In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.

Dihydromyricetin is a natural bioactive flavonoid with unique GABA_A 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 GABA_A 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.

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.

Recent advances in developing and screening candidate pharmacotherapies for psychiatric disorders have depended on rodent models. Eating disorders are a set of psychiatric disorders that have traditionally relied on behavioral therapies for effective long-term treatment. However, the clinical use of Lisdexamfatamine for binge eating disorder (BED) has furthered the notion of using pharmacotherapies for treating binge eating pathologies. While there are several binge eating rodent models, there is not a consensus on how to define pharmacological effectiveness within these models. Our purpose is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. These findings will help provide guidance for determining pharmacological effectiveness for potential novel or repurposed pharmacotherapies.

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.