Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide

The synthetic oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide or CDDO-Im) is an extremely potent activator of Nrf2 signaling. In cells undergoing adipogenesis, CDDO-Im prevents lipid accumulation in an Nrf2-dependent manner. However, in vivo evidenc...

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Bibliographic Details
Published in:European journal of pharmacology 2009-10, Vol.620 (1), p.138-144
Main Authors: Shin, Soona, Wakabayashi, Junko, Yates, Melinda S., Wakabayashi, Nobunao, Dolan, Patrick M., Aja, Susan, Liby, Karen T., Sporn, Michael B., Yamamoto, Masayuki, Kensler, Thomas W.
Format: Article
Language:English
Subjects:
Adipocytes - drug effects
Adipocytes - metabolism
Animals
Anti-Obesity Agents - pharmacology
Biological and medical sciences
Body Weight - drug effects
Diet-induced obesity
Dietary Fats - pharmacology
Energy Metabolism - drug effects
Fatty acid synthase
Fatty Acids - biosynthesis
Female
Gene Expression Regulation, Enzymologic - drug effects
Imidazoles - pharmacology
Liver - drug effects
Liver - enzymology
Liver - metabolism
Medical sciences
Metabolic diseases
Mice
NF-E2-Related Factor 2 - deficiency
NF-E2-Related Factor 2 - metabolism
Nrf2
Obesity
Obesity - chemically induced
Obesity - metabolism
Obesity - physiopathology
Obesity - prevention & control
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - pharmacology
Oxidation-Reduction
Pharmacology. Drug treatments
Triterpenoid
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Summary:The synthetic oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide or CDDO-Im) is an extremely potent activator of Nrf2 signaling. In cells undergoing adipogenesis, CDDO-Im prevents lipid accumulation in an Nrf2-dependent manner. However, in vivo evidence for effects of CDDO-Im on obesity is lacking. The goals of these studies were to determine if CDDO-Im can prevent high-fat diet-induced obesogenesis in the mouse, and to elucidate the molecular target of drug action. Wild-type and Nrf2-disrupted C57BL/6J female mice were dosed 3 times per week with 30 μmol/kg CDDO-Im or vehicle by oral gavage, during 95 days of access to a control diet or a high-fat diet. Body weights, organ weights, hepatic fat accumulation and gene expression were measured. Treatment with CDDO-Im effectively prevented high-fat diet-induced increases in body weight, adipose mass, and hepatic lipid accumulation in wild-type mice but not in Nrf2-disrupted mice. Wild-type mice on a high-fat diet and treated with CDDO-Im exhibited higher oxygen consumption and energy expenditure than vehicle-treated mice, while food intake was lower in CDDO-Im-treated than vehicle-treated mice. Levels of gene transcripts for fatty acid synthesis enzymes were downregulated after CDDO-Im treatment in the liver of wild-type mice. This inhibitory effect of CDDO-Im on lipogenic gene expression was significantly reduced in Nrf2-disrupted mice. The results indicate that CDDO-Im is an exceedingly potent agent for preventing obesity, and identify the Nrf2 pathway as a novel target for management of obesogenesis.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2009.08.022