Rego MLM, Leslie E, Schmall E
… +8 more, Capra B, Hudson S, Ahrens ML, Katz B, Davy KP, Hedrick VE, DiFeliceantonio AG, Davy BM
Obesity (Silver Spring)
· 2026 Feb · PMID 41255123
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OBJECTIVE: This study examined the impact of a 2-week eucaloric diet high in ultraprocessed foods (UPF) compared to a diet without UPF (non-UPF) on ad libitum energy intake (EI) and food selection in individuals aged 18-...OBJECTIVE: This study examined the impact of a 2-week eucaloric diet high in ultraprocessed foods (UPF) compared to a diet without UPF (non-UPF) on ad libitum energy intake (EI) and food selection in individuals aged 18-25. METHODS: In a randomized, crossover, proof-of-concept trial, participants completed two 14-day controlled feeding periods (81% UPF vs. 0% UPF), with a 4-week washout. Diets were matched for macronutrients, fiber, added sugar, diet quality, and energy density. Following each condition, participants consumed an ad libitum buffet meal including UPF and non-UPF. Energy and food grams consumed were quantified. Statistical analyses were conducted for the full sample, late adolescents (aged 18-21), and young adults (aged 22-25). RESULTS: Twenty-seven individuals aged 22 ± 2 years (mean BMI = 24 ± 3 kg/m) were included. Diet compliance was ~99% overall. There was no effect of diet condition on meal total kcal or grams consumed or UPF or non-UPF consumption in the full sample (all p > 0.05). In the exploratory age subgroup analysis, an interaction between diet and age was observed for total EI (p < 0.001), where total EI increased among adolescents following the UPF diet (p = 0.03, d = 0.79), but not in young adults. CONCLUSIONS: Late adolescents may be susceptible to increased EI following a UPF diet. Future trials are warranted to evaluate this possibility. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05550818.
OBJECTIVE: Limited data exist on telemedicine prescribing of semaglutide and tirzepatide. The effects of a telehealth obesity management program combining the provision of semaglutide and tirzepatide with a behavioral pr...OBJECTIVE: Limited data exist on telemedicine prescribing of semaglutide and tirzepatide. The effects of a telehealth obesity management program combining the provision of semaglutide and tirzepatide with a behavioral program tailored for long-acting antiobesity medications (AOMs) were evaluated. METHODS: In this single-arm study, 180 participants recruited from a telehealth medical obesity program received a virtual behavioral program tailored for long-acting AOMs, Bluetooth wireless scales, and a blood pressure (BP) cuff. Participants' (mean age = 44.1; 91% female; 81% White; mean weight = 102.8 kg) weight, BP, eating habits, dietary quality, physical activity, and side effects were assessed at baseline and at 12 and 24 weeks. Wilcoxon rank sum tests were conducted, and p values were adjusted using a false discovery rate approach. Intent-to-treat analysis was performed using last observation carried forward (LOCF). RESULTS: Weight loss was 7.2% (SD = 5.2%) at 12 weeks and 12.3% (SD = 6.9%) at 24 weeks (p < 0.0001). Mean BP declined from 131.0/83.8 (SD = 17.2/12.2) to 122.5/78.7 (SD = 13.7/10.1) at 12 weeks and 120.0/78.2 (SD = 13.5/10.6) at 24 weeks (p < 0.0001). Participants significantly improved their eating habits, diet quality, and activity. Side effects were markedly lower than in previously reported trials. CONCLUSIONS: Virtually delivered treatment combining telemedicine and a behavioral program tailored for long-acting AOMs demonstrated clinically significant improvements in weight, BP, diet, and activity over 24 weeks. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06034457.
OBJECTIVE: Most studies have investigated how childhood BMI impacts risks of single diseases. We investigated whether sex-specific patterns of disease diagnoses from ages 15 to 60 years differed by childhood BMI. METHODS...OBJECTIVE: Most studies have investigated how childhood BMI impacts risks of single diseases. We investigated whether sex-specific patterns of disease diagnoses from ages 15 to 60 years differed by childhood BMI. METHODS: We included 112,952 children (55,603 girls) from the Copenhagen School Health Records Register, born 1962-1996, with measured weights and heights. BMI at 7 years was classified as underweight (4.3%), normal weight (83.1%), overweight (9.2%), or obesity (3.5%). Hospital-based diagnoses came from national registers. Sex-specific cumulative incidences were calculated for the 50 most frequent diseases per BMI group. RESULTS: Individuals with childhood obesity had the highest estimated mean number of hospital-based diagnoses by age 60, 18.2 (95% CI: 16.9-19.5) in females and 15.1 (13.8-16.4) in males. Corresponding estimates for normal weight were 14.7 (14.5-14.9) in females and 11.7 (11.5-11.8) in males. Among females and males with obesity in childhood, the most common diagnosis before age 60 years was adult overweight/obesity (36.4% and 11.8%, respectively). There were only minor differences for other diseases by childhood BMI categories. CONCLUSIONS: Adults with obesity in childhood had the highest number of hospital-based diagnoses. Disease patterns across the life course were generally similar by childhood BMI groups apart from adult overweight and obesity.
D'Adamo L, Christian C, Jebeile H
… +8 more, Wilfley DE, Eddy KT, Boutelle K, Zucker N, Peterson CB, Celio-Doyle A, Le Grange D, Goldschmidt AB
Obesity (Silver Spring)
· 2026 Jan · PMID 41253722
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OBJECTIVE: Self-directed dietary restraint (i.e., outside of evidence-based weight management programs) has been associated with disordered eating in youth. This study examined associations between maladaptive facets of...OBJECTIVE: Self-directed dietary restraint (i.e., outside of evidence-based weight management programs) has been associated with disordered eating in youth. This study examined associations between maladaptive facets of dietary restraint and disordered eating among youth with higher weight. METHODS: Participants (N = 529; mean age = 10.8 ± 2.08; BMI ≥ 85th percentile) self-reported dietary restraint (restraint over eating, avoidance of eating, food avoidance, desire for an empty stomach, and dietary rules) and disordered eating behaviors (i.e., objective and subjective binge eating, driven exercise, and vomiting) over the past 3 months. Network analysis estimated partial correlations between restraint factors and disordered eating behaviors. RESULTS: The restraint item most strongly associated with disordered eating behaviors was "dietary rules," which was associated with "driven exercise" and "subjective binge eating." The disordered eating behavior most strongly connected to restraint was "subjective binge eating," which was positively associated with "dietary rules," "desire for an empty stomach," and "food avoidance." CONCLUSIONS: Trying to follow definite dietary rules may be associated with disordered eating behaviors in youth with higher weight. Prospective research is needed to examine causality among youth undergoing weight management interventions, which could inform screening and monitoring of restraint prior to and during weight management.
Corpodean F, Kachmar M, Yang S
… +5 more, Heymsfield SB, Katzmarzyk PT, Schauer PR, Cook MW, Albaugh VL
Obesity (Silver Spring)
· 2026 Feb · PMID 41250827
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OBJECTIVE: This study examined the association between obesity severity and cardiometabolic and renal disease, using BMI as a surrogate for obesity severity. METHODS: This is a cross-sectional study using data from the U...OBJECTIVE: This study examined the association between obesity severity and cardiometabolic and renal disease, using BMI as a surrogate for obesity severity. METHODS: This is a cross-sectional study using data from the United States Behavioral Risk Factor Surveillance System (BRFSS), 2011-2023. Survey-weighted logistic regression estimated odds ratios (OR) for the diagnosis of diabetes, hypertension, hyperlipidemia, kidney disease, myocardial infarction, stroke, and coronary artery disease among increasing BMI categories. RESULTS: Higher BMI was associated with increased odds of all conditions. For BMI ≥ 50 kg/m, odds were notably elevated for diabetes (OR 8.32; 95% CI: 7.78-8.91), hypertension (OR 6.07; 95% CI: 5.58-6.61), and kidney disease (OR 3.60; 95% CI: 3.21-4.03). The odds of cardiovascular disease also rose substantially, including myocardial infarction (OR 2.89; 95% CI: 2.56-3.28) and coronary artery disease (OR 3.44; 95% CI: 3.08-3.84). Mean age at diabetes diagnosis decreased with increasing BMI, from 52.2 years in Class I to 45.3 years in Class IV obesity. CONCLUSIONS: Obesity severity is incrementally associated with cardiometabolic and renal disease burden, particularly among adults with BMI ≥ 50 kg/m. These findings highlight the urgent need for early, aggressive interventions targeting individuals with all classes of obesity.
Kracht CL, Brown DMY, Gorczyca AM
… +4 more, Jakicic JM, Szabo-Reed A, Washburn R, Donnelly JE
Obesity (Silver Spring)
· 2026 Feb · PMID 41243427
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OBJECTIVE: We examined whether wake-time movement composition was associated with weight loss maintenance among individuals who experienced clinically meaningful weight loss (> 5% of initial weight) using compositional d...OBJECTIVE: We examined whether wake-time movement composition was associated with weight loss maintenance among individuals who experienced clinically meaningful weight loss (> 5% of initial weight) using compositional data analysis. METHODS: This was a secondary analysis from a behavioral weight loss maintenance intervention on weight regain over 12 months following clinically meaningful 3-month weight loss. Body weight was assessed at baseline, after weight loss (3 months), and at end of intervention (15 months). Wake-time behaviors (sedentary time [ST], light physical activity [LPA], and moderate-to-vigorous PA [MVPA]) were assessed at two time points during the maintenance intervention using accelerometry. Compositional data analysis was used to examine associations between wake-time movement composition and weight regain (kg). RESULTS: Among 153 individuals (80.4% female, 69.9% White), wake-time movement composition was related to weight regain (p = 0.001). MVPA was negatively associated with weight regain (p's < 0.05). Reallocating 10 min/day from ST or LPA to MVPA was associated with less weight regain (ST: -0.32 kg [-0.53, -0.12]; LPA: -0.37 kg [-0.59, -0.15]). Individuals who maintained clinically meaningful weight loss and those who did not differed in wake-time movement composition, driven by MVPA (36.1 vs. 24.3 min/day). CONCLUSIONS: The composition of wake-time behaviors, specifically MVPA, reduces weight regain after clinically meaningful weight loss in a behavioral weight loss maintenance intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01664715.
Kim T, Pearson MJ, Hong H
… +7 more, Nason S, Seck K, Antipenko J, Presedo N, DiMarchi R, Roell WC, Habegger K
Obesity (Silver Spring)
· 2026 Feb · PMID 41236053
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OBJECTIVE: Glucagon-receptor (GCGR) agonism reguglates bile acid (BA) metabolism and promotes weight loss in diet-induced obese (DIO) mice. Thus, we hypothesized that BA signaling contributes to GCGR-stimulated weight lo...OBJECTIVE: Glucagon-receptor (GCGR) agonism reguglates bile acid (BA) metabolism and promotes weight loss in diet-induced obese (DIO) mice. Thus, we hypothesized that BA signaling contributes to GCGR-stimulated weight loss. METHODS: To test this hypothesis, we utilized BA-binding resins (BARs; colesevelam [Colsv] and cholestyramine [Cstyr]) to prevent intestinal BA reuptake. DIO C57Bl/6J mice were administered the GCGR agonist IUB288 or vehicle, in the presence or absence of BARs. RESULTS: To our surprise, combined IUB288 and Colsv treatment reduced body weight and food intake compared to IUB288 or Colsv treatment groups in high fat diet (HFD)-fed mice. Moreover, acute IUB288 + Colsv treatment reduced fasting-stimulated HFD, but not chow, intake compared to IUB288 or Colsv treatments alone. We observed improved glucose homeostasis and reduced plasma cholesterol with combined IUB288 and Colsv, but not Colsv alone. Excitingly, liver steatosis was suppressed with IUB288 but not Colsv alone, and this benefit was further enhanced with combined treatment. Plasma BA profiles were regulated by both IUB288 and Colsv with concomitant modulation of liver and ileum BA regulatory mRNA expression. Similar findings were observed with the first-generation BAR Cstyr. CONCLUSIONS: Together, these studies suggest that BARs enhance the antiobesity effect of GCGR agonism in DIO mice, representing a novel antiobesity strategy.
Nejat S, Menikdiwela KR, Iskander O
… +13 more, Walker H, Scoggin S, Yosofvand M, Moussa H, Zu Y, Dufour JM, Chakroborty A, Vandanmagsar B, Thornalley PJ, Kalupahana NS, Dhanasekara CS, Dehbi M, Moustaid-Moussa N
OBJECTIVE: DNAJB3, a heat shock protein, plays a critical role in metabolic aberrations associated with obesity and type 2 diabetes (T2D). This study investigated how DNAJB3 deficiency exacerbates inflammation and glucos...OBJECTIVE: DNAJB3, a heat shock protein, plays a critical role in metabolic aberrations associated with obesity and type 2 diabetes (T2D). This study investigated how DNAJB3 deficiency exacerbates inflammation and glucose intolerance in diet-induced obese mice. METHODS: Male and female DNAJB3 knockout (KO) and wild-type (WT) mice were fed high-sucrose (17 kcal%) and high-fat (HF: 45 kcal%) or low-fat (LF: 10 kcal%) diets for 12 weeks. Body weight, food intake, glucose tolerance, and energy expenditure were assessed; blood, adipose, and liver tissues were collected for histological and gene expression analyses. RESULTS: HF-fed KO females exhibited higher body and fat mass and lower glucose clearance and energy expenditure, compared to other groups. Males showed a clear HF diet effect across both genotypes. Increased serum leptin, interleukin 6, and insulin levels were observed in HF-KO females, while HF-KO males showed higher leptin and resistin levels compared to other groups. Additionally, inflammatory and glucose transporter gene expression was altered by DNAJB3 deficiency in adipose tissues and the pancreas, highlighting the impaired glucose metabolism. CONCLUSIONS: These findings suggest the importance of DNAJB3 in glucose and metabolic regulation, especially in females, and its potential use as a therapeutic target for obesity and T2D.
Young DR, Vesco KK, Oshiro CE
… +6 more, Sidell MA, LeBlanc E, Rosenquist N, Mayhew M, Zhou B, Boone-Heinonen J
Obesity (Silver Spring)
· 2026 Feb · PMID 41224672
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OBJECTIVE: This study aimed to identify physical activity trajectories through pregnancy and examine associations with postpartum weight retention. METHODS: We included pregnancies from one health care system from 2009 t...OBJECTIVE: This study aimed to identify physical activity trajectories through pregnancy and examine associations with postpartum weight retention. METHODS: We included pregnancies from one health care system from 2009 to 2020. Data were collected from electronic health records and physical activity from self-report before pregnancy and during each trimester. High, medium, and low physical activity groups were identified using discrete trajectory analysis. The outcome was the percentage of postpartum weight retention in the first year after pregnancy, measured as postpartum BMI as a percentage of prepregnancy BMI. All postpartum BMI measures from 21 through 365 days were analyzed using mixed effects regression models using R version 4.4.1. RESULTS: Among 58,828 pregnancies, 54.7% were in Hispanic participants, 24.8% White, 10.3% Asian/Pacific Islander, 9.0% Black, and 1.3% other. Mean BMI after delivery was 105.2% ± 8.9% of prepregnancy BMI. Physical activity trajectories were high (3.4%), medium (64.9%), and low (31.6%). Compared with the low and medium physical activity trajectories, individuals in the high physical activity trajectory had greater odds of achieving prepregnancy BMI (OR: 1.314; 95% CI: 1.172-1.472 and OR: 1.285; 95% CI: 1.149-1.436, respectively). CONCLUSIONS: Individuals with high physical activity from preconception through pregnancy have less weight retention at 360 days post partum than women with lower physical activity.
The off-label use of glucagon-like peptide-1 receptor agonists (GLP-1ra) among people without obesity and/or diabetes is rapidly expanding, despite a lack of clinical justification or safety data in this population. This...The off-label use of glucagon-like peptide-1 receptor agonists (GLP-1ra) among people without obesity and/or diabetes is rapidly expanding, despite a lack of clinical justification or safety data in this population. This Perspective explores the sociomedical dimensions of this trend, highlighting key research gaps and emerging hypotheses around the off-label use of GLP-1ra to an individual goal of slimness rather than health. We propose that off-label GLP-1ra use by people with normative or mildly elevated weight reveals deeper tensions between scientific progress, stigma, and cultural ideals of the body. Understanding this phenomenon requires moving beyond biomedical efficacy to interrogate the psychological, behavioral, and sociopolitical implications of pharmacological thinness. Cross-cultural and intersectional approaches from the social sciences are key to understanding this emergent phenomenon.
OBJECTIVE: This study aimed to determine whether weight reduction mediated by antiobesity medications (AOMs) contributes to the risk reduction in obesity-associated cancer. METHODS: PubMed, Embase, the Cochrane Central R...OBJECTIVE: This study aimed to determine whether weight reduction mediated by antiobesity medications (AOMs) contributes to the risk reduction in obesity-associated cancer. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov website were systematically searched for randomized controlled trials of AOMs from inception to December 2024. Relative risks were calculated using a random-effects model. RESULTS: The analysis included 25 randomized controlled trials with 40,731 participants. Compared with placebo, AOMs showed no association with the risk of overall obesity-related cancer (RR = 1.03, 95% CI: 0.78 to 1.37) or site-specific cancer. Consistently, every 5 kg weight reduction mediated by AOMs was not associated with the risk of overall obesity-related cancer (RR = 0.97, 95% CI: 0.84 to 1.12) or site-specific cancer. However, subgroup analysis revealed that coagonists (tirzepatide, cotadutide, and cagrilintide) significantly reduced overall obesity-associated cancer risk (RR = 0.43, 95% CI: 0.19 to 0.97), and every 5 kg weight reduction mediated by coagonists was marginally associated with a reduced overall obesity-associated cancer risk (RR = 0.79, 95% CI: 0.62 to 1.00). CONCLUSIONS: Weight reduction mediated by current AOMs was not associated with a reduced risk of overall or site-specific obesity-associated cancer in patients with overweight or obesity, while a decreased risk of overall obesity-associated cancer was observed in coagonist users.
Li X, Cao D, Sapin H
… +5 more, Wang F, Hunter Gibble T, Raibulet NK, Denning M, Kaplan LM
Obesity (Silver Spring)
· 2026 Jan · PMID 41187013
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OBJECTIVE: This post hoc analysis of SURMOUNT trials assessed the association of baseline physical function (PF) with obesity-related complications (ORCs), efficacy measures, and PF. The mechanism of tirzepatide-led impr...OBJECTIVE: This post hoc analysis of SURMOUNT trials assessed the association of baseline physical function (PF) with obesity-related complications (ORCs), efficacy measures, and PF. The mechanism of tirzepatide-led improvements in PF was evaluated. METHODS: Outcomes were assessed among participants (SURMOUNT-1 = 2539; SURMOUNT-3 = 579; SURMOUNT-4 = 670) grouped by baseline quartiles (Q) of SF-36v2 PF scores within study (higher scores = better PF). Least-squares mean changes from baseline in efficacy measures and PF were estimated using ANCOVA. Pearson's correlation between weight reduction and improvement in PF was calculated. RESULTS: In SURMOUNT-1, participants with lower baseline PF had more ORCs. Tirzepatide-treated participants showed similar reductions in weight (kg; -20.1% to -22.8%), waist circumference (-17.2 to -20.2 cm), and BMI (-7.2 to -9.0 kg/m) across quartiles. Participants with lower baseline PF reported greater improvements in PF with tirzepatide (Q1 = 12.5; Q4 = -0.8). Results were similar in SURMOUNT-3 and SURMOUNT-4. A weak to mild correlation was noted between weight reduction and improved PF; the strength of correlation decreased from Q1 to Q4. CONCLUSIONS: Lower baseline PF was associated with a higher prevalence of ORCs. Patients taking tirzepatide experienced substantial weight loss, regardless of their baseline PF. Tirzepatide may improve PF through both weight loss-dependent and -independent mechanisms, especially in those with lower baseline PF. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: SURMOUNT-1, NCT04184622; SURMOUNT-3, NCT04657016; SURMOUNT-4, NCT04660643.
Spatocco I, Mele G, De Rosa G
… +10 more, Fusco C, Ruggiero K, Pellegrini V, Carreras F, La Grotta R, Ceriello A, Procaccini C, Matarese G, Prattichizzo F, de Candia P
Obesity (Silver Spring)
· 2026 Jan · PMID 41186974
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OBJECTIVE: Obesity is characterized by a proinflammatory condition contributing to poor outcomes, but its association with autoimmunity is inconclusive. To fill this gap in knowledge, we searched PubMed and Embase for st...OBJECTIVE: Obesity is characterized by a proinflammatory condition contributing to poor outcomes, but its association with autoimmunity is inconclusive. To fill this gap in knowledge, we searched PubMed and Embase for studies analyzing the association between obesity and the prevalence and/or incidence of autoimmune diseases. METHODS: Adjusted odds ratios (OR) or hazard ratios (HR) with 95% CI relating to the prevalence or incidence of autoimmune diseases in people with BMI > 30, compared to BMI < 25, were pooled using generic inverse variance and fixed effect models. Of 1,311 records, 26 (8 cross-sectional and 18 longitudinal) studies were included in the meta-analysis. RESULTS: Obesity, compared with normal weight, was associated with increased prevalence of rheumatoid arthritis and psoriasis (OR = 1.11 [1.06, 1.16], p < 0.00001; OR = 1.35 [1.14, 1.59], p = 0.0004, respectively) and increased risk of developing rheumatoid arthritis (HR = 1.30 [1.15, 1.49], p < 0.0001), psoriasis (HR = 1.18 [1.16, 1.20], p < 0.00001), multiple sclerosis (HR = 1.49 [1.25, 1.77], p < 0.00001), and Crohn's/ulcerative colitis (HR = 1.35 [1.11, 1.65], p < 0.003). Obesity was also significantly associated with incidence of any autoimmune disease (HR = 1.41 [1.24, 1.62], p < 0.00001). CONCLUSIONS: Although definitive conclusions are still precluded for the single diseases, overall evidence supports obesity as a risk factor for autoimmunity.
Gam S, Hermann AP, Juhl CB
… +2 more, Hansen SG, Gram B
Obesity (Silver Spring)
· 2026 Jan · PMID 41177144
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OBJECTIVE: This study aimed to investigate whether a single infusion of 5 mg zoledronic acid, given before bariatric surgery to prevent bone loss, could also hinder the loss of muscle mass, strength, and physical functio...OBJECTIVE: This study aimed to investigate whether a single infusion of 5 mg zoledronic acid, given before bariatric surgery to prevent bone loss, could also hinder the loss of muscle mass, strength, and physical function. METHODS: In this double-blinded study, patients referred for bariatric surgery were randomized 1:1 to either intervention (INT: single dose zoledronic acid 5 mg) or placebo (CON). Assessments were conducted at baseline and 12 months postoperatively. The outcomes were body composition (DXA), muscle strength for knee extensor (KE) and knee flexor (KF), and physical function. RESULTS: Fifty-nine patients (age: 48.9 ± 6.3 years, BMI: 42.3 ± 5.3 kg/m) were allocated to INT (n = 31) or CON (n = 28). At 12 months, no between-group differences were observed in body weight, fat mass, or lean body mass. Both groups experienced ~14% loss of lean body mass. No between-group differences were observed for absolute or relative muscle strength. Absolute strength declined by 11%-18%, while relative strength improved by 10%-22%. No between-group differences were found in physical function measures, all of which improved by 5%-18%. CONCLUSIONS: A single infusion of 5 mg zoledronic acid did not prevent the loss of muscle mass or strength or improve physical function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04742010; EudraCT number: 2019-001650-26.
Recent advances in indirect calorimetry have expanded the capacity to characterize energy metabolism in rodent models. However, the lack of standardized analytical and reporting practices continues to impair between-stud...Recent advances in indirect calorimetry have expanded the capacity to characterize energy metabolism in rodent models. However, the lack of standardized analytical and reporting practices continues to impair between-study comparability and reproducibility. A recently published consensus guide addresses these limitations by providing methodological and statistical recommendations for preclinical energy expenditure research. This Perspective summarizes the main elements of the guide and highlights their relevance for enhancing analytical rigor, data harmonization, and integration with emerging computational frameworks.
Li Y, Sharma R, Usiyevich A
… +4 more, Shen X, Zhang KW, Khamaru K, Matikainen-Ankney BA
Obesity (Silver Spring)
· 2026 Jan · PMID 41152694
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OBJECTIVE: Despite successful weight loss, many individuals with obesity regain weight, yet cognitive factors in the weight loss state remain unclear. Here, we tested whether obesity induces deficits in cognitive flexibi...OBJECTIVE: Despite successful weight loss, many individuals with obesity regain weight, yet cognitive factors in the weight loss state remain unclear. Here, we tested whether obesity induces deficits in cognitive flexibility, a core component of reinforcement learning (RL), after body weight normalizes. METHODS: Male and female C57BL/6J mice were exposed to high-fat diet-induced obesity followed by weight loss. Weight loss and control mice were tested on a modified probabilistic reversal learning (PRL) task to assess cognitive flexibility and a progressive-ratio (PR) task to evaluate motivation. RL modeling was applied to dissociate latent decision-making parameters. RESULTS: Post-weight-loss mice exhibited persistent impairments in PRL efficiency. Males showed reduced late-phase reversal efficiency (p < 0.001), while females showed early-phase inefficiency but later recovery (p < 0.05). RL modeling revealed reduced learning rates in both sexes, indicating impaired value updating despite intact motivation, as PR performance did not differ between groups. Across tasks, food intake remained unchanged, suggesting reduced efficiency reflected cognitive inflexibility rather than diminished appetite. CONCLUSIONS: Weight loss after obesity produced sex-specific RL deficits. These findings dissociated motivational drive from cognitive flexibility and highlighted maladaptive decision-making as a feature of the weight loss state. This demonstrates the need for targeted interventions addressing post-weight-loss cognitive barriers.
OBJECTIVE: Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a crucial enzyme in the glycerophosphate shuttle, linking glycolysis, lipogenesis, and oxidative phosphorylation, making it a potential target for obe...OBJECTIVE: Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a crucial enzyme in the glycerophosphate shuttle, linking glycolysis, lipogenesis, and oxidative phosphorylation, making it a potential target for obesity treatment. Given the metabolic benefits of eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, we hypothesized that EPA modulates the GPD2-centered glycerophosphate shuttle to reduce adiposity, glucose intolerance, and inflammation while increasing energy expenditure. METHODS: Male and female GPD2 knockout (KO) and wild-type (WT) littermates were fed a high-fat diet (HF) without or with an 18 g EPA/kg (EPA) diet for 13 weeks. Body weight, glucose tolerance, and metabolic profiles were assessed, and blood and tissues were collected following euthanasia. RESULTS: Male GPD2 KO mice exhibited reduced adiposity and lower lipid accumulation in hepatic and adipose tissues compared to WT males. These effects were linked to lipid metabolism and beige fat activation. EPA supplementation reduced body weight and promoted glucose clearance in both WT and KO males, with enhanced hepatic lipid oxidation. However, GPD2 deficiency and EPA had minimal metabolic effects in females. CONCLUSIONS: Our findings highlight potential mechanisms by which GPD2 combats obesity by mediating lipid metabolism. Our findings further demonstrate the sex-dependent nature of EPA's metabolic benefits, independent of GPD2 deficiency.