Identification, tissue distribution, and anorexigenic effect of amylin in Siberian sturgeon (Acipenser baeri).

Amylin is a 37-amino acid polypeptide that has been found to be involved in feeding regulation in some mammals, birds, and goldfish. We cloned amylin of Siberian sturgeon and detected its distribution pattern in 15 tissues. The expression levels in the periprandial period (pre-and post-feeding), the changes in the food intake, and the expression levels of related appetite factors after the intraperitoneal injection of amylin were detected. The expression of amylin was found to be the highest in the hypothalamus. Compared with 1 h pre-feeding, the expression levels of amylin in the hypothalamus and duodenum were increased significantly 1 h post-feeding. Compared with the control group (saline), intraperitoneal injection of 50 ng/g, 100 ng/g, and 200 ng/g of amylin significantly inhibited food intake at 1 h post injection, but not at 3 h and 6 h. The injection of 50 ng/g, 100 ng/g, and 200 ng/g amylin significantly inhibited the cumulative feed. After 1 h of 50 ng/g amylin injection, the levels of MC4R and somatostatin in the hypothalamus increased significantly, while the levels of amylin and NPY decreased significantly. The levels of CCK in the valvular intestine were increased significantly. Insulin in the duodenum was also increased significantly, but there was no significant change in ghrelin in the duodenum. These results show that amylin inhibits feeding in Siberian sturgeon by down-regulating the appetite-stimulating factor NPY and up-regulating the appetite-suppressing factors somatostatin, MC4R, CCK, and insulin. This study provides a theoretical basis for studying the feeding function and action mechanisms of amylin in Siberian sturgeon.

Whey Protein Drink Ingestion before Breakfast Suppressed Energy Intake at Breakfast and Lunch, but Not during Dinner, and Was Less Suppressed in Healthy Older than Younger Men.

Ageing is associated with changes in feeding behavior. We have reported that there is suppression of energy intake three hours after whey protein drink ingestion in young, but not older, men. This study aimed to determine these effects over a time period of 9 h. Fifteen younger (27 ± 1 years, 25.8 ± 0.7 kg/m2) and 15 older (75 ± 2 years, 26.6 ± 0.8 kg/m2) healthy men were studied on three occasions on which they received, in a randomized order, a 30 g/120 kcal, 70 g/280 kcal whey-protein, or control (~2 kcal) drink. Ad-libitum energy intake (sum of breakfast, lunch, and dinner) was suppressed in a protein load responsive fashion (P = 0.001). Suppression was minimal at breakfast, substantial at lunch (~-16%, P = 0.001), no longer present by dinner, and was less in older than younger men (-3 ± 4% vs. -8 ± 4%, P = 0.027). Cumulative protein intake was increased in the younger and older men (+20% and +42%, P < 0.001). Visual analogue scale ratings of fullness were higher and desire to eat and prospective food consumption were lower after protein vs. control, and these effects were smaller in older vs. younger men (interaction effect P < 0.05). These findings support the use of whey-protein drink supplements in older people who aim to increase their protein intake without decreasing their overall energy intake.

Impact of timing of the anorexigen sibutramine administration on reproductive end-points of male rats.

Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.

The Appetite-Suppressant and GLP-1-Stimulating Effects of Whey Proteins in Obese Subjects are Associated with Increased Circulating Levels of Specific Amino Acids.

The satiating effect of whey proteins depends upon their unique amino acid composition because there is no difference when comparing whey proteins or a mix of amino acids mimicking the amino acid composition of whey proteins. The specific amino acids underlying the satiating effect of whey proteins have not been investigated to date. AIMS AND METHODS: The aim of the present study was to evaluate the appetite-suppressant effect of an isocaloric drink containing whey proteins or maltodextrins on appetite (satiety/hunger measured by a visual analogue scale or VAS), anorexigenic gastrointestinal peptides (circulating levels of glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY)) and amino acids (circulating levels of single, total [TAA] and branched-chain amino acids [BCAA]) in a cohort of obese female subjects (n = 8; age: 18.4 ± 3.1 years; body mass index, BMI: 39.2 ± 4.6 kg/m2). RESULTS: Each drink significantly increased satiety and decreased hunger, the effects being more evident with whey proteins than maltodextrins. Similarly, circulating levels of GLP-1, PYY and amino acids (TAA, BCAA and alanine, arginine, asparagine, citrulline, glutamine, hydroxyproline, isoleucine, histidine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tyrosine, and valine) were significantly higher with whey proteins than maltodextrins. In subjects administered whey proteins (but not maltodextrins), isoleucine, leucine, lysine, methionine, phenylalanine, proline, tyrosine, and valine were significantly correlated with hunger (negatively), satiety, and GLP-1 (positively). CONCLUSIONS: Eight specific amino acids (isoleucine, leucine, lysine, methionine, phenylalanine, proline, tyrosine, and valine) were implicated in the appetite-suppressant and GLP-1-stimulating effects of whey proteins, which may be mediated by their binding with nutrient-sensing receptors expressed by L cells within the gastrointestinal wall. The long-term satiating effect of whey proteins and the effectiveness of a supplementation with these amino acids (i.e., as a nutraceutical intervention) administered during body weight reduction programs need to be further investigated.

Anorexigenic effects of substance P in Coturnix japonica.

Substance P (SP) is an 11-amino acid tachykinin-related peptide that has anorexigenic effects in birds and mammals although the central mechanism is not well understood. Hence, the objective was to identify appetite-associated hypothalamic mechanisms in Japanese quail (Coturnix japonica). Seven days post-hatch, quail were intracerebroventricularly injected with 0, 0.25, 0.5 or 1.0 nmol of SP and monitored for 180 min. On a cumulative basis, quail that received 0.5 and 1.0 nmol of SP consumed less food for 90 min post-injection. On a non-cumulative basis, food intake was reduced in 0.5 nmol-injected birds at 30 min post-injection. Water intake was not affected. A comprehensive behavior analysis was performed, revealing that SP-injected chicks displayed less feeding pecks and reduced locomotion compared to vehicle-injected birds. To identify molecular mechanisms, the hypothalamus was isolated at 1 h post-injection and real-time PCR was performed to measure mRNA. Agouti-related peptide (AgRP) mRNA was reduced in SP-injected chicks. Immunohistochemistry was used to quantify c-Fos-expressing cells in appetite-associated hypothalamic nuclei. There were more reactive cells in the lateral hypothalamus (LH) and the paraventricular nucleus (PVN) of SP- than vehicle-injected chicks. The LH and PVN were collected for gene expression analysis. Corticotropin-releasing factor (CRF) and urotensin 2 (UTS2) mRNAs were greater in SP- than vehicle-injected chicks in the PVN. In the LH, CRF receptor sub-type 2 (CRFR2) mRNA was greater and kappa opioid receptor mRNA was reduced in SP- compared to vehicle-injected quail. Thus, SP induces a potent anorexia in quail that coincides with increased LH-specific CRFR2 mRNA and increased UTS2 mRNA in the PVN. Future studies will evaluate whether SP-induced anorexigenic effects are mediated through CRF receptors.

Hypothalamic mechanisms associated with corticotropin-releasing factor-induced anorexia in chicks.

Central administration of corticotropin-releasing factor (CRF), a 41-amino acid peptide, is associated with potent anorexigenic effects in rodents and chickens. However, the mechanism underlying this effect remains unclear. Hence, the objective of the current study was to elucidate the hypothalamic mechanisms that mediate CRF-induced anorexia in 4 day-old Cobb-500 chicks. After intracerebroventricular (ICV) injection of 0.02 nmol of CRF, CRF-injected chicks ate less than vehicle chicks while no effect on water intake was observed at 30 min post-injection. In subsequent experiments, the hypothalamus samples were processed at 60 min post-injection. The CRF-injected chicks had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), and paraventricular nucleus (PVN) of the hypothalamus than vehicle-treated chicks. CRF injection was associated with decreased whole hypothalamic mRNA abundance of neuropeptide Y receptor sub-type 1 (NPYR1). In the ARC, CRF-injected chicks expressed more CRF and CRF receptor sub-type 2 (CRFR2) mRNA but less agouti-related peptide (AgRP), NPY, and NPYR1 mRNA than vehicle-injected chicks. CRF-treated chicks expressed greater amounts of CRFR2 and mesotocin mRNA than vehicle chicks in the PVN and VMH, respectively. In the DMN, CRF injection was associated with reduced NPYR1 mRNA. In conclusion, the results provide insights into understanding CRF-induced hypothalamic actions and suggest that the anorexigenic effect of CRF involves increased CRFR2-mediated signaling in the ARC and PVN that overrides the effects of NPY and other orexigenic factors.

Oestradiol and leptin have separate but additive anorexigenic effects and differentially target fat mass in rats.

We recently showed that male rats exhibit lower hypophagia and body weight loss compared to female rats following central leptin delivery, suggesting a role for oestradiol in leptin responsiveness. Accordingly, we delivered Ob (leptin) or GFP (control) gene into the brain of male rats that were simultaneously treated with oestradiol or vehicle. In a reciprocal approach, we compared oestradiol-deficient (OVX) with intact females (sham) that received leptin or control vector. Changes in food intake), body weight and body composition were examined. In males, oestradiol and leptin resulted in lower cumulative food intake (15%) and endpoint body weight (5%), although rats receiving dual treatment (oestradiol-leptin) ate 28% less and weighed 22% less than vehicle-control. Changes in food intake were unique to each treatment, with a rapid decrease in vehicle-leptin followed by gradual renormalisation. By contrast, hypophagia in oestradiol-control was of lower amplitude and sporadic. Leptin selectively targeted fat mass and endpoint abdominal fat mass was 65%-80% lower compared to their respective control groups. In females, both leptin groups had lower body weight (endpoint values 20% lower than control groups) with the highest extent in sham animals (endpoint value was 28% less in sham-leptin than in sham-control). OVX rats rapidly started regaining their lost body weight reminiscent of the pattern in males. Leptin rapidly and robustly reduced fat mass with endpoint values 30%-35% less than control treated animals. It appears that leptin and oestradiol decreased food intake and body weight via different mechanisms, with the pattern of oestradiol-leptin being reminiscent of that observed in females and the pattern of OVX-leptin reminiscent of that observed in males. Oestrogen status did not influence initial fat mass loss by leptin. It can be concluded that oestradiol modulates the long-term response to central leptin overexpression, although its actions on energy homeostasis are additive and independent of those of leptin.

Caffeine Transiently Affects Food Intake at Breakfast.

BACKGROUND: Caffeine is frequently added to dietary supplements with claims it facilitates weight loss. OBJECTIVE: The purpose of this study was to test the hypothesis that caffeine administration reduces laboratory and free-living food intake by reducing appetite and that these effects vary by body mass index (BMI). PARTICIPANTS/SETTING: Fifty adults aged 18 to 50 years completed the study (42% male). Exclusion criteria included no previous experience with caffeine, previous adverse event following caffeine consumption, taking any medications or having a medical condition contraindicating caffeine or stimulant consumption or affecting appetite or eating, and reported tobacco use within the past 6 months. DESIGN AND INTERVENTION: Participants visited the laboratory on four separate occasions to complete a double-blind, placebo-controlled, randomized, crossover study. On the first three visits, participants consumed a beverage containing 0, 1, or 3 mg/kg caffeine (order randomized). Thirty minutes later, participants consumed a buffet breakfast, ad libitum. After leaving the laboratory, participants completed hourly appetite assessments and dietary habit books until midnight or bedtime. The fourth session consisted of questionnaires, debriefing, and compensation. MAIN OUTCOME MEASURES: Total and macronutrient intake and appetite sensations in and out of the laboratory were measured. STATISTICAL ANALYSES PERFORMED: Intake data were analyzed using mixed analysis of covariance (ANCOVA). Appetite sensations were analyzed using repeated measures mixed ANCOVA. RESULTS: Total laboratory energy intake was lower (∼10%) after 1 mg/kg caffeine (650.4±52.2 kcal at 1 mg/kg; 721.2±63.2 at 0 mg/kg; 714.7±79.0 at 3 mg/kg) (P=0.046). In the laboratory, appetite sensations were not significantly different by caffeine treatment. Out of the laboratory, neither total intake nor appetite was significantly different by caffeine treatment. There were no significant interactions between caffeine treatment and BMI on intake and appetite sensations in or out of the laboratory. CONCLUSIONS: These results suggest caffeine has weak, transient effects on energy intake and do not support caffeine as an effective appetite suppressant.

An evening milk drink can affect word recall in Indonesian children with decreased sleep efficiency: A randomized controlled trial.

STUDY OBJECTIVES: Sleep is important for memory consolidation in children. This study intended to find out whether an evening milk-based drink could influence sleep efficiency and memory recall in a group of Indonesian children (5-6 years old) with sleep deprivation. METHODS: Children were randomly allocated to one of three interventions: Reference product, satiety-stimulating product, and a relaxing product. The intervention lasted for 6 weeks and children consumed two servings per day of each 200 ml, the serving in the morning being the same for all children. All measurements took place at baseline and at the end of the intervention. Sleep parameters were studied using actigraphy and a sleep diary during three consecutive days. Memory consolidation was tested using a 20 word-pair list, which was memorized the evening before being recalled the next morning at home-base. Anthropometry was measured using standard equipment. RESULTS: The Satiety group showed a significant decrease in word recall, and a significant increase in nocturnal awakenings that was inversely associated with sleep efficiency at the end of the intervention. Sleep efficiency did not differ between the three groups being 75.5 ± 8.6% and 75.7 ± 6.3% at baseline and end of the intervention, respectively. Despite the lower energy intake in the Standard (reference) group, this condition showed the highest increase in weight. DISCUSSION: Evening growing-up milks can affect memory recall, sleep characteristics, and growth. However, to correct sleep efficiency and sleep duration, improvement of parental behavior may be the most important factor with nutrition providing a supplementary effect.

Short-term effects of a green coffee extract-, Garcinia c ambogia- and L-carnitine-containing chewing gum on snack intake and appetite regulation.

INTRODUCTION: Different studies have assessed the influence of chewing gum to aid control of appetite and reduce food intake. PURPOSE: The aims of the present study were to evaluate the effects of chewing gum on satiety, food hedonics and snack intake and to explore the potential effects of the combination of Garcinia c ambogia, green coffee extract and L-carnitine on satiety, when administered in a gum format. METHODS: This was a prospective study in which 57 subjects randomly received three kinds of treatments, in a crossover design: (1) active gum; (2) placebo gum; and (3) no gum. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preference Questionnaire and visual analog scales. RESULTS: There was a significant reduction in low-fat sweet snack intake with placebo gum and the active gum compared to no gum and a reduction in high-fat sweet snack intake with the active gum compared to placebo gum and no gum. Total caloric intake was only reduced in the active gum condition. Both the active and placebo gum conditions significantly reduced hunger and prospective food consumption and increased fullness compared to no gum and were associated with a reduced wanting for sweet food in the LFPQ, consistent in a reduction in the relative preference for sweet snacks versus savoury snacks. CONCLUSION: This study supports the notion that chewing gum containing nutraceutical products might aid in the control over snack intake and reduce hunger sensations.

Desenvolvimento e aplicação de método analí­tico para detecção de estimulantes em suplementos nutricionais adulterados / The development and application of analytical method for the detection of stimulants in adulterated nutritional supplements

A adição fraudulenta de ativos farmacêuticos em suplementos nutricionais é um problema mundial. É comum encontrar mensagens sobre perda de peso, aumento da capacidade intelectual e/ou física, e estímulo sexual na embalagem de suplementos adulterados com fármacos sintéticos ocultos em formulações aparentemente inofensivas para os usuários. No Brasil, a disponibilidade de dados sobre a adulteração de suplementos nutricionais é escassa. No presente trabalho, foi desenvolvido e aplicado um método analítico empregando cromatografia gasosa com detector de nitrogênio fósforo (GC-NPD) para a detecção, identificação e quantificação de estimulantes/anorexígenos não declarados nos rótulos de suplementos alimentares, tais como: cafeína, femproporex, anfepramona, fenfluramina, sibutramina, fentermina, efedrina, fenilpropanolamina, pseudoefedrina e 4- metilhexan-2-amina. A técnica de extração/solubilização com metanol foi utilizada, ressaltando a utilização de baixa quantidade de amostra, solvente e padrões de estimulantes. Após o desenvolvimento e validação do método, as análises foram aplicadas em amostras de suplementos nutricionais obtidos em lojas especializadas em suplementos, de diversas partes do estado de São Paulo (n=125). Das 125 amostras de suplemento nutricional analisadas, 38 delas (30%) apresentaram resultado positivo para alguma das substâncias de interesse, dentre elas, sibutramina, cafeína e efedrina mediante a metodologia escolhida. As amostras positivas foram posteriormente analisadas qualitativamente por LC-MS/MS, no propósito de confirmar o resultado positivo obtido. A técnica analítica empregada proporciona seletividade, linearidade, precisão, exatidão, recuperação e limites em conformidade ao objetivo que foram destinadas. Os métodos de preparo de amostra desenvolvidos e validados demonstraram ser simples, práticos, eficientes e diferenciados pelo baixo uso de amostra e solvente

The fraudulent addition of active pharmaceutical compounds in nutritional supplements is, indeed, a worldwide problem. Often, it can be found several advertisements on various supplement packaging assuring weight loss, increased intellectual and/or physical capacity and sexual stimulation. These products may have been 'spiked' with synthetic drugs containing formulations which are apparently harmless to users. In Brazil, the availability of data about adulteration of nutritional supplements is scarce. In the present work, an analytical method using gas chromatography coupled with a nitrogen-phosphorus detector (GC-NPD) was developed and applied for the detection, identification and quantification of undeclared stimulants and/or anorectic agents in food supplement labels, such as: caffeine, fenproporex, amfepramone, fenfluramine, sibutramine, phentermine, ephedrine, phenylpropanolamine, pseudoephedrine e 4- metilhexan -2- amine. The extraction/solubilization with methanol presented satisfactory results, emphasizing the use of low amount of sample, solvent and standards of analytes. After the development and validation, the method was applied in samples of nutritional supplements obtained from specialty stores in various parts of the state of São Paulo (n = 125). From the 125 nutritional supplement samples analyzed, 38 of them (30%) presented positive results for some of the substances of interest, among them sibutramine, caffeine and ephedrine according to the chosen methodology. The positive samples were subsequently analyzed qualitatively by LCMS / MS, in order to confirm the positive result obtained. The analytical technique employed provides selectivity, linearity, precision, accuracy, recovery and limits in accordance with the intended purpose. The sample preparation methods developed and validated to be simple, practical, efficient and differentiated by the low sample and solvent usage

Apolipoprotein A-IV exerts its anorectic action through a PI3K/Akt signaling pathway in the hypothalamus.

Apolipoprotein A-IV (apoA-IV) is a satiation factor that acts in the hypothalamus, however, the intracellular mechanisms responsible for this action are still largely unknown. Here we report that apoA-IV treatment elicited a rapid activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway in cultured primary hypothalamic neurons, and this effect was significantly attenuated by pretreatment with LY294002, an inhibitor of the PI3K pathway. To determine if the activation of PI3K is required for apoA-IV's inhibitory effect on food intake, apoA-IV was administered intracerebroventricularly. We found that apoA-IV significantly reduced food intake and activated PI3K signaling in the hypothalamus, and these effects were abolished by icv pre-treatment with LY294002. To identify the distinct brain sites where apoA-IV exerts its anorectic action, apoA-IV was administered into the ventromedial hypothalamus (VMH) through implanted bilateral cannula. At a low dose (0.5 µg), apoA-IV significantly inhibited food intake and activated PI3K signaling pathway in the VMH of lean rats, but not in high-fat diet-induced obese (DIO) rats. These results collectively demonstrate a critical role of the PI3K/Akt pathway in apoA-IV's anorectic action in lean rats and suggest a defective PI3K pathway in the VMH is responsible for the impaired apoA-IV's anorectic action in the DIO animals.

Intravenous administration of oxytocin in rats acutely decreases deprivation-induced chow intake, but it fails to affect consumption of palatable solutions.

Despite its limited ability to cross the blood-brain barrier, peripherally administered oxytocin (OT) acutely decreases food intake, most likely via the brainstem and hypothalamic mechanisms. Studies performed to date have focused mainly on the effects of subcutaneous or intraperitoneal OT on the consumption of only solid calorie-dense diets (either standard or high-fat), whereas it is unknown whether, similarly to central OT, peripherally administered peptide reduces intake of calorie-dilute and non-caloric palatable solutions. In this project, we established that 0.1µg/kg intravenous (IV) OT is the lowest anorexigenic dose, decreasing deprivation-induced standard chow intake by ca. 40% in rats and its effect does not stem from aversion. We then used this dose in paradigms in which effects of centrally acting OT ligands on consumption of palatable solutions had been previously reported. We found that IV OT did not change episodic intake of individually presented palatable solutions containing 10% sucrose, 0.1% saccharin, combined 10% sucrose-0.1% saccharin or 4.1%. Intralipid and it failed to affect daily scheduled consumption of a sucrose solution in non-deprived rats. In a two-bottle choice test, IV OT did not shift animals' preference from sucrose to Intralipid. Finally, OT injected IV prior to the simultaneous presentation chow and a sucrose solution in food-deprived rats significantly decreased chow intake, whereas sugar water consumption remained unchanged. We conclude that IV OT reduces deprivation-induced chow intake without causing aversion, but the dose effective in decreasing energy-driven consumption of high-calorie food fails to affect consumption of palatable calorie-dilute solutions.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

A randomized, placebo-controlled trial of beloranib for the treatment of hypothalamic injury-associated obesity.

AIMS: Hypothalamic injury-associated obesity (HIAO) results from damage to the hypothalamus that often occurs with surgical removal/radiation therapy of tumours in the hypothalamic region, such as craniopharyngioma. There is currently no rigorously studied pharmaceutical treatment for the intractable weight gain and cardiometabolic consequences that occur in patients with HIAO. We aimed to assess efficacy, safety and tolerability of beloranib treatment for 4 to 8 weeks in patients with HIAO. MATERIALS AND METHODS: This Phase 2a, double-blind, placebo-controlled study included 14 patients with HIAO, randomized to receive beloranib 1.8 mg or placebo subcutaneously twice weekly for 4 weeks with an optional 4-week open-label extension in which all patients received beloranib. The primary endpoint was change in weight from baseline to Week 4. RESULTS: Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m2 and weight of 126 (22) kg. Compared with placebo (N = 4), beloranib 1.8 mg (N = 8) resulted in a mean (95% CI) difference in weight of -3.2 (-5.4, -0.9) kg after 4 weeks. Weight loss continued through the 8 weeks in patients randomized to beloranib (mean -6.2 [-8.2, -4.1] kg). Beloranib treatment was associated with improvements in high-sensitivity CRP. Adverse events were mild to moderate. No patients who received beloranib discontinued treatment. CONCLUSION: Beloranib treatment resulted in progressive weight loss in patients with HIAO that was comparable to that observed with beloranib in patients with exogenous obesity. These findings indicate a novel mechanism for treating obesity in patients with HIAO.

Modification of aftertaste with a menthol mouthwash reduces food wanting, liking, and ad libitum intake of potato crisps.

This research investigated the effect of modifying the aftertaste of potato crisps on (1) temporal sensory perception and (2) appetite using three mouthwash conditions (no mouthwash, a water mouthwash, and a menthol mouthwash). For the sensory study, 17 screened female subjects were trained on the Temporal Dominance of Sensations (TDS) methodology. Subjects undertook TDS to monitor all sensory attributes during the mastication of a 2 g crisp until swallowing (at 20s), then conducted the mouthwash, and then continued the TDS task to monitor aftertaste until 90s. For the appetite study, 36 subjects (18 male, 18 female) completed 100 mm Visual Analogue Scales (VAS) for desire, liking, hunger, and thirst, followed by an ad libitum eating task. For the VAS scales testing, subjects chewed and swallowed a 2 g crisp, and then immediately conducted the mouthwash before completing the VAS scales. For the ad libitum task, subjects were given 12 min to consume as many crisps as they desired on a plate (up to 50 g). Every three minutes they were required to conduct a mouthwash. TDS results showed that in comparison with no mouthwash, the water mouthwash significantly reduced aftertaste attributes such as savoury, salty, and fatty mouthcoating, and the menthol mouthwash significantly increased aftertaste attributes of cooling, minty, and tingly. The water mouthwash did not influence desire and liking of crisps, or hunger and thirst. The water mouthwash did not influence ad libitum intake of the crisps over a 12 min period. The menthol mouthwash significantly reduced desire and liking of the crisps, as well as hunger and thirst. Furthermore, the menthol mouthwash significantly reduced ad libitum crisp intake by 29% over the 12 min period.

Appetite Suppression and Antiobesity Effect of a Botanical Composition Composed of Morus alba, Yerba mate, and Magnolia officinalis.

Background. Obesity and its comorbidities continue to challenge the world at an alarming rate. Although the long term solution lies on lifestyle changes in the form of dieting and exercising, drug, medical food, or dietary supplement interventions are required for those who are already obese. Here we describe a standardized blend composed of extracts from three medicinal plants: Morus alba, Yerba mate, and Magnolia officinalis for appetite suppression and metabolic disorders management. Method. Extracts were standardized to yield a composition designated as UP601. Appetite suppression activity was tested in acute feed intake rat model. Efficacy was evaluated in C57BL/6J mouse models treated with oral doses of 1.3 g/kg/day for 7 weeks. Orlistat at 40 mg/kg/day was used as a positive control. Body compositions of mice were assessed using a dual energy X-ray absorptiometry (DEXA). ELISA was done for insulin, leptin, and ghrelin level quantitation. Nonalcoholic steatohepatitis (NASH) scoring was conducted. Results. Marked acute hypophagia with 81.8, 75.3, 43.9, and 30.9% reductions in food intake at 2, 4, 6, and 24 hours were observed for UP601. Decreases in body weight gain (21.5% compared to the HFD at weeks 7 and 8.2% compared to baseline) and calorie intake (40.5% for the first week) were observed. 75.9% and 46.8% reductions in insulin and leptin, respectively, 4.2-fold increase in ghrelin level, and reductions of 18.6% in cholesterol and 59% in low-density lipoprotein were documented. A percentage body fat of 18.9%, 47.8%, 46.1%, and 30.4% was found for mice treated with normal control, HFD, Orlistat, and UP601, respectively. 59.3% less mesenteric fat pad and improved NASH scores were observed for UP601. Conclusion. UP601, a standardized botanical composition from Morus alba, Yerba mate, and Magnolia officinalis could be used as a natural alternative for appetite suppression, maintaining healthy body weight and metabolism management.

Satiety effects of psyllium in healthy volunteers.

Controlling hunger between meals is a challenge for many individuals. This manuscript comprises 2 sequential clinical trials investigating the effects of psyllium (Metamucil) on satiety, both using a randomized, double-blind, placebo-controlled cross-over design. The first study determined the effects of 3.4 g, 6.8 g, and 10.2 g of psyllium taken before breakfast and lunch for 3 days. The second study determined the effects of 6.8 g (taken before breakfast and lunch on Days 1 and 2 and before breakfast on Day 3) on the satiety of participants receiving an energy restricted meal in the morning (breakfast) for 3 days. Efficacy endpoints were mean inter-meal hunger, desire to eat, and Satiety Labeled Intensity Magnitude Visual Analog Scale scores. In Study 1, all 3 psyllium doses resulted in directional or statistically significant mean reductions in hunger and desire to eat, and increased fullness between meals compared to placebo, with both higher doses better than placebo or 3.4 g. The 6.8 g dose provided more consistent (p ≤ 0.013) satiety benefits versus placebo. In Study 2, satiety was assessed similarly to Study 1. A significant (p ≤ 0.004) decrease in the 3-day mean hunger and desire to eat, as well as an increase in fullness for psyllium relative to placebo was observed. Most adverse events were mild gastrointestinal symptoms and were similar for psyllium compared to placebo. These results indicate that psyllium supplementation contributes to greater fullness and less hunger between meals.

Anorexic action of deoxynivalenol in hypothalamus and intestine.

Although deoxynivalenol (DON) suppresses food intake and subsequent weight gain, its contribution to anorexia mechanisms has not been fully clarified. Thus, we investigated the anorexic actions of DON in the hypothalamus and intestine, both organs related to appetite. When female B6C3F1 mice were orally exposed to different doses of DON, a drastic anorexic action was observed at a dose of 12.5 mg/kg body weight (bw) from 0 to 3 h after administration. Exposure to DON (12.5 mg/kg bw) for 3 h significantly increased the hypothalamic mRNA levels of anorexic pro-opiomelanocortin (POMC) and its downstream targets, including melanocortin 4 receptor, brain-derived neurotrophic factor, and tyrosine kinase receptor B; at the same time, orexigenic hormones were not affected. In addition, exposure to DON significantly elevated the hypothalamic mRNA levels of proinflammatory cytokines (IL-1ß, TNF-α, and IL-6) and activated nuclear factor-kappa B (NF-κB), an upstream factor of POMC. These results suggest that DON-induced proinflammatory cytokines increased the POMC level via NF-κB activation. Moreover, exposure to DON significantly enhanced the gastrointestinal mRNA levels of anorexic cholecystokinin (CCK) and transient receptor potential ankyrin-1 channel (TRPA1), a possible target of DON; these findings suggest that DON induced anorexic action by increasing CCK production via TRPA1. Taken together, these results suggest that DON induces anorexic POMC, perhaps via NF-κB activation, by increasing proinflammatory cytokines in the hypothalamus and brings about CCK production, possibly through increasing intestinal TRPA1 expression, leading to anorexic actions.