Abstract
Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.
Highlights
In 2015, it was estimated that more than 415 million adults globally had diabetes mellitus, of which over 90% suffered from type 2 diabetes (T2D), and this number is projected to rise to around 642 million by 2040 [1]
Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major key enzymes involved in the breakdown of triglycerides to fatty acid derivatives and their activity are regulated by insulin
It could be interesting to investigate the effect of FaOH and FaDOH on a wider range of transcription factors involved in adipogenesis, recruitment of PPARγ coactivators, and glucose transporters in order to elucidate their possible mechanisms of action and evaluate their potential antidiabetic effects in preclinical trials
Summary
In 2015, it was estimated that more than 415 million adults globally had diabetes mellitus, of which over 90% suffered from type 2 diabetes (T2D), and this number is projected to rise to around 642 million by 2040 [1]. Upon ligand binding to the PPAR/RXR heterodimer, a conformational change in the LBD leads to release of the corepressor and binding of a coactivator resulting in expression of the target gene. PPARβ/δ shares similar functions with PPARα, and is ubiquitously expressed and has a key role in fatty acid oxidation in skeletal muscle, liver and heart, and appears to be an important regulator of energy expenditure, and glucose and lipid metabolism [14,15,16]. Activation of PPARγ leads to differential recruitment of coactivators and subsequent modulation of PPARγ activity This process alters the transcription of several target genes involved in carbohydrate and lipid metabolism resulting in for example facilitation of GU and lipid uptake, decrease in free fatty acid levels and amelioration of insulin resistance [11,17,18,19,20,21,22]. The screening platform has for example been used to identify promising antidiabetic alkamides and polyacetylenes from purple coneflower (Echinacea purpurea (L.) Moench, Asteraceae) and carrots (Daucus carota L., Apiaceae), respectively, and how this has been done will be described
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