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

Soona Shin, Junko Wakabayashi, Melinda S. Yates, Nobunao Wakabayashi, Patrick M. Dolan, Susan M Aja, Karen T. Liby, Michael B. Sporn, Masayuki Yamamoto, Thomas W Kensler

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)138-144
Number of pages7
JournalEuropean Journal of Pharmacology
Volume620
Issue number1-3
DOIs
StatePublished - Oct 12 2009

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Keywords

  • Diet-induced obesity
  • Fatty acid synthase
  • Nrf2
  • Triterpenoid

ASJC Scopus subject areas

  • Pharmacology

Cite this

Shin, S., Wakabayashi, J., Yates, M. S., Wakabayashi, N., Dolan, P. M., Aja, S. M., Liby, K. T., Sporn, M. B., Yamamoto, M., & Kensler, T. W. (2009). Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide. European Journal of Pharmacology, 620(1-3), 138-144. https://doi.org/10.1016/j.ejphar.2009.08.022