein lipase–mediated lipolysis, and β-oxidation (15). This is accompanied by a modest increase in HDL cholesterol (5–20%), secondary to transcriptional induction of apolipoprotein A-I/A-II synthesis in liver (15). In man, the primary effect of PPARα is to reduce plasma triglyceride concentration; effects on plasma Continue reading >>

Peroxisome Proliferator-activated Receptor (ppar) In Metabolic Syndrome And Type 2 Diabetes Mellitus.

Peroxisome Proliferator-activated Receptor (ppar) In Metabolic Syndrome And Type 2 Diabetes Mellitus.

Abstract Type 2 diabetes mellitus, a global epidemic, is largely attributed to metabolic syndrome and its clustering of cardiovascular risk factors including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The two primary approaches to optimally control risk factors associated with metabolic syndrome are lifestyle changes and medications. Although many pharmacological targets have been identified, clinical management of cardiovascular risk factors associated with metabolic syndrome and type 2 diabetes is still dismal. Recent evidence suggests premises of the peroxisome proliferator-activated receptor (PPAR) ligands in the combat against type 2 diabetes and metabolic syndrome including obesity and insulin resistance. Three subtypes of the PPAR nuclear fatty acid receptors have been identified: alpha, beta/delta and gamma. PPARalpha is believed to participate in fatty acid uptake (beta- and omega-oxidation) mainly in the liver and heart. PPARbeta/delta is involved in fatty acid oxidation in muscle. PPARgamma is highly expressed in fat to facilitate glucose and lipid uptake, stimulate glucose oxidation, decrease free fatty acid level and ameliorate insulin resistance. Synthetic ligands for PPARalpha and gamma such as fibric acid and thiazolidinediones have been used in patients with type 2 diabetes and pre-diabetic insulin resistance with significantly improved HbA(1c) and glucose levels. In addition, nonhypoglycemic effects may be elicited by PPAR agonists or dual agonists including improved lipid metabolism, blood pressure control and endothelial function, as well as suppressed atherosclerotic plaque formation and coagulation. However, issues of safety and clinical indication remain undetermined for use of PPAR agonists for the incidence of heart disease Continue reading >>

Ppar Agonists

Ppar Agonists

A family of drugs that activate certain proteins in the body called peroxisome proliferator-activated receptors (PPARs). The PPAR agonists can help to improve blood glucose levels and levels of blood lipids (fats and cholesterol) and may also reduce risks of atherosclerosis because PPARs regulate the expression of genes that affect blood lipid metabolism, the generation of adipocytes (fat cells), and blood glucose control. Over the years, researchers have come to recognize that a number of risk factors for cardiovascular disease tend to occur together, including insulin resistance, elevated blood glucose levels, Type 2 diabetes, blood lipid abnormalities, and inflammation. Consequently, they are on the lookout for drugs that might address all of these risk factors at once. Scientists have identified three different forms of PPARs, dubbing them PPAR-alpha, PPAR-gamma, and PPAR-delta (also called PPAR-beta). PPAR-alpha, the first form of PPAR to be identified, is produced primarily in the skeletal muscle and the liver, where it is involved in the body’s breakdown and transport of fatty acids. PPAR-alpha may also play a role in reducing inflammation. PPAR-gamma is made primarily in fat cells and affects the production of fat cells and the metabolism of lipids and reduces insulin resistance. PPAR-delta is produced in virtually all of the cells throughout the body and may have roles in energy metabolism and reducing inflammation. All three forms of PPAR are also made in the endothelial cells lining the blood vessels and in inflammatory cells, suggesting that they may play a role in the development of atherosclerosis. When activated, the PPARs stimulate metabolic pathways that may reduce the risk of atherosclerosis, but some research (mainly in mice) indicates that they may Continue reading >>

Ppar Agonist

Ppar Agonist

PPAR-alpha and-gamma pathways PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar. Classification[edit] PPAR-alpha and PPAR-gamma are the molecular targets of a number of marketed drugs. The main classes of PPAR agonists are: PPAR-alpha agonists[edit] PPARα (alpha) is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate). They were originally indicated for cholesterol disorders and more recently for disorders that feature high triglycerides. PPAR-gamma agonists[edit] PPARγ (gamma) is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles, as well as from a number of natural compounds. Known inhibitors include the experimental agent GW-9662. They are also used in treating hyperlipidaemia in atherosclerosis. Here they act by increasing the expression of ABCA1, which transports extra-hepatic cholesterol into HDL. Increased uptake and excretion from the liver therefore follows. Animal studies have shown their possible role in amelioration of pulmonary inflammation, especially in asthma.[1] PPAR-delta agonists[edit] PPARδ (delta) is the main target of a research chemical named GW501516. It has been shown that agonism of PPARδ changes the body's fuel preference from glucose to lipids.[2] Dual and pan PPAR agonists[edit] A fourth class of dual PPAR agonists, so-called glitazars, which bind to both the α and γ PPAR isoforms, are currently under active investigation for Continue reading >>

Peroxisome Proliferator-activated Receptor-alpha (pparalpha): At The Crossroads Of Obesity, Diabetes And Cardiovascular Disease.

Peroxisome Proliferator-activated Receptor-alpha (pparalpha): At The Crossroads Of Obesity, Diabetes And Cardiovascular Disease.

Abstract Cardiovascular disease is the leading cause of morbidity and mortality world-wide. The burden of disease is also increasing as a result of the global epidemics of diabetes and obesity. Peroxisome proliferator-activated receptor alpha (PPARalpha), a member of this nuclear receptor family, has emerged as an important player in this scenario, with evidence supporting a central co-ordinated role in the regulation of fatty acid oxidation, lipid and lipoprotein metabolism and inflammatory and vascular responses, all of which would be predicted to reduce atherosclerotic risk. Additionally, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has indicated the possibility of preventive effects in diabetes-related microvascular complications, although the mechanisms of these effects warrant further study. The multimodal pharmacological profile of PPARalpha has prompted development of selective PPAR modulators (SPPARMs) to maximise therapeutic potential. It is anticipated that PPARalpha will continue to have important clinical application in addressing the major challenge of cardiometabolic risk associated with type 2 diabetes, obesity and metabolic syndrome. Continue reading >>

Ppar-α As A Key Nutritional And Environmental Sensor For Metabolic Adaptation1,2

Ppar-α As A Key Nutritional And Environmental Sensor For Metabolic Adaptation1,2

Abstract Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. There is evidence that genetic variants within the PPARα gene have been associated with a risk of the development of dyslipidemia and cardiovascular disease by influencing fasting and postprandial lipid concentrations; the gene variants have also been associated with an acceleration of the progression of type 2 diabetes. The interactions between genetic PPARα variants and the response to dietary factors will help to identify individuals or populations who can benefit from specific dietary recommendations. Interestingly, certain nutritional conditions, such as the prolonged consumption of a protein-restricted diet, can produce long-lasting effects on PPARα gene expression through modifications in the methylation of a specific locus surrounding the PPARα gene. Thus, this review underlines our current knowledge about the important role of PPAR-α as a mediator of the metabolic response to nutritional and environmental factors. Continue reading >>

Pathogenic Role Of Diabetes-induced Ppar-α Down-regulation In Microvascular Dysfunction

Pathogenic Role Of Diabetes-induced Ppar-α Down-regulation In Microvascular Dysfunction

Abstract Two independent clinical studies have reported that fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has robust therapeutic effects on microvascular complications of diabetes, including diabetic retinopathy (DR) in type 2 diabetic patients. However, the expression and function of PPARα in the retina are unclear. Here, we demonstrated that PPARα is expressed in multiple cell types in the retina. In both type 1 and type 2 diabetes models, expression of PPARα, but not PPARβ/δ or PPARγ, was significantly down-regulated in the retina. Furthermore, high-glucose medium was sufficient to down-regulate PPARα expression in cultured retinal cells. To further investigate the role of PPARα in DR, diabetes was induced in PPARα knockout (KO) mice and wild-type (WT) mice. Diabetic PPARα KO mice developed more severe DR, as shown by retinal vascular leakage, leukostasis, pericyte loss, capillary degeneration, and over-expression of inflammatory factors, compared with diabetic WT mice. In addition, overexpression of PPARα in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation. Furthermore, PPARα overexpression inhibited endothelial cell migration and proliferation. These findings revealed that diabetes-induced down-regulation of PPARα plays an important role in DR. Up-regulation or activation of PPARα may represent a novel therapeutic strategy for DR. Continue reading >>

Metformin Stimulates Igfbp-2 Gene Expression Through Pparalpha In Diabetic States

Metformin Stimulates Igfbp-2 Gene Expression Through Pparalpha In Diabetic States

The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p < 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability. In biological fluids, the insulin-like growth factor binding protein (IGFBP) family proteins can complex with both IGF-I and II, and are regulators of IGF actions on metabolism and growth1,2. Currently, there are six mammalian IGFBPs designated IGFBP-1–6 have been characterized3 and newly IGFBP-7 was identified as a member of the IGFBP superfamily4. The primary function of the IGFBPs is to restrict the bioavailability of IGF-1 in target tissues5. Among the IGFBPs, IGFBP-2 modulates IGF-1 b Continue reading >>

State-of-the-art Paper Peroxisome Proliferator-activated Receptors At The Crossroads Of Obesity, Diabetes, And Cardiovascular Disease

State-of-the-art Paper Peroxisome Proliferator-activated Receptors At The Crossroads Of Obesity, Diabetes, And Cardiovascular Disease

Since their discovery in the early 1990s, the members of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors have been recognized as therapeutic targets against dyslipidemia and diabetes. Recent studies also identified anti-inflammatory actions of PPARs in cells constituting the atherosclerotic lesion. Delineation of this activity extended the therapeutic potential of PPAR activators beyond their original design as metabolic controllers. The PPAR family consists of 3 PPAR isoforms: α, β/δ, and γ, which exert different and sometimes overlapping effects on whole-body physiology in particular on lipid and glucose metabolism. This review summarizes the current knowledge on the role of PPARs in cardiovascular disease, the metabolic syndrome, atherosclerosis, and cardiac function. Continue reading >>

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