Part of the Special Issue: Metabolism 2014 – Alterations of metabolic pathways as therapeutic targets
- Open Access funded by Austrian Science Fund (FWF)
- Under a Creative Commons license
Open Access
Abstract
Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant.
Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.
Graphical abstract
Keywords
- PPAR gamma;
- Nuclear receptor;
- Natural product;
- Nutrition;
- Diabetes
Abbreviations
- 9-(S)-HODE, (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid;
- AF-2, activation function-2;
- CAP, c-Cbl-associated protein;
- Cdk5, cyclin-dependent kinase 5;
- DCM,dichloromethane;
- DIO, diet-induced obesity;
- DPP-4, dipeptidylpeptidase 4;
- EMA,European Medicines Agency;
- FDA, Food and Drug Administration;
- Glut4, glucose transporter type 4;
- HDL, high-density lipoprotein;
- HUVEC, human umbilical vein endothelial cells;
- LBD, ligand-binding domain;
- LDL, low-density lipoprotein;
- MAPK,mitogen-activated protein kinase;
- MeOH, methanol;
- NF-κB, nuclear factor-kappaB;
- PPAR, peroxisome proliferator-activated receptor;
- RXR, retinoid X receptor;
- PDB,protein data bank;
- PPRE, peroxisome proliferator response element;
- SPPARMs,selective PPARγ modulators;
- TCM, traditional Chinese medicine;
- TNF-α, tumor necrosis factor alpha
Chemical compounds studied in this article
- Pioglitazone (PubChem CID: 4829);
- Magnolol (PubChem CID: 72300);
- Honokiol (PubChem CID: 72303);
- Falcarindiol (PubChem CID: 5281148);
- Resveratrol (PubChem CID: 445154);
- Amorfrutin 1 (PubChem CID: 10132170);
- Rosiglitazone (PubChem CID: 77999);
- Quercetin (PubChem CID: 5280343);
- (−)-Catechin (PubChem CID: 73160);
- Linolenic acid (PubChem CID: 5280934)
1. Significance of metabolic disorders
The metabolic syndrome is currently a major worldwide epidemic. It strongly associates with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases, which are major pathologies contributing to mortality and morbidity worldwide. At present the metabolic syndrome is already affecting more than a quarter of the world's adult population. Its prevalence is further growing in both adults and children due to a life style characterized by high calorie nutrition combined with low physical activity [1] and [2].
The metabolic syndrome represents by definition a disorder related to imbalance of energy utilization and storage. Its features include abdominal obesity, hypertension, dyslipidemia (increased blood serum triglycerides; low high-density lipoprotein (HDL) and high low-density lipoprotein (LDL) cholesterol levels), insulin resistance with elevated fasting blood glucose, and glucose intolerance as well as establishment of pro-thrombotic and pro-inflammatory states [3]. People affected by the metabolic syndrome have a greater risk of developing cardiovascular diseases and type 2 diabetes. Moreover, recent research indicates that metabolic syndrome associated obesity causes chronic low-grade local tissue inflammation and increased susceptibility to other disease conditions such as fatty liver, sleep disturbances, cholesterol gallstones, polycystic ovary syndrome, asthma, and some types of cancer [3] and [4].
The two main approaches in metabolic syndrome management are in the first place life style modifications that aim at restoring energy balance by reduced calorie intake and increased energy expenditure by physical activity, and on second place pharmaceutical interventions [1] and [3]. Employed drugs target different relevant aspects of the metabolic syndrome such as body weight and fat distribution, insulin resistance, hypertension, dyslipidemia, hyperglycemia, or the established prothrombotic and proinflammatory state [3]. For the treatment of patients suffering from type 2 diabetes, aside from life-style alterations, insulin and insulin analogs were first applied [5]. Later a number of oral anti-hyperglycemic pharmaceuticals were developed and successfully used [6] including sulfonylureas (increasing insulin secretion) [7], biguanides (insulin sensitizers; e.g. metformin), alpha-glucosidase inhibitors (slowing the digestion of starch in the small intestine), meglitinides (increasing insulin secretion), dipeptidylpeptidase 4 (DPP-4) inhibitors (increasing insulin secretion) [6], as well as thiazolidinediones (agonists of PPARγ). Recent research strategies also explore targeting the nuclear factor-kappaB (NF-κB) pathway [8], mitogen-activated protein kinases (MAPK) signaling[9], fatty acid-binding proteins [10], as well as other targets involved in fatty acid metabolism [11] and [12]. PPARγ, the molecular target of the thiazolidinediones, is particularly involved in the regulation of insulin sensitivity, inflammation, fatty acid storage, and glucose metabolism, and therefore represents an especially interesting pharmacological target which is able to simultaneously modulate several of the underlying pathologies of the metabolic syndrome [13] and [14].
