Puppala S, Hamann AR, Stevens CM
… +3 more, Ruggiero A, Cox LA, Kavanagh K
Obesity (Silver Spring)
· 2026 Mar · PMID 41603630
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OBJECTIVE: Obesity is an imperfect correlate of metabolic health. Visceral adipose tissue (VAT) characteristics are considered determinants of poor health and subcutaneous adipose tissue (SAT) considered protective. Ther...OBJECTIVE: Obesity is an imperfect correlate of metabolic health. Visceral adipose tissue (VAT) characteristics are considered determinants of poor health and subcutaneous adipose tissue (SAT) considered protective. There is a gap in knowledge regarding shared vs. unique SAT and VAT function across the metabolic syndrome (MetS) spectrum. METHODS: We quantified SAT and VAT transcriptomes in a nonhuman primate model of MetS. We calculated quantitative MetS risk scores using composite factors, applied unbiased clustering methods (weighted gene correlation network analysis) to identify transcripts that correlated with MetS risk scores, and performed pathway enrichment analysis. RESULTS: We found convergence in SAT and VAT on T-cell signaling genes and pathways, with T-cell exhaustion signaling prominent. Pathways unique to VAT highlighted interferon signaling and innate/adaptive immune cross talk in response to pathogens. Pathways unique to SAT included innate immune cell signaling, centered on vascular involvement. Although molecular signatures highlight T-cell signaling, T-cell abundance in VAT was unrelated to MetS scores. CONCLUSIONS: T-cell signaling and exhaustion predominate in metabolically unhealthy adaptations of both SAT and VAT. This novel handling of transcript data using an unbiased clustering approach and the creation of continuous MetS scores lead to new insights regarding adipose depot responses and T-cell biology.
OBJECTIVE: This study assessed whether changes in body composition or fat distribution after weight loss are associated with cardiometabolic improvements, independent of weight loss magnitude. METHODS: We analyzed data f...OBJECTIVE: This study assessed whether changes in body composition or fat distribution after weight loss are associated with cardiometabolic improvements, independent of weight loss magnitude. METHODS: We analyzed data from a 1-year lifestyle intervention in adults with obesity and type 2 diabetes (Study I) and a 12-week hypocaloric diet intervention in adults with overweight/obesity without diabetes (Study II). Body composition was assessed by DXA and fat distribution by either abdominal computed tomography (Study I) or DXA-derived trunk to total fat ratio (Study II). Insulin sensitivity was assessed by glucose clamp (Study I) and HOMA-IR (both studies). Additional markers included glucose, lipids, and blood pressure. Changes in body composition and fat distribution were adjusted for baseline values and weight loss using regression analysis. RESULTS: Body weight decreased by 9.8% in Study I and 5.3% in Study II, with fat mass accounting for 64% (95% CI: 0.51%-0.77%) and 77% (95% CI: 0.68%-0.86%) of weight lost, respectively. Clamp-derived insulin sensitivity increased by 50% (Study I), and HOMA-IR decreased by 26% in both studies. No cardiometabolic changes were associated with weight loss-adjusted changes in body fat percentage or fat distribution. CONCLUSIONS: Cardiometabolic improvements from weight loss appear independent of changes in body fat percentage or fat distribution.
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...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/.
Koch HR, Monroe DC, Fordahl S
… +3 more, Finlayson G, Wideman L, McNeil J
Obesity (Silver Spring)
· 2026 Mar · PMID 41565462
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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,...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/m; 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.
Campos A, Ghusn W, Cifuentes L
… +13 more, Sacoto D, Fansa S, Anazco D, Ricardo-Silgado ML, Hashem A, Schaefer M, Harmsen WS, Gunn HJ, Peterson C, Larsen D, Varghese ST, Hurtado MD, Acosta A
Obesity (Silver Spring)
· 2026 Mar · PMID 41562388
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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 li...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/m) 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.
De la Peña-Armada R, Longo-Silva G, Rodríguez-Martín M
… +2 more, Yang HW, Garaulet M
Obesity (Silver Spring)
· 2026 Feb · PMID 41559528
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OBJECTIVE: This longitudinal study aims to identify the key factors influencing the weight loss trajectory during a 24-week intervention and their relevance at different stages of the treatment. METHODS: We studied 1252...OBJECTIVE: This longitudinal study aims to identify the key factors influencing the weight loss trajectory during a 24-week intervention and their relevance at different stages of the treatment. METHODS: We studied 1252 participants (age 18-65 years) of a cognitive behavioral program to lose weight. Body weight was measured weekly, and a range of variables at baseline and throughout the treatment period were assessed. Linear regression analyses were conducted to understand the factors involved in the weight loss trajectory across three treatment periods (0-6, 7-12, 13-24 weeks). RESULTS: The rate of weight loss progressively decreased from the 1st to the 3rd period (770-198 g/week). During the 1st period, the recent history of the individual, including baseline metabolic status, dietary habits, and motivation, was the highest-ranked determinant. In the 2nd period, the sole predictor was the long-term personal history of obesity, that is, the duration of the individual's lifetime spent with overweight/obesity. In the 3rd period, emotional eating behaviors and related barriers emerged as the two highest-ranked determinants of reduced rate of weight loss. CONCLUSIONS: Findings suggest targeted interventions that address the specific challenges of each period of weight loss interventions. As treatment progresses, strategies focused on emotional-related behaviors may be crucial for sustaining weight loss. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02829619.
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) issue...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.
De Luca M, Cohen RV, Belluzzi A
… +10 more, Navarra G, Di Lorenzo N, Petry TBZ, Sbraccia P, Busetto L, Buscemi S, Barazzoni R, Ragghianti B, Mannucci E, Monami M
Obesity (Silver Spring)
· 2026 Feb · PMID 41539943
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OBJECTIVE: This review compared antiobesity strategies-obesity management medications (OMM), endoscopic bariatric procedures (EBP), and metabolic bariatric surgery (MBS)-with lifestyle intervention, placebo, or no therap...OBJECTIVE: This review compared antiobesity strategies-obesity management medications (OMM), endoscopic bariatric procedures (EBP), and metabolic bariatric surgery (MBS)-with lifestyle intervention, placebo, or no therapy (LSI/Pbo/NT). METHODS: This network meta-analysis included randomized clinical trials comparing OMM, EBP, and MBS versus LSI/Pbo/NT or active comparators in adults with obesity. MEDLINE and Embase were searched up to December 1, 2024. The primary endpoint was total body weight loss percentage (TBWL%), analyzed at 26-52, 53-104, 105-156, and ≥ 156 weeks. This study was registered with PROSPERO (CRD42024623707). RESULTS: Of 139 RCTs, 54 evaluated MBS (n = 61,961), 21 EBP (n = 2934), and 64 OMM (n = 5991). At 26-52 weeks, most treatments showed significant effects versus the reference. TBWL% exceeded 10% with most surgeries and tirzepatide. Long-term data were lacking for most OMM and all EBP. Most treatments maintained their efficacy over time, except greater curvature plication. EBP and MBS were generally associated with a higher SAE risk than OMM; BPD showed the highest long-term SAE incidence. CONCLUSIONS: MBS appears superior in the long term (particularly for higher-efficacy procedures, such as RYGB, SG, SADI, and BPD). EBP, except ESG, was less effective than newer OMM. Semaglutide and tirzepatide showed no inferior short-term results in comparison with MBS.
Wadden TA, Oquendo MA, Kushner RF
… +4 more, Cao D, Karanikas CA, Kechter A, Murphy MA
Obesity (Silver Spring)
· 2026 Mar · PMID 41537305
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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...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.
Morwani-Mangnani J, Bogaards FA, Umanets A
… +8 more, Hul GB, Gijbels A, Goossens GH, Deelen J, Beekman M, Afman L, Blaak EE, Slagboom PE
Obesity (Silver Spring)
· 2026 Mar · PMID 41536020
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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...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.
Bays HE, Toth P, Alkhouri N
… +7 more, Pullman J, Freilich B, Neutel J, Ji S, Stubbe S, Hedges P, Lian B
Obesity (Silver Spring)
· 2026 Mar · PMID 41508550
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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 o...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 s...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.
Sellers HG, Brown ZL, Khalil NS
… +10 more, Haigh SB, Shivers MA, Patel TV, Joshua AT, Weintraub NL, Barman SA, Belin de Chantemele EJ, Kirov SA, Stepp DW, Fulton DJR
Obesity (Silver Spring)
· 2026 Feb · PMID 41456932
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OBJECTIVE: This study utilized AAV gene delivery as an approach to induce and reverse hyperphagia in mice. We hypothesized that the delivery of orexigenic neuropeptides to the brain via AAV precipitates obesity and that...OBJECTIVE: This study utilized AAV gene delivery as an approach to induce and reverse hyperphagia in mice. We hypothesized that the delivery of orexigenic neuropeptides to the brain via AAV precipitates obesity and that the implementation of genetic switches to reverse transgene expression would elicit weight loss. METHODS: We utilized capsid-modified AAV-PHP.eB and AAV-CAP.B10 to deliver AgRP, NPY, a leptin superantagonist, and ghrelin to the mouse brain. Cre-LoxP, TETOFF, and cumate expression systems were used to alter transgene expression. RESULTS: Delivery of three out of four orexigenic neuropeptides to the brain precipitated severe obesity. Cre-mediated excision of AgRP from the brain caused a return to baseline weight, confounded by tamoxifen-associated weight loss. Doxycycline-mediated suppression of AgRP in a TETOFF vector paused weight gain but did not elicit weight loss. Cumate induction of AgRP in the brain was unaffected by systemic administration, suggesting that cumate inadequately penetrates the blood-brain barrier. CONCLUSIONS: Brain-targeted delivery of orexigenic peptides induces obesity in mice. This allows for temporally controlled, convenient, and robust preclinical models of obesity. The implementation of genetic switches enabled suppression/removal of AgRP expression, but we unexpectedly observed that removal of hyperphagic stimuli does not elicit robust weight loss.
Faccioli N, Poitou C, Georget M
… +10 more, Bertin F, Azar-Kolakez A, Carette C, Faucher P, Gatta-Cherifi B, Gonneau-Lejeune J, Linglart A, Clément K, Le Beyec‐Le Bihan J, Dubern B
Obesity (Silver Spring)
· 2026 Feb · PMID 41451896
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OBJECTIVE: Pathogenic variants in five established leptin-melanocortin pathway genes (LEP, LEPR, MC4R, PCSK1, POMC) are associated with severe early-onset obesity and are targets for emerging treatments. However, these v...OBJECTIVE: Pathogenic variants in five established leptin-melanocortin pathway genes (LEP, LEPR, MC4R, PCSK1, POMC) are associated with severe early-onset obesity and are targets for emerging treatments. However, these variants are rare in these patients, suggesting the involvement of additional genes interacting with this pathway. METHODS: Next-generation sequencing (NGS) analysis was performed in 395 patients with severe obesity, including 213 children (mean BMI: 56.3 kg/m; BMI-z-score: 4.6). The analysis targeted 20 genes, including the 5 established genes. Rare genetic variants were assessed for pathogenicity using prediction algorithms, genetic databases, and literature review. Phenotypic data were retrospectively collected, focusing on obesity severity, age of onset, familial history, eating behavior disorder, neurodevelopmental and endocrine-associated diseases, and obesity complications. RESULTS: Pathogenic heterozygous variants were identified in 34 patients (8.6%), 18 of them harboring pathogenic variants in the 15 additional genes. In adults, early-onset obesity was more frequent in potentially pathogenic variants carriers than in non-carriers (83.3% vs. 55.0%, p = 0.04). No differences were observed in the other phenotypic characteristics. CONCLUSIONS: This supports the relevance of expanded genetic testing in severe obesity. Early-onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments.
OBJECTIVE: This study compared the efficacy of a GLP-1 receptor agonist (GLP1-RA) (semaglutide, 0.5 mg/week), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and repetitive transcranial magnetic stimulation (rTMS), a...OBJECTIVE: This study compared the efficacy of a GLP-1 receptor agonist (GLP1-RA) (semaglutide, 0.5 mg/week), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and repetitive transcranial magnetic stimulation (rTMS), a new emerging treatment for obesity, in reducing body weight (BW) after 1 year in patients with obesity and type 2 diabetes (T2D). METHODS: We included 40 patients with T2D treated with a SGLT2i, 37 patients with T2D treated with the GLP1-RA semaglutide, and 30 patients treated with rTMS in this retrospective comparative analysis. rTMS was administered three times per week for 5 weeks. All patients received dietary advice about moderate caloric restriction (-300 kcal/day). RESULTS: After 12 months the weight loss with rTMS (-8.2 ± 1.0 kg) was not significantly different from that with semaglutide (-5.7 ± 0.9 kg). Weight loss with SGLT2i (-2.0 ± 0.7 kg) was significantly less than with both semaglutide (p = 0.01) and rTMS (p < 0.0001). Individuals receiving SGLT2i therapy experienced weight regain from month 6 to month 12, while BW declined progressively in patients treated with semaglutide and rTMS. CONCLUSIONS: Treatment with rTMS produced a comparable reduction in BW to that observed with the GLP1-RA semaglutide (at the dose of 0.5 mg/week) and represents a promising intervention for the treatment of obesity and T2D. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03009695.
Zhang X, Doolittle ML, Fan T
… +11 more, Tripathi U, Ng YE, Jiang X, Passos JF, Jurk D, Monroe DG, Tchkonia T, Kirkland JL, Robbins PD, Khosla S, LeBrasseur NK
Obesity (Silver Spring)
· 2026 Mar · PMID 41437892
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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 m...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.
OBJECTIVE: This study aimed to characterize bariatric surgery-induced changes in serum metabolites while accounting for changes in glomerular filtration rate (GFR) to understand the metabolic benefits to the kidney of ba...OBJECTIVE: This study aimed to characterize bariatric surgery-induced changes in serum metabolites while accounting for changes in glomerular filtration rate (GFR) to understand the metabolic benefits to the kidney of bariatric surgery. METHODS: This was a prospective, single-center cohort of 27 adults with severe obesity who underwent bariatric surgery. Serum metabolomics and measured GFR (mGFR) were performed 1-3 months prior to and 6 months after surgery. In generalized estimating equation (GEE) models, we examined bariatric surgery- and mGFR-associated changes in serum metabolites. We used MetaboAnalyst to perform pathway analyses. RESULTS: Bariatric surgery was significantly associated with changes in 223 serum metabolites after adjustment. Following bariatric surgery, several pathways were downregulated (alpha-linoleic acid and linoleic acid, methionine, kynurenine, and alanine-glucose metabolism pathways; raw p < 0.05) or upregulated (phenylacetate, bile acid biosynthesis, taurine and hypo-taurine metabolism, porphyrin metabolism pathways; raw p < 0.05). Creatinine demonstrated a significant mGFR-independent decrease following surgery. The top metabolites significantly associated with mGFR included N,N,N-trimethyl-alanyl proline betaine (TMAP), followed by creatinine. CONCLUSIONS: We discovered several GFR-independent metabolomic changes after bariatric surgery which may underlie its beneficial kidney effects including decreased inflammation, oxidation, and insulin resistance. Further studies are needed to investigate the potential mechanistic role of identified metabolites to clarify mechanisms of obesity-related kidney disease.
Pierce SL, Porter RM, Kompaniyets L
… +2 more, He S, Goodman AB
Obesity (Silver Spring)
· 2026 Feb · PMID 41423941
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OBJECTIVE: This study examined associations between CDC's 2022 extended BMI percentiles (BMIp) and cardiometabolic biomarkers. METHODS: Using electronic medical record data, we included patients aged 6-17 years with BMI ...OBJECTIVE: This study examined associations between CDC's 2022 extended BMI percentiles (BMIp) and cardiometabolic biomarkers. METHODS: Using electronic medical record data, we included patients aged 6-17 years with BMI ≥ 85th percentile who had at least one of the following: total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides, alanine aminotransferase (ALT), and hemoglobin A1c (HbA1c). We calculated adjusted prevalence ratios (aPR) for (1) borderline or abnormal and (2) abnormal lab values by extended BMIp (85th-< 95th, 95th-< 98th, 98th-< 99th, 99th-< 99.9th, ≥ 99.9th). RESULTS: Compared to those with overweight (BMIp 85th-< 95th), patients in higher extended BMIp categories had a higher prevalence of borderline or abnormal HbA1c (aPR range: 1.46-2.79), ALT (aPR range: 1.58-2.59), triglycerides (aPR range: 1.24-1.46), total cholesterol (aPR range: 1.11-1.23), HDL (aPR range: 1.40-1.94), and LDL (aPR range: 1.23-1.55). Dose-response relationships were observed for multiple cardiometabolic biomarkers. Similar patterns were found for abnormal lab values. CONCLUSIONS: Many US youth aged 6-17 with overweight and obesity had borderline or abnormal cardiometabolic biomarkers. Risks varied within obesity: higher extended BMIp were linked to a greater likelihood of borderline or abnormal lab values. Identifying extended BMIp thresholds tied to these risks could facilitate clinical practice, including identifying high-risk patients and informing escalation of care.