Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity.

BACKGROUND: Retinoic acid (RA) is known to play a role in weight regulation. Because mice without ALDH1A1, a major RA synthesizing enzyme, are resistant to diet-induced obesity, we tested a hypothesis that pharmacological inhibition of RA synthesis can suppress weight gain in a murine model of diet-induced obesity.

METHODS: C57BL/6J male mice were fed a high fat diet (HFD) for 8 weeks to induce obesity and then randomized to a HFD with or without WIN 18,446, an RA synthesis inhibitor, for an additional 9 weeks. Body weight, body composition, energy expenditure, activity, and food intake were measured. Levels of retinoids, lipids, and genes involved in the metabolism of retinoid and lipids were also determined.

RESULT: s Mice treated with WIN 18,446 gained significantly less weight and had decreased adipose tissue weight, adipocyte size, and macrophage infiltration in adipose tissue. In addition, we observed higher UCP1 expression in adipose tissues and decreased expression of RA responsive genes and genes involved in fatty acid synthesis in the livers and lungs of mice treated with WIN 18,446.

CONCLUSIONS: Pharmacological suppression of RA synthesis via inhibition of ALDH1A1 may be a potential target for treatment of obesity.