Sex-Specific Effects on Total Body Fat Gain with 4-Week Daily Dosing of Raspberry Ketone [4-(4-Hydroxyphenyl)-2-butanone] and Ketogenic Diet in Mice

Background: Raspberry ketone (RK: [4-(4-Hydroxyphenyl)-2-butanone]) is a dietary supplement marketed for weight control. RK is structurally unrelated to the ketone bodies elevated with a ketogenic diet (KD). This study aims to determine whether RK oral supplementation with KD improves the weight loss outcomes in high-fat diet (HFD; 45% fat)-fed mice. Methods: Male and female C57BL/6J mice were HFD-fed for 9 weeks and switched to KD (80% fat) or a control diet (CD; 10% fat) or continued with the HFD for 4 weeks. Coincident with the diet switch, each diet group received oral RK (200 mg/kg/day) or a vehicle. Results: In male KD-fed mice, oral RK reduced body weight by ~6% (KD_Veh: −9.2 ± 1% vs. KD_RK: −15.1 ± 1%) and fat composition by ~18% (KD_Veh: −16.0 ± 4% vs. KD_RK: −34.2 ± 5%). HFD and KD feeding induced glucose intolerance in both male and female mice. Oral RK decreased the glucose area under the curve in female mice by ~6% (KD_Veh: 44,877 ± 957 vs. KD_RK: 42,040 ± 675 mg*min/dl). KD also had gut microbiota alterations with higher alpha diversity in males and more beta diversity with RK. These findings suggest sex-specific weight loss effects with RK and KD in mice.