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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.

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Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is a popular nutraceutical used for weight management and appetite control. We sought to determine the physiological benefits of RK on the meal patterns and cardiovascular changes associated with an obesogenic diet. In addition, we explored whether the physiological benefits of RK promoted anxiety-related behaviors. Male and female C57BL/6J mice were administered a daily oral gavage of RK 200 mg/kg, RK 400 mg/kg, or vehicle for 14 days. Commencing with dosing, mice were placed on a high-fat diet (45% fat) or low-fat diet (10% fat). Our results indicated that RK 200 mg/kg had a differential influence on meal patterns in males and females. In contrast, RK 400 mg/kg reduced body weight gain, open-field total distance travelled, hemodynamic measures (i.e., reduced systolic blood pressure (BP), diastolic BP and mean BP), and increased nocturnal satiety ratios in males and females. In addition, RK 400 mg/kg increased neural activation in the nucleus of the solitary tract, compared with vehicle. RK actions were not influenced by diet, nor resulted in an anxiety-like phenotype. Our findings suggest that RK has dose-differential feeding and cardiovascular actions, which needs consideration as it is used as a nutraceutical for weight control for obesity.

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Objectives Raspberry ketone (RK), the characteristic aromatic phenol derived from red raspberries (Rubus idaeus L.), has purported anti-obesity properties. This work aims to 1) conduct pharmacokinetic (PK) studies to compare the bioavailability of orally dosed RK among four cohorts of mice: male vs female, lean vs. obese; 2) Characterize major RK metabolites generated in vivo; 3) Develop targeted metabolomic approaches of bioanalysis. Methods PK-1: Polyphenol-free diet fed normal-weight C57BL/6 mice (male and female, n = 3–5) received a single dose of RK (200 mg/kg) by gavage. Blood, brain and white adipose tissue (WAT) were then collected at various time-points. 12 h excretion of urine and feces were also collected. PK-2: Another two cohorts of mice were fed on low-fat-diet or high-fat-diet (HFD) for 8 weeks before RK dosing and sample collection. Phenolics in biosamples were extracted and analyzed using ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ/MS). Results 28 RK-related metabolites including newly discovered RK structurally-related metabolites (SRMs) and typical microbial phenolic acid metabolites (PAMs) were identified and quantified at varying levels in different biosamples using two validated analytical methods. PK results indicated fast absorption of RK (Cmax ∼15 min) and efficient bioconversion into diverse SRMs and PAMs as detected in plasma, brain and WAT specimens. In PK-1 study, total bioavailability including RK and 7 major SRMs, expressed as accumulative area-under-the-curve (AUC, 0–12 h), was lower in females than males (566 vs. 675 nmol/mL*min), which can be explained by the faster absorption and elimination in females. In PK-2 study, total bioavailability in obese mice was almost doubled that of lean mice (1197 vs. 679 nmol/mL*min), while the peak time of RK metabolites and elimination half-lives were generally delayed. Moreover, the rapid and remarkable accumulation of RK and its metabolites in brain and WAT are suggestive of RK's direct effects on lipid-rich tissues. Conclusions Orally administered RK is highly bioavailable, including in the brain and WAT, and are rapidly metabolized in mice. Our findings are critical for elucidating the sites and mechanisms of action of RK for long-term management of diet-induced obesity. Funding Sources This work was supported by the NIH R01AT008933. Supporting Tables, Images and/or Graphs

Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin’s poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC0→24) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC0→24 in male and female mice, respectively. Electrophysiology studies in α5β3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (−12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM’s anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM’s potential anti-intoxicating properties.