Influence of Diet-Induced Obesity on the Bioavailability and Metabolism of Raspberry Ketone (4-(4-Hydroxyphenyl)-2-Butanone) in Mice

Objectives: Raspberry ketone (RK) is the primary aroma compound in red raspberries and a dietary supplement for weight loss. This work aims to 1) compare RK bioavailability in male versus female, normal-weight versus obese mice; 2) characterize RK metabolic pathways. Methods: Study 1: C57BL/6J male and female mice fed a low-fat diet (LFD; 10% fat) receive a single oral gavage dose of RK (200 mg kg⁻¹). Blood, brain, and white adipose tissue (WAT) are collected over 12 h. Study 2: Male mice are fed a LFD or high-fat diet (45% fat) for 8 weeks before RK dosing. Samples collected are analyzed by UPLC-MS/MS for RK and its metabolites. Results: RK is rapidly absorbed (T_max ≈ 15 min), and bioconverted into diverse metabolites in mice. Total bioavailability (AUC_{0–12 h}) is slightly lower in females than males (566 vs 675 nmol mL⁻¹ min⁻¹). Total bioavailability in obese mice is almost doubled that of control mice (1197 vs 679 nmol mL⁻¹ min⁻¹), while peaking times and elimination half-lives are delayed. Higher levels of RK and major metabolites are found in WAT of the obese than normal-weight animals. Conclusions: RK is highly bioavailable, rapidly metabolized, and exhibits significantly different pharmacokinetic behaviors between obese and control mice. Lipid-rich tissues, especially WAT, can be a direct target of RK.