PPAR and its medical activities Essay

Differentiated adipocyte is a key of insulin sensitizing effect. PPAR- controls the expression of numerous factor secreted form adipose tissue that influence insulin sensitivity, (e.g., adiponectin and leptin) and upregulates the GLUT4 transporter expression that involved in glucose homeostasis (35). PPAR- not only play a role in metabolic homeostasis, but also involved in several disease that induced by inflammation. PPAR- is also expressed in various immune system cell types, particularly in antigen precenting cells such as dendritic cells and macrophages (36). Inflammation is also play a role in cardiovascular event as a cascade of obesity and diabetes. Activating PPAR- is proven to be a good theurapetic method for reducing negative effect of obesity and would give a best outcome while consuming high level of fat from diet (37).
Many natural and synthetic agonists of PPARs are used in the treatment of glucose and lipid disorders and another diseases. PPARs perform different activities, mainly via endogenous ligands produced in the metabolic pathways of fatty acids and they are called lipid sensors. PPARs agonists have different properties and specificities for individual PPARs receptors, different absorption and distribution, and distinctive gene expression profiles, which ultimately lead to different clinical outcomes (38,39). The synthesis of new drug generation, PPAR-/ dual agonists connecting positive influences on both lipid and glucose metabolism has been recently developed as a response to the treatment challenge of coexisting type 2 diabetes mellitus with dyslipidemia. These double agonists not only have anti-diabetic activity but also reduce atherosclerosis development. They also shown anti-inflammatory, improve endothelial function, decrease plasma free fatty acids and lower blood pressure (40).
TZD has well known to be an effective agonist for PPAR- for years. However, the adverse effects of TZD which led restricted clinical application are suggested to be a result of full PPAR- activation, contrasting the weak agonistic effect of endogenous PPAR- ligands such as fatty acids and prostanoids. Long term-activation of PPAR- TZD is known to be a risk factor by attenuating endhothelial dysfunction (41). Great research efforts have recently been underwent to explore the potential of selective PPAR- modulators (SPPARMs), compounds that improve glucose homeostasis but elicit reduced side effects due to partial PPAR- agonism based on selective receptor-cofactor interactions and target gene regulation. An example for a recently identified SPPARM is N-acetylfarnesylcysteine. New emerging compounds with in vitro and in vivo effectiveness as both a full and partial agonist are depending on the investigated PPAR- target gene (35).
Natural products are an important source for the discovery and development of new drugs. Natural products possess high chemical pattern diversity and are optimized to give different biological functions, proposing them a high drug-likeliness and making them a complete source for identification of new drug. It was not surprise if there are many significant research efforts to explore the PPAR- activating potential of a wide range of natural products originating from medicinal plants (42). PPAR--ligands were often identified in plants that are common food sources, including the tea plant, soybeans, palm oil, ginger, and grapes.