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This Article Full Text (PDF) All Versions of this Article: 297/6/E1420    most recent ajpendo.00362.2009v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Preitner, F. Articles by Kahn, B. PubMed PubMed Citation Articles by Preitner, F. Articles by Kahn, B.

RESEARCH ARTICLE

LONG-TERM FENRETINIDE TREATMENT PREVENTS HIGH FAT DIET-INDUCED OBESITY, INSULIN RESISTANCE AND HEPATIC STEATOSIS

¹University of Lausanne, Lausanne, Switzerland ²University of Aberdeen ³Beth Israel Deaconess Medical Center

Submitted 3 June 2009 ; revised 13 October 2009 ; accepted in final form 13 October 2009

The synthetic retinoid, Fenretinide (FEN), increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis. We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wildtype mice were fed HF diet +/- FEN from 4-5 weeks to 36-37 weeks of age (preventive study) or following 22 weeks of HF diet-induced obesity (12 week intervention study). RBP4 knockout mice were also fed HF diet +/- FEN in a preventive study. FEN had minimal effects on HF-diet-induced body weight gain but markedly reduced HF-induced adiposity and hyperleptinemia in both studies. FEN-HF mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HF mice without FEN. Fenretinide did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HF mice compared with controls and was improved 3.6-fold in FEN-HF compared to HF mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production and suppression of serum FFA levels in HF mice. Remarkably, Fenretinide also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced HF-induced increase of adiposity and hyperleptinemia. In conclusion, long-term therapy with Fenretinide partially prevents or reverses obesity, insulin resistance and hepatic steatosis in mice on HF diet. The anti-adiposity effects are independent of the RBP4-lowering effect.

retinol binding protein 4; type 2 diabetes; hyperleptinemia; retinoids