Obesity (Silver Spring, Md.)最新文献

Objective: The huge obesity prevalence and related metabolic disorders highlight the urgent need for new therapeutic strategies beyond lifestyle interventions. Despite the availability of novel pharmacological treatments, the search for more effective and safe antiobesity compounds remains a challenge. Recent advances in high-performance computational drug discovery have enabled the rapid screening and identification of potential antiobesity compounds [Correction added on 10 February 2026, after first online publication: "Methods" was deleted from this sentence.]. However, these in silico procedures frequently require complex computational knowledge that limits the use of these techniques for most researchers and hampers interdisciplinary works.

Methods: To address this gap, we have developed OBE-DB, an accessible and user-friendly platform integrating computational tools that facilitates the prediction of potential antiobesity molecules through two complementary approaches: (i) shape similarity analysis against a curated database of approved obesity drugs and (ii) inverse virtual screening of user-submitted molecules against a set of therapeutic protein targets linked to obesity.

Results: Our results demonstrate that the server effectively screens and ranks compounds with high predicted activity, outperforming conventional in silico techniques in terms of accuracy and usability.

Conclusion: The OBE-DB web server represents a significant advancement by providing researchers with an intuitive tool to accelerate early-stage drug discovery for obesity treatment. The server is freely accessible without registration, providing users with a detailed report via email upon completion of the predictions. This innovative database and web server is accessible online via https://bio-hpc.ucam.edu/obe-db/.

Objective: This cross-sectional study examined associations between sleep, body weight, body composition, appetite, and food reward after bariatric surgery.

Methods: A single 7-day study period in 22 female adults (age, 53.5 ± 9.3 years; BMI, 35.5 ± 8.5 kg/m²; body fat: 44.9% ± 8.6%) who underwent bariatric surgery ≥ 1 year prior to enrollment assessed: actigraphy-measured sleep (duration, efficiency, midpoint, and variability [coefficient of variation]) and activity energy expenditure (AEE); sleep architecture and apnea-hypopnea index (AHI) via in-home polysomnography; energy intake via food diaries; resting EE via indirect calorimetry; fasting appetite via visual analog scales; and food reward via Leeds Food Preference Questionnaire.

Results: Weight regain was 10.6% relative to nadir postsurgery weight. Rapid eye movement (REM) sleep duration was associated with lower body fat percentage (r = -0.52, p = 0.02). Participants with AHI ≥ 5 had a greater waist to hip ratio compared to those with AHI < 5 (mean difference = 0.09, p = 0.01). Sleep timing and duration variability was associated with fasting prospective food consumption (r = 0.44, p = 0.05 and r = 0.47, p = 0.03, respectively). Greater sleep duration was associated with lower AEE (r = -0.62, p < 0.01) and explicit liking for sweet foods (r = 0.45, p = 0.04).

Conclusions: Our exploratory results underscore the need to evaluate whether sleep behaviors, including total and REM sleep duration, AHI, and sleep regularity, predict long-term weight loss maintenance after bariatric surgery.

Objective: This study compared the effects of phentermine-topiramate-ER (mid-dose 7.5/46 mg) versus placebo on weight loss and cardiovascular disease (CVD) risk outcomes when used as an adjunct to a digitally enhanced lifestyle intervention (DELI).

Methods: We conducted a 12-month, randomized, double-blind, placebo-controlled trial at a single tertiary academic center in the United States (June 2020-June 2022). Eighty participants with obesity (BMI ≥ 30 kg/m²) were enrolled in the DELI program, consisting of in-person and telehealth modalities, dietary and physical activity goals, and use of a smartphone application integrated with digital devices (Apple Watch and Bluetooth-enabled weight scale and blood pressure monitor). Participants were randomized 1:1 to receive either phentermine-topiramate-ER (n = 42) or placebo (n = 38) in addition to the DELI.

Results: At 3 months, the phentermine-topiramate group lost a mean of 10.82 kg versus 4.04 kg in the placebo group (mean difference -6.78 kg; p = 0.002). At 12 months, weight loss was 15.32 kg versus 5.85 kg, respectively (mean difference -9.48 kg; p < 0.001). Participants receiving phentermine-topiramate-ER experienced a 3.35% reduction in the estimated atherosclerotic CVD risk compared to baseline (p = 0.004).

Conclusions: Phentermine-topiramate-ER, when combined with a DELI, produced significant and sustained weight loss and reduced CVD risk in adults with obesity.

Trial registration: ClinicalTrials.gov: NCT04408586.

Objective: Obesity has been traditionally defined by BMI alone, but this metric has limitations in assessing body fat composition and adiposity complications. The Lancet Diabetes and Endocrinology Commission (LDEC) issued a new obesity definition to address these challenges, stratified by preclinical and clinical groups. We evaluated the epidemiology of preclinical and clinical obesity in the UK Biobank and associations with incident cardiovascular disease (CVD).

Methods: We performed retrospective cohort analyses of 502,233 adults enrolled in the UK Biobank. Obesity was categorized using the new definition from LDEC. Clinical obesity was defined as adiposity-related dysfunction assessed via ICD10 codes, physical immobility, and abnormal laboratory values. Preclinical obesity had no additional metabolic deficits.

Results: The prevalence of preclinical and clinical obesity was 31.2% and 36.6%, and most were in the WHO overweight category. Clinical obesity was more prevalent in men, elderly, South Asians, and lower education or income level groups. Individuals with clinical obesity without baseline CVD had an increased hazard of incident stroke, heart failure, and myocardial infarction.

Conclusions: In a large UK cohort, preclinical and clinical obesity were common, but the risk for incident CVD was elevated for those with clinical obesity.

Objective: This post hoc analysis assessed psychiatric changes with tirzepatide in adults with obesity, without known major psychopathology, from SURMOUNT-1, SURMOUNT-2, and SURMOUNT-3.

Methods: In participants (N = 4056) treated with tirzepatide (5/10/15 mg or maximum tolerated dose 10/15 mg) versus placebo, depressive symptoms and suicidal ideation and behavior (SI/SB) were measured using the Patient Health Questionnaire-9 (PHQ-9) and Columbia-Suicide Severity Rating Scale (C-SSRS), respectively. Nervous system and psychiatric disorder adverse events (AEs) were collected.

Results: Mean (SD) baseline PHQ-9 scores were 2.7 (3.0) for tirzepatide and 2.6 (3.1) for placebo, indicating no/minimal symptoms of depression. At week 72, scores were 1.9 (2.7) and 2.4 (3.3), respectively (estimated treatment difference [SE]: -0.6 [0.1]); p < 0.001. Tirzepatide-treated participants were less likely to shift to a more severe PHQ-9 category (18.2% vs. 24.3%; p < 0.001). Using the C-SSRS, 0.6% of participants in each group reported SI, most of which was considered low risk. SB (nonfatal) occurred in 0.1% of tirzepatide-treated participants versus none with placebo. AEs were generally similar across groups.

Conclusions: In this post hoc analysis, tirzepatide versus placebo did not appear to be associated with an increased risk of depression in participants with overweight/obesity and without known major psychopathology. Rates of SI/SB observed with tirzepatide were similar to those of other incretin-based therapies. Further study of tirzepatide's safety in persons with significant psychiatric illness may be warranted.

Trial registration: ClinicalTrials.gov identifiers: NCT04184622, NCT04657003, and NCT04657016.

Objective: We previously identified distinct muscle and liver insulin resistance (IR) metabotypes in middle-aged and older adults. The PERSON study showed that a low-fat, high-protein, high-fiber diet benefits the muscle IR group, while a high-monounsaturated fatty acid diet benefits the liver IR group. We also developed the MetaboHealth score, reflecting risks of mortality, frailty, and cognitive decline. This study aimed to examine whether MetaboHealth interacts with IR metabotypes to influence (i) cardiometabolic health and (ii) body composition outcomes in the PERSON study, informing precision nutrition strategies.

Methods: In total, 242 adults aged 40-75 with IR were randomized to follow an isocaloric low-fat, high-protein, high-fiber or high-monounsaturated fatty acid diet for 12 weeks. Of these, 184 with complete data were grouped into MetaboHealth tertiles (higher = poorer health). Outcomes included a 7-point oral glucose tolerance test and DXA-based body composition. Linear mixed models assessed four-way interactions.

Results: No interaction was observed for cardiometabolic outcomes. Significant interactions were found for android, gynoid, total fat percentage, and fat mass index. In the healthiest tertile, matched diets led to greater fat loss. In the poorest tertile, both diets were similarly effective. MetaboHealth remained unchanged.

Conclusions: Combining metabotype with MetaboHealth may enhance personalized dietary strategies for fat loss in insulin-resistant adults.

Objective: This study aimed to determine doses of VK2735, a novel glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) receptor dual agonist, that are effective for weight loss over 13 weeks of treatment.

Methods: VENTURE was a phase 2, randomized, double-blind, placebo-controlled, dose-ranging study of weekly subcutaneous VK2735 in adults with obesity or overweight and ≥ 1 weight-related comorbidity. Participants with diabetes mellitus were ineligible. The primary endpoint was percent change from baseline in body weight at Week 13. Secondary efficacy endpoints were observed and change from baseline weight loss and the proportion of participants losing ≥ 5% and ≥ 10% of baseline weight.

Results: Study was conducted between August 2023 and February 2024. Mean weight reduction with active treatment ranged from 9.2 kg (2.5 mg dose) to 14.6 kg (15 mg dose), corresponding to 9.1% and 14.7% weight reductions, respectively; the placebo group had a 1.8 kg (1.7%) reduction. In the active treatment groups, 93% (130/140) of participants had a ≥ 5% weight reduction, compared with 12% (4/34) of participants with placebo treatment. The common adverse events (AEs) were gastrointestinal, which decreased in reported frequency after dose titration to steady state.

Conclusions: All subcutaneous doses of VK2735 significantly reduced body weight. The AE profile of VK2735 was primarily gastrointestinal, with decreased reported frequency upon continued use.

Trial registration: ClinicalTrials.gov identifier NCT06068946.

Objective: The role of genetic risk scores (GRS) in predicting responses to the obesity interventions in Japanese individuals remains underexplored. We aimed to examine GRS and introduce and evaluate a novel efficiency score derived from data envelopment analysis (DEA) for predicting the outcomes of a combined diet and exercise program.

Methods: Data from 145 individuals who completed an 8- to 12-week low-carbohydrate diet and resistance training intervention were retrospectively analyzed. GRS were calculated from 75 SNPs identified in a previous Japanese genome-wide association study. DEA was applied to generate efficiency scores using GRS as an input reflecting genetic load and initial BMI and body fat percentage as outputs reflecting phenotypic status. Linear regression analyses were performed to compare the predictive utility of GRS and efficiency scores.

Results: BMI and other measures decreased following the intervention. Linear-regression analyses revealed that DEA-derived efficiency scores strongly predicted the change in BMI percentage, whereas GRS did not.

Conclusions: Weight loss was achieved independently of GRS. GRS-derived efficiency score offered superior prediction of intervention effectiveness to that of GRS alone, suggesting that while GRS based on cross-sectional data may not predict responsiveness to interventions, integrated metrics also incorporating phenotypic data show potential for personalizing weight management strategies, pending further validation.

Objective: Aging alters mesenchymal stromal cell (MSC) function, leading to dysregulated adipogenesis across tissues through biased lineage commitment. Fat redistribution from adipose depots to skeletal muscle and bone marrow is common in aging, but the underlying mechanisms remain unclear. This study investigates how MSC senescence modulates adipogenesis.

Methods: Primary MSCs were isolated from mouse skeletal muscle (FAPs), adipose tissue (APCs), and bone marrow (BMSCs). Single-cell RNA sequencing was performed to compare transcriptional profiles among these populations. In vitro adipogenic differentiation and DNA damage-induced senescence assays were conducted, and the effects of autologous conditioned media from senescent MSCs on adipogenesis were assessed.

Results: Transcriptional analyses revealed that FAPs and APCs share greater similarity with each other than with BMSCs. All MSC types exhibited adipogenic potential and developed a robust senescence-associated secretory phenotype (SASP) upon senescence induction. Conditioned media from senescent MSCs enhanced adipogenesis in BMSCs but inhibited adipogenesis in FAPs and APCs, revealing tissue-specific paracrine effects.

Conclusions: MSC senescence reprograms adipogenic bias in a tissue-dependent, non-cell autonomous manner, contributing to age-related fat redistribution among adipose tissue, skeletal muscle, and bone marrow. Understanding these mechanisms may provide new therapeutic approaches for improving tissue composition and function in the context of aging.

As governments become aware of the increasing prevalence of obesity in their countries, they install taxes for the amount of sugar in sodas. This is leading to reductions in sugar intake and cardiovascular disease, as predicted, but unintentionally also to considerable increases in the consumption of non-nutritive sweeteners (NNS). Since many studies on the safety of NNS are highly conflicting, it is unclear at present whether NNS are a healthy substitute for sugar.