title: Small-molecule activators of AMP-activated protein kinase (AMPK), RSVA314 and RSVA405, inhibit adipogenesis.
abstract: AMP-activated protein kinase (AMPK) is a sensor and regulator of cellular energy metabolism potentially implicated in a broad range of conditions, including obesity and Alzheimer's disease. Its role in the control of key metabolic enzymes makes this kinase a central player in glucose and lipid homeostasis. Recently, by screening a library of synthetic small molecules selected for their structural similarity with the natural polyphenol resveratrol, we identified RSVA314 and RSVA405 as potent indirect activators of AMPK (half-maximal effective concentration [EC₅₀] = 1 μmol/L in cell-based assays). Here we show that RSVA314 and RSVA405 can significantly activate AMPK and inhibit acetyl-CoA carboxylase (ACC), one target of AMPK and a key regulator of fatty acid biogenesis, in nondifferentiated and proliferating 3T3-L1 adipocytes. We found that RSVA314 and RSVA405 treatments inhibited 3T3-L1 adipocyte differentiation by interfering with mitotic clonal expansion during preadipocyte proliferation (half-maximal inhibitory concentration [IC₅₀] = 0.5 μmol/L). RSVA314 and RSVA405 prevented the adipogenesis-dependent transcriptional changes of multiple gene products involved in the adipogenic process, including peroxisome proliferator-activated receptor (PPAR)-γ, CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase, fatty acid binding protein 4 (aP2), RANTES or resistin. Furthermore, orally administered RSVA405 at 20 and 100 mg/kg/d significantly reduced the body weight gain of mice fed a high-fat diet. This work shows that the novel small-molecule activators of AMPK (RSVA314 and RSVA405) are potent inhibitors of adipogenesis and thus may have therapeutic potential against obesity.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York, USA. vdidier@nshs.edu
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chandakkar
authors.forename: Haitian
authors.initials: H
authors.lastname: Zhao
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000627:Aminophenols / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000627:Aminophenols; D000975:Antioxidants; D022763:CCAAT-Enhancer-Binding Protein-alpha; D004041:Dietary Fats; D020536:Enzyme Activators; D006835:Hydrazones; D047495:PPAR gamma; C570842:RSVA314; C570843:RSVA405; D013267:Stilbenes; D064429:Fatty Acid Synthases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol