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 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.
Shin
Soona
S
Department of Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
Wakabayashi
Junko
J
Yates
Melinda S
MS
Wakabayashi
Nobunao
N
Dolan
Patrick M
PM
Aja
Susan
S
Liby
Karen T
KT
Sporn
Michael B
MB
Yamamoto
Masayuki
M
Kensler
Thomas W
TW
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D019440:Anti-Obesity Agents; D004041:Dietary Fats; D005227:Fatty Acids; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid
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