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

Abstract

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 micromol/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.

• Authors: Soona Shin, Junko Wakabayashi, Melinda S Yates, Nobunao Wakabayashi, Patrick M Dolan, Susan Aja, Karen T Liby, Michael B Sporn, Masayuki Yamamoto, Thomas W Kensler
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 620 Issue 1-3 Pg. 138-44 (Oct 12 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19698707 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Anti-Obesity Agents
• Dietary Fats
• Fatty Acids
• Imidazoles
• NF-E2-Related Factor 2
• Oleanolic Acid

Topics

• Adipocytes (drug effects, metabolism)
• Animals
• Anti-Obesity Agents (pharmacology)
• Body Weight (drug effects)
• Dietary Fats (pharmacology)
• Energy Metabolism (drug effects)
• Fatty Acids (biosynthesis)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Imidazoles (pharmacology)
• Liver (drug effects, enzymology, metabolism)
• Mice
• NF-E2-Related Factor 2 (deficiency, metabolism)
• Obesity (chemically induced, metabolism, physiopathology, prevention & control)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Oxidation-Reduction