Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties

Abstract

Aims/hypothesis The nuclear receptor peroxisome proliferatoractivated receptor gamma (PPARγ) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARγ-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARγ. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARγ-binding and pharmacological properties of this family of plant metabolites. Methods Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg −1 day −1 amorfrutin B. Results Amorfrutin B showed low nanomolar binding affinity to PPARγ, and micromolar binding to the isotypes PPARα and PPARβ/δ. Amorfrutin B selectively modulated PPARγ activity at low nanomolar concentrations. In insulinresistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention. Conclusions/interpretation The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.

Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma

“…Recently, low nanomolar-binding natural products termed amorfrutins were described, which feature properties of SPPARMs [41,72]. These simple 2-hydroxy benzoic acid derivatives (structurally related to salicylic acids) showed a lower increase in the expression of genes involved in fat storage than did rosiglitazone.…”

“…Pharmacological interference with the phosphorylation event at serine 273 of PPARg has been proposed as a new strategy to increase insulin sensitivity because simple inhibition of the kinase CDK5 -that is essential in sensory and other pathwaysmay be difficult to control physiologically [77]. However, it seems that the underlying phosphorylation event of PPARg may be difficult to reproduce [72].…”

“…Making use of this specific mechanism may hold promise for future development. For example, the above-mentioned antidiabetic amorfrutins were at least as efficient as rosiglitazone in inhibiting the recruitment of NCoR1 peptides to the LBD of PPARg [41,72].…”

“…However, in vitro tests assaying coactivator/repressor peptide recruitment to the LBD of PPARg have been developed as alternatives for large-scale compound screening to identify hit molecules that activate PPARg by disturbing interactions with its repressor NCoR1 [72]. Moreover, it becomes evident that PPARg is modulated by various cellular signaling cascades, including for example mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases (ERK)s and by the resulting post-translational modifications of PPARg [83].…”

Integrative Analysis of Transcriptomics, Proteomics, and Metabolomics Data of White Adipose and Liver Tissue of High-Fat Diet and Rosiglitazone-Treated Insulin-Resistant Mice Identified Pathway Alterations and Molecular Hubs

“…14 Homeostasis model assessment of insulin resistance (HOMA-IR) was determined as follows: fasting glucose (mg/dL) × fasting insulin (μU/mL)/405. 19 …”