Novel Dual PPARα/δ Agonist F3SM Increased Oxidative Muscle Fiber and Ameliorated Metabolic Disorders in Non‐trained Mice

Abstract

OBJECTIVESedentary lifestyle and over‐nutrition are the underlying driving forces behind the development of metabolic diseases, particularly diabetes, dyslipidemia, obesity, etc. Physical inactivity reduced proportion of oxidative muscle fibers, and is associated with these metabolic dysfunctions. PPARβ/δ is the targeted nuclear receptor directly responsible for reprogramming the fiber‐specific contractile, links muscle fiber type to energy metabolism. PPARα activation contributes to hepatic fatty acid oxidation and lipid metabolism. Here we tested if moderate PPARα/β activation is a feasible substitute therapeutic strategy to sedentary lifestyle related metabolic disorders.METHODSWe used a combination of virtual docking, SPR‐based binding, luciferase reporter and target gene transcriptional assays to analyze the interaction mode, affinity and agonistic activity of F3SM to PPAR in vitro, respectively. With reference to exercise, the impact of F3SM on muscle endurance and strength were comparatively studied in normal mice. Serum metabolomics study was used to analyse the overall metabolic alterations. And the insulin sensitizing and anti‐dyslipidemia effects of F3SM were examined in high‐diet‐induced (HFD) obesity mice.RESULTSF3SM interacted with PPARα/β‐LBD, showed specific binding with PPARα/β, displayed potent PPARδ agonism (EC50 1.37 ± 0.33nM) and accompanied by a relative weaker PPARα agonism (EC50 75.18 ± 1.88nM), but without PPARγ activation. Target gene expression assay confirmed transcriptional activation of PPARα and PPARβ by F3SM respectively in the target tissues. Similar to exercise training, F3SM enhanced the running capability of normal mice in a dose‐dependent manner and increased the proportion of oxidative skeletal muscle fibers. Correspondingly, F3SM treated muscle was also confirmed to be fatigue‐resistant. Furthermore, serum fatty acid metabolism and whole serum metabolism disclosed the levels of intermediate metabolites and key enzymes in fatty acid oxidation pathways were increased following F3SM treatment. Thus serum unsaturated fatty acid levels, especially polyunsaturated fatty acids were raised. More importantly, F3SM indeed was capable of ameliorating glucose intolerance and hyperlipidemia in the HFD mice. In consistent with this, F3SM significantly promoted the uptake of fatty acids into hepatocytes in a dose‐dependent and insulin‐independent manner.CONCLUSIONSDual PPARα/β activation by F3SM increases the proportion of oxidative muscle fibres and switches the energy source to enhanced utilization of fatty acids. Moderate PPARα/β activation could replicate the metabolic benefits of exercise training and may be a promising strategy in combating sedentary lifestyle related metabolic diseases.Support or Funding InformationNational Science and Technology Major Project(2012ZX09301‐003), National Natural Science Foundation of China (81430090, 81773790)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.