Leptin mediates the increase in blood pressure associated with obesity.

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

Effect of exercise training on insulin-stimulated glucose disposal: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults. SUBJECTS: MEDLINE, EMBASE, and CENTRAL databases were searched until January 2021. Randomized controlled trials lasting ≥4 weeks, including adults, and evaluating the effect of exercise on insulin-stimulated glucose disposal measured using the hyperinsulinemic euglycemic clamp, were included. METHODS: Three reviewers extracted summary data from published trials. The primary outcome was insulin-stimulated glucose disposal. Standardized weighted mean differences (SMD) in glucose disposal between intervention and control were compared. The PEDro scale was used to assess risk of bias. RESULTS: We included 25 trials (36 interventions, N = 851). Exercise increased insulin-stimulated glucose disposal relative to control, SMD = 0.52 (95% confidence interval [CI]: 0.39, 0.65; p < 0.001; I2 = 47%) without significantly suppressing hepatic glucose production. In trials without isotopic tracers, exercise increased glucose disposal (SMD = 0.63; 95% CI: 0.48, 0.77; p < 0.001, I2 = 55%). In trials with isotopic tracers, exercise increased glucose disposal only when tracers were added to the exogenous glucose used for clamping (SMD = 0.34; 95% CI: 0.03, 0.66, p = 0.034. I2 = 0%). In a meta-regression model including aerobic exercise, weight change, and tracer technique, only percent weight change explained between trial heterogeneity (ß = 0.069; 95% CI: 0.005, 0.013). The PEDro rating indicated relatively low risk of bias (5.8 ± 0.22). CONCLUSIONS: Exercise training for at least four weeks significantly increases insulin-stimulated glucose disposal. Weight loss maximizes the effect and may be needed to improve hepatic insulin sensitivity. Differences in tracer methodology contribute to divergent outcomes and should be considered when assessing conclusions from research examining the effect of exercise on insulin action. REGISTRATION: PROSPERO (CRD42019124381).

Orlistat mouth rinse: Using the tongue to deliver antiobesity medication in a double-blind randomized crossover pilot trial.

AIM: To investigate the effects of an orlistat mouth rinse on the intake of a high-fat meal. METHODS: A double-blind, balanced order, crossover study was conducted in participants (n = 10, body mass index 25-30 kg/m2 ) assigned to receive placebo or orlistat (24 mg/mL) prior to a high-fat meal. Participants were divided into low- or high-fat consumers based on calories consumed from fat following placebo administration. RESULTS: The orlistat mouth rinse decreased total and fat calories consumed during the high-fat meal in high-fat consumers, and did not alter calories consumed in low-fat consumers (P < 0.05). CONCLUSIONS: Orlistat decreases long-chain fatty acid (LCFA) absorption by inhibiting lipases that breakdown triglycerides. Orlistat mouth rinse decreased fat intake in high-fat consumers, suggesting that orlistat inhibited the detection of LCFAs from the high-fat test meal. Lingual delivery of orlistat is predicted to eliminate the risk of oil incontinence and promote weight loss in individuals who prefer fat.

Technical report: an online international weight control registry to inform precision approaches to healthy weight management.

BACKGROUND: Personalizing approaches to prevention and treatment of obesity will be a crucial aspect of precision health initiatives. However, in considering individual susceptibility to obesity, much remains to be learned about how to support healthy weight management in different population subgroups, environments and geographical locations. SUBJECTS/METHODS: The International Weight Control Registry (IWCR) has been launched to facilitate a deeper and broader understanding of the spectrum of factors contributing to success and challenges in weight loss and weight loss maintenance in individuals and across population groups. The IWCR registry aims to recruit, enroll and follow a diverse cohort of adults with varying rates of success in weight management. Data collection methods include questionnaires of demographic variables, weight history, and behavioral, cultural, economic, psychological, and environmental domains. A subset of participants will provide objective measures of physical activity, weight, and body composition along with detailed reports of dietary intake. Lastly, participants will be able to provide qualitative information in an unstructured format on additional topics they feel are relevant, and environmental data will be obtained from public sources based on participant zip code. CONCLUSIONS: The IWCR will be a resource for researchers to inform improvements in interventions for weight loss and weight loss maintenance in different countries, and to examine environmental and policy-level factors that affect weight management in different population groups. This large scale, multi-level approach aims to inform efforts to reduce the prevalence of obesity worldwide and its associated comorbidities and economic impacts. TRIAL REGISTRATION: NCT04907396 (clinicaltrials.gov) sponsor SB Roberts; Tufts University IRB #13075.

Exercise as a Moderator of Persistent Neuroendocrine Symptoms of COVID-19.

Precipitated by chronic psychological stress, immune system dysregulation, and a hyperinflammatory state, the sequelae of postacute COVID-19 (long COVID) include depression and new-onset diabetes. We hypothesize that exercise counters the neuropsychiatric and endocrine sequelae of long COVID by inducing the release of circulating factors that mediate the anti-inflammatory response, support brain homeostasis, and increase insulin sensitivity.

Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. Design, Setting, and Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). Main Outcomes and Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. Conclusions and Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04074161.

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial.

BACKGROUND: This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. STUDY QUESTION: Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight? STUDY DESIGN: We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18-65 years of age without diabetes and with the body mass index (BMI) of 30-45 kg/m2. MEASURES AND OUTCOMES: The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. RESULTS: Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were -1.99%, -1.69%, and -1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%). CONCLUSIONS: Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30-39.9 kg/m2, especially participants with hyperinsulinemia.

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main Outcomes and Measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

Obesity, the most common comorbidity in SARS-CoV-2: is leptin the link?

Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host's first line of defense against a human coronavirus infection. However, most coronaviruses are armed with one strategy or another to overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. The multifaceted nature of obesity including its effects on immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Elevated circulating leptin concentrations are a hallmark of obesity, which is associated with a leptin-resistant state. Leptin is secreted by adipocytes in proportion to body fat and regulates appetite and metabolism through signaling in the hypothalamus. However, leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response. Therefore, it seems appropriate that its dysregulation would have serious consequences during an infection. We propose that leptin may be the link between obesity and its high prevalence as a comorbidity of the SARS-CoV-2 infection. In this article, we present a synthesis of the mechanisms underpinning susceptibility to respiratory viral infections and the contribution of the immunomodulatory effects of obesity to the outcome.

Two weeks of moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes.

We previously showed that nightly exposure to moderate hypoxia reduces fasting glucose levels and improves both whole-body skeletal muscle and hepatic insulin sensitivity in individuals with obesity. The goal of this study was to extend this observation in an "at home" setting and determine if nightly exposure to moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Eight adults, ages 20-65 years with type 2 diabetes enrolled in our study and slept for 14 consecutive nights at home in a hypoxic tent maintained at 15% O2 (~2400 m). The primary endpoint was insulin sensitivity (Matsuda Index) calculated from a 75-g oral glucose tolerance test. Secondary endpoints included calculations of insulin secretion and beta-cell function, including the area-under-the-curve (AUC) for glucose and insulin, the Insulinogenic Index, and the Disposition Index. We observed the Matsuda Index trended towards a 29% increase following 14 nights of moderate hypoxia (from 1.7 ± 0.7 to 2.2 ± 1.7; p = 0.06). Two-hour glucose AUC was significantly reduced from 501 ± 99 to 439 ± 65 mg/dL × h (p = 0.01). We conclude that 14 nights of moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Future studies should confirm whether exposure to moderate hypoxia consistently improves glucose homeostasis in larger sample sizes.

Safety and pharmacokinetics of naringenin: A randomized, controlled, single-ascending-dose clinical trial.

AIMS: To evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole-orange (Citrus sinensis) extract. METHODS AND METHODS: In a single-ascending-dose randomized crossover trial, 18 adults ingested doses of 150 mg (NAR150), 300 mg (NAR300), 600 mg (NAR600) and 900 mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash-out period of at least 1 week. Blood safety markers were evaluated pre-dose and 24 hours post-dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150 and NAR600. Four- and 24-hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed-effects linear model. RESULTS: There were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76 ± 7.88 µM (NAR150) and 48.45 ± 7.88 µM (NAR600); time to peak: 3.17 ± 0.74 hours (NAR150) and 2.41 ± 0.74 hours (NAR600); area under the 24-hour concentration-time curve: 67.61 ± 24.36 µM × h (NAR150) and 199.05 ± 24.36 µM × h (NAR600); and apparent oral clearance: 10.21 ± 2.34 L/h (NAR150) and 13.70 ± 2.34 L/h (NAR600). Naringenin half-life was 3.0 hours (NAR150) and 2.65 hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67 ± 5.74 µM (4 hours) and 0.35 ± 0.30 µM (24 hours). After NAR900 ingestion, serum concentrations were 43.11 ± 5.26 µM (4 hours) and 0.24 ± 0.30 µM (24 hours). CONCLUSIONS: Ingestion of 150 to 900 mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 µM) is effective in primary human adipocytes, ingestion of 300 mg naringenin twice/d will likely elicit a physiological effect.

Effect of daily consumption of cranberry beverage on insulin sensitivity and modification of cardiovascular risk factors in adults with obesity: a pilot, randomised, placebo-controlled study.

Cranberries are high in polyphenols, and epidemiological studies have shown that a high-polyphenol diet may reduce risk factors for diabetes and CVD. The present study aimed to determine if short-term cranberry beverage consumption would improve insulin sensitivity and other cardiovascular risk factors. Thirty-five individuals with obesity and with elevated fasting glucose or impaired glucose tolerance participated in a randomised, double-blind, placebo-controlled, parallel-designed pilot trial. Participants consumed 450 ml of low-energy cranberry beverage or placebo daily for 8 weeks. Changes in insulin sensitivity and cardiovascular risk factors including vascular reactivity, blood pressure, RMR, glucose tolerance, lipid profiles and oxidative stress biomarkers were evaluated. Change in insulin sensitivity via hyperinsulinaemic-euglycaemic clamp was not different between the two groups. Levels of 8-isoprostane (biomarker of lipid peroxidation) decreased in the cranberry group but increased in the placebo group (-2·18 v. +20·81 pg/ml; P = 0·02). When stratified by baseline C-reactive protein (CRP) levels, participants with high CRP levels (>4 mg/l) benefited more from cranberry consumption. In this group, significant differences in the mean change from baseline between the cranberry (n 10) and the placebo groups (n 7) in levels of TAG (-13·75 v. +10·32 %; P = 0·04), nitrate (+3·26 v. -6·28 µmol/l; P = 0·02) and 8-isoprostane (+0·32 v. +30·8 pg/ml; P = 0·05) were observed. These findings indicate that 8 weeks of daily cranberry beverage consumption may not impact insulin sensitivity but may be helpful in lowering TAG and changing certain oxidative stress biomarkers in individuals with obesity and a proinflammatory state.

Increased Human Growth Hormone After Oral Consumption of an Amino Acid Supplement: Results of a Randomized, Placebo-Controlled, Double-Blind, Crossover Study in Healthy Subjects.

BACKGROUND: Human growth hormone (hGH) is best known for influencing bone and muscle growth, as well as body composition, but the use of recombinant hGH is controversial. Amino acids are a potentially safer alternative; however, preliminary investigations of the effects of oral amino acids on hGH release have been inconclusive. Therefore, we tested the effects of a novel blend of amino acids optimized to increase hGH release. STUDY QUESTION: Does an investigational amino acid supplement affect hGH release? STUDY DESIGN: This was a randomized, placebo-controlled, double-blind, crossover study that included 16 (12 men, 4 women; age 32 ± 14 years; body mass index 26.4 ± 5.0 kg/m) healthy participants. All participants received both placebo and the amino acid supplement after an overnight fast and completed all study visits. Treatment order was randomized, and each treatment was separated by a 1-week washout period. MEASURES AND OUTCOMES: The primary outcomes were the percent change in hGH from baseline to 120 minutes and the area under the curve of hGH over baseline. Serum hGH was measured using enzyme-linked immunosorbent assay at baseline and 15, 30, 60, 90, and 120 minutes. RESULTS: At 120 minutes, hGH levels increased by 682% (8-fold) from baseline and were significantly higher than placebo (P = 0.01). In addition, a significantly higher mean area under the curve was observed for the amino acid supplement compared with the placebo [20.4 (95% confidence interval, 19.9-21.0 ng/mL) vs. 19.7 (95% confidence interval, 18.7-20.6 ng/mL); P = 0.04]. CONCLUSIONS: These results show that a single dose of the oral amino acid supplement was sufficient to significantly increase hGH levels in healthy adult men and women. CLINICAL TRIAL REGISTRY:: clinicaltrials.gov NCT01540773.

Psychiatric adverse events and effects on mood with prolonged-release naltrexone/bupropion combination therapy: a pooled analysis.

BACKGROUND/OBJECTIVES: Prolonged-release (PR) naltrexone 32 mg/bupropion 360 mg (NB) is approved for chronic weight management as an adjunct to reduced-calorie diet and increased physical activity. Central nervous system-active medications have the potential to affect mood; therefore, post hoc analysis of clinical trial data was conducted to evaluate psychiatric adverse events (PAEs) and effects on mood of NB therapy versus placebo. SUBJECTS/METHODS: Data were pooled from 5 prospective, double-blind, randomized, placebo-controlled clinical trials (duration range, 24-56 weeks) of NB in subjects with overweight or obesity. PAEs were collected via AE preferred terms, organized into major subtopics (e.g., anxiety, depression, sleep disorders), and divided into category terms (e.g., anxiety, potential anxiety symptoms). Additionally, the Inventory of Depressive Symptomatology Self Report (IDS-SR; score range 0-84) and the Columbia Classification Algorithm of Suicide Assessment (C-CASA) evaluated treatment-emergent depressive/anxiety symptoms and suicidal behavior/ideation, respectively. RESULTS: Baseline characteristics and comorbidities were comparable for placebo (n = 1515) and NB (n = 2545). Most common PAEs in the NB group (using category grouping; NB vs placebo) were sleep disorders (12.7 vs 7.9%, P < 0.001), anxiety (5.4 vs 3.3%, P = 0.029), and depression (1.8 vs 2.7%, P = 0.014); PAEs were more frequent during dose escalation and generally mild or moderate. Mean (SD) changes in IDS-SR total score from baseline to endpoint were small in both groups: 0.13 (5.83) for NB and -0.45 (5.65) for placebo. Retrospective AE categorization via C-CASA confirmed no completed suicides, suicide attempts, or preparatory acts toward imminent suicidal behavior. CONCLUSIONS: This large pooled analysis of 5 clinical trials provides additional safety information about the NB PAE profile. Anxiety and sleep disorder-related PAEs were more frequent with NB versus placebo but were mostly mild to moderate and generally occurred early. Depression-related PAEs were less common with NB than placebo, and NB was not associated with suicidal ideation or behavior in this patient population.

Pilot Study of the Tart Cherry Juice for the Treatment of Insomnia and Investigation of Mechanisms.

BACKGROUND: Insomnia is common in the elderly and is associated with chronic disease, but use of hypnotics increases the incidence of falls. Montmorency tart cherry juice has improved insomnia by self-report questionnaire. STUDY QUESTION: Is insomnia confirmed by polysomnography and is tryptophan availability a potential mechanism for treating insomnia? STUDY DESIGN: A placebo-controlled balanced crossover study with subjects older than 50 years and insomnia were randomized to placebo (2 weeks) or cherry juice (2 weeks) (240 mL 2 times/d) separated by a 2-week washout. MEASURES AND OUTCOMES: Sleep was evaluated by polysomnography and 5 validated questionnaires. Serum indoleamine 2,3-dioxygenase (IDO), the kynurenine-to-tryptophan ratio, and prostaglandin E2 were measured. In vitro, Caco-2 cells were stimulated with interferon-gamma, and the ability of cherry juice procyanidin to inhibit IDO which degrades tryptophan and stimulates inflammation was measured. The content of procyanidin B-2 and other major anthocyanins in cherry juice were determined. RESULTS: Eleven subjects were randomized; 3 with sleep apnea were excluded and referred. The 8 completers with insomnia increased sleep time by 84 minutes on polysomnography (P = 0.0182) and sleep efficiency increased on the Pittsburgh Sleep Quality Index (P = 0.03). Other questionnaires showed no significant differences. The serum kynurenine-to-tryptophan ratio decreased, as did the level of prostaglandin E2 (both P < 0.05). In vitro, cherry juice procyanidin B-2 dose-dependently inhibited IDO. CONCLUSIONS: Cherry juice increased sleep time and sleep efficiency. Cherry juice procyanidin B-2 inhibited IDO, increased tryptophan availability, reduced inflammation, and may be partially responsible for improvement in insomnia.

Effect of Two Oat-based Cereals on Subjective Ratings of Appetite.

Viscosity generated by oat ß-glucan induces gastrointestinal mechanisms that influence appetite. Two oat-based ready-to-eat cereals (RTEC) with similar amounts of ß-glucan but differing in their protein and sugar content were compared for their effects on appetite. Forty-seven healthy individuals, ≥18 years old, enrolled in a crossover trial consumed RTEC1 or RTEC2 in random order at least a week apart. Breakfasts contained 250kcals cereal and 105kcals fat-free milk. Subjective ratings of appetite were completed at baseline, and at 30, 60, 120, 180 and 240 minutes after consumption of the breakfast meals. Responses were analyzed as area under the curve (AUC) and per time-point. Significance was set at α=0.05. Fullness (p=0.01) and stomach fullness (p=0.02) were greater with RTEC 1 compared to RTEC 2 at 240 minutes. Stomach fullness (p=0.01) was greater at 30 minutes, and desire to eat (p=0.04) was reduced at 120 minutes with RTEC2 compared to RTEC1. There was no difference in the AUC for hunger, fullness, stomach fullness, desire to eat, or prospective intake. Ready-to-eat cereals containing similar amounts of oat ß-glucan differed in the timing of significant differences in fullness or desire to eat, but appetite ratings over a four hour period did not differ.

Pomegranate juice and extract extended lifespan and reduced intestinal fat deposition in Caenorhabditis elegans.

Pomegranate juice with a high content of polyphenols, pomegranate extract, ellagic acid, and urolithin A, have anti-oxidant and anti-obesity effects in humans. Pomegranate juice extends lifespan of Drosophila melanogaster. Caenorhabditis elegans (C. elegans) (n = 6) compared to the control group in each treatment, lifespan was increased by pomegranate juice in wild type (N2, 56 %, P < 0.001) and daf-16 mutant (daf-16(mgDf50)I) (18 %, P = 0.00012), by pomegranate extract in N2 (28 %, P = 0.00004) and in daf-16(mgDf50)I (10 %, P < 0.05), or by ellagic acid (11 %, P < 0.05). Pomegranate juice reduced intestinal fat deposition (IFD) in C. elegans (n = 10) N2 (-68 %, P = 0.0003) or in the daf-16(mgDf50)I (-33 %, P = 0.0034). The intestinal fat deposition was increased by pomegranate extract in N2 (137 %, P < 0.0138) and in daf-16(mgDf50)I (26 %, P = 0.0225), by ellagic acid in N2 (66 %, P < 0.0001) and in daf-16(mgDf50)I (74 %, P < 0.0001), or by urolithin A in N2 (57 %, P = 0.0039) and in daf-16(mgDf50)I (43 %, P = 0.0001). These effects were partially mediated by the daf-16 pathway. The data may offer insights to human aging and obesity due to homology with C. elegans.

Instant Oatmeal Increases Satiety and Reduces Energy Intake Compared to a Ready-to-Eat Oat-Based Breakfast Cereal: A Randomized Crossover Trial.

BACKGROUND: Foods that enhance satiety can help consumers to resist environmental cues to eat and help adherence to calorie restriction. The objective of this study was to compare the effect of 2 oat-based breakfast cereals on appetite, satiety, and food intake. METHODS: Forty-eight healthy individuals, 18 years of age or older, were enrolled in a randomized, crossover trial. Subjects consumed isocaloric servings of either oatmeal or an oat-based ready-to-eat breakfast cereal (RTEC) in random order at least a week apart. Visual analogue scales measuring appetite and satiety were completed before breakfast and throughout the morning. Lunch was served 4 hours after breakfast. The physicochemical properties of oat soluble fiber (ß-glucan) were determined. Appetite and satiety responses were analyzed by area under the curve. Food intake and ß-glucan properties were analyzed using t tests. RESULTS: Oatmeal increased fullness (p = 0.001) and reduced hunger (p = 0.005), desire to eat (p = 0.001), and prospective intake (p = 0.006) more than the RTEC. Energy intake at lunch was lower after eating oatmeal compared to the RTEC (p = 0.012). Oatmeal had higher viscosity (p = 0.03), ß-glucan content, molecular weight (p < 0.001), and radius of gyration (p < 0.001) than the RTEC. CONCLUSIONS: Oatmeal suppresses appetite, increases satiety, and reduces energy intake compared to the RTEC. The physicochemical properties of ß-glucan and sufficient hydration of oats are important factors affecting satiety and subsequent energy intake.

Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development.

The Caenorhabditis elegans model is a rapid and inexpensive method to address pharmacologic questions. We describe the use of C. elegans to explore 2 pharmacologic questions concerning candidate antiobesity drugs and illustrate its potential usefulness in pharmacologic research: (1) to determine a ratio of betahistine-olanzapine that blocks the olanzapine-induced intestinal fat deposition (IFD) as detected by Nile red staining and (2) to identify the mechanism of action of a pharmaceutical candidate AB-101 that reduces IFD. Olanzapine (53 µg/mL) increased the IFD (12.1 ± 0.1%, P < 0.02), which was blocked by betahistine (763 µg/mL, 39.3 ± 0.01%, P < 0.05) in wild-type C. elegans (N2). AB-101 (1.0%) reduced the IFD in N2 (P < 0.05), increased the pharyngeal pumping rate (P < 0.05), and reversed the elevated IFD induced by protease inhibitors atazanavir and ritonavir (P < 0.05). AB-101 did not affect IFD in a ACS null mutant strain acs-4(ok2872) III/hT2[bli-4(e937) let-?(q782) qIs48](I;III) suggesting an involvement of the lipid oxidation pathway and an upregulation of CPT-1. Our studies suggest that C. elegans may be used as a resource in pharmacologic research. This article is intended to stimulate a greater appreciation of its value in the development of new pharmaceutical interventions.

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release.

GSK-1614235 and KGA-2727 are potent, selective inhibitors of the SGLT1 sodium-dependent glucose transporter. Nonclinical (KGA-2727) and clinical (GSK-1614235) trials assessed translation of SGLT1 inhibitor effects from rats to normal human physiology. In rats, KGA-2727 (0.1 mg/kg) or vehicle was given before oral administration of 3-O-methyl-α-d-glucopyranose (3-O-methylglucose, 3-OMG) containing 3-[3H]OMG tracer. Tracer absorption and distribution were assessed from plasma, urine, and fecal samples. SGLT1 inhibition reduced urine 3-OMG recovery and increased fecal excretion. SGLT1 inhibitor effects on plasma glucose, insulin, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were also measured during a standard meal. Incremental glucose, insulin, and GIP concentrations were decreased, indicating downregulation of ß-cell and K cell secretion. Minimal effects were observed in the secretion of the L cell product, GLP-1. With the use of a three-way, crossover design, 12 healthy human subjects received placebo or 20 mg GSK-1614235 immediately before or after a meal. Five minutes into the meal, 3-OMG was ingested. Postmeal dosing had little impact, yet premeal dosing delayed and reduced 3-OMG absorption, with an AUC0-10 of 231±31 vs. 446±31 µg·h(-1)·ml(-1), for placebo. Recovery of tracer in urine was 1.2±0.7 g for premeal dosing and 2.2±0.1 g for placebo. Incremental concentrations of insulin, C-peptide, and GIP were reduced for 2 h with premeal GSK-1614235. Total GLP-1 concentrations were significantly increased, and a trend for increased peptide YY (PYY) was noted. SGLT1 inhibitors block intestinal glucose absorption and reduce GIP secretion in rats and humans, suggesting SGLT1 glucose transport is critical for GIP release. Conversely, GLP-1 and PYY secretion are enhanced by SGLT1 inhibition in humans.