Honokiol: a non-adipogenic PPARγ agonist from nature.
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.
Keywords
NMR
HPLC
sodium carboxymethyl cellulose
SEM
metabolic disease
high-performance liquid chromatography
gst
ampk
nox
mtor
traditional chinese medicine
thin layer chromatography
glutathione-s-transferase
nf-κb
mammalian target of rapamycin
nuclear magnetic resonance
dimethyl sulfoxide
fcs
pbs
fetal calf serum
peroxisome proliferator-activated receptor gamma
tlc
bovine serum albumin
dmso
bmp
natural product
bsa
anova
srebp
pparγ
dmem
phosphate buffered saline
lbd
3-isobutyl-1-methylxanthine
amp-activated kinase
atcc
american type culture collection
badge
cmcna
dulbecco's modified eagle's medium
ec(50)
egfp
ibmx
mef
nadph-dependent oxidase
nbs
peroxisome proliferator-activated receptor
rxr
spf
tcm
tr-fret
analysis of variance
bisphenol a diglycidyl ether
bone morphogenic protein 4
effective concentration 50%
enhanced green fluorescent protein
ligand-binding domain
mouse embryonic fibroblasts
newborn bovine serum
nuclear factor κb
retinoic x receptor
specific pathogen free
standard error of the mean
sterol regulatory element binding protein
time-resolved fluorescence resonance energy transfer
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74041
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0x95644003c57E6F55A65596E3D9Eac6813e3566dA
Article ID:
74041
Unique Identifier:
10.1016/j.bbagen.2013.06.021
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Scimatic Chain (ID: 481)
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