Investigation of an ALDH1A1-Specific Inhibitor, FSI-TN42, as a Treatment for Obesity in Female Mice.

Background/Objectives: Retinoic acids (RA) are involved in regulation of weight and energy metabolism. Mice lacking a RA synthesis enzyme, ALDH1A1, are resistant to diet-induced obesity. We previously identified an ALDH1A1-specific inhibitor, FSI-TN42 (N42), and demonstrated its efficacy in suppressing weight gain in male C57BL/6 mice fed a high-fat diet (HFD). In this report, we evaluated whether N42 is similarly effective in female mice. Methods: Two studies were performed. In the first study, C57BL/6 female mice were fed a HFD for 12 weeks to induce obesity, after which half were switched to a HFD supplemented with N42 (1 g/kg diet). A control group of mice was maintained on a low-fat purified diet throughout the study. Body weight was determined weekly, and fasting or fed blood glucose was determined at 4-8-week intervals. In the second study, obese female C57BL/6 mice were transitioned from a HFD to either (1) a moderate-fat diet (MFD) or (2) MFD + N42 for 9 weeks. Results: N42 significantly suppressed weight gain in female mice maintained on a HFD. However, it did not enhance weight loss when administered alongside a MFD diet, which alone induced significant weight loss comparable to mice fed a control diet throughout the study. Conclusions: The ALDH1A1 inhibitor N42 suppresses weight gain in female mice, consistent with prior findings in male mice. However, unlike in males, N42 did not enhance weight loss under conditions of caloric reduction, likely due to more profound weight loss induced by the lower-calorie diet in female mice.