title: Amorfrutins are potent antidiabetic dietary natural products.
abstract: Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Weidner
authors.forename: Jens C
authors.initials: JC
authors.lastname: de Groot
authors.forename: Aman
authors.initials: A
authors.lastname: Prasad
authors.forename: Anja
authors.initials: A
authors.lastname: Freiwald
authors.forename: Claudia
authors.initials: C
authors.lastname: Quedenau
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kliem
authors.forename: Annabell
authors.initials: A
authors.lastname: Witzke
authors.forename: Vitam
authors.initials: V
authors.lastname: Kodelja
authors.forename: Chung-Ting
authors.initials: CT
authors.lastname: Han
authors.forename: Sascha
authors.initials: S
authors.lastname: Giegold
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumann
authors.forename: Bert
authors.initials: B
authors.lastname: Klebl
authors.forename: Karsten
authors.initials: K
authors.lastname: Siems
authors.forename: Lutz
authors.initials: L
authors.lastname: Müller-Kuhrt
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.forename: Rita
authors.initials: R
authors.lastname: Schüler
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
authors.forename: Konrad
authors.initials: K
authors.lastname: Büssow
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements; D007887:Fabaceae / Q000737:chemistry*; D015870:Gene Expression / Q000187:drug effects; D006035:Glycyrrhiza / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000209:etiology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012459:Salicylates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012459:Salicylates