Fenretinide prevents high-fat diet induced obesity and associated hyperleptinemia and insulin resistance in mice

Nimesh Mody1,2, Frederic Preitner1,3, Barbara Kahn1. 1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, 2currently Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, United Kingdom, 3currently Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Introduction: Serum RBP4 levels are elevated in insulin resistant humans and in many mouse models of obesity and insulin resistance including high-fat diet. The synthetic retinoid, Fenretinide [N-(4-hydroxyphenyl)retinamide] has been shown to lower serum RBP4 levels in rodents and humans. We previously found that Fenretinide treatment of mice on a high fat diet prevented elevations in serum RBP4 levels, ameliorated insulin resistance and normalized glucose tolerance.

Methods: To determine whether Fenretinide treatment alters energy balance and lipid homeostasis, we placed male FVB mice on high-fat diet +/- Fenretinide (HF and FEN-HF) for 34 weeks and compared them to chow fed controls.

Results: FEN-HF treatment for 16 weeks did not affect body weight as compared to HF controls. However, by 22 weeks of diet, FEN-HF mice gained less weight compared to HF controls. Body fat analysis revealed that the reduced weight gain was due to reduced fat mass gain. Visceral (intra-abdominal) and subcutaneous fat masses were not increased in FEN-HF mice but increased 1.5-2 fold in HF mice. Fenretinide treatment prevented hyperleptinemia in FEN-HFD mice after 8 weeks and 22 weeks of treatment. Fenretinide did not have detectable effects on food intake, lipid assimilation or energy expenditure. Similar results were obtained with only 12 weeks of Fenretinide treatment following 22 weeks of HF-diet induced obesity. Strikingly, in RBP4 knockout mice, FEN also reduced HF-induced adiposity, hyperleptinemia, hyperinsulinemia and impaired insulin tolerance.

Conclusion: Fenretinide has globally beneficial effects to inhibit the progression of diet-induced obesity, insulin resistance and glucose intolerance. These effects appear to be at least partially independent of the serum RBP4-lowering effect.