International Journal of Obesity最新文献

Background: Metabolic dysregulation, a defining feature of obesity, disrupts essential signalling pathways involved in nutrient sensing and mitochondria homeostasis. The nuclear factor erythroid 2-related factor 2 (NRF-2) serves as a pivotal regulator of the cellular stress response, and recent studies have implicated it in the pathogenesis of obesity, diabetes, and metabolic syndrome. Curcumin, a polyphenolic compound derived from turmeric, has been identified as a potent activator of NRF-2. Evidence suggests curcumin impacts obesity and metabolic disorders by modulating gut microbiota composition, increasing energy expenditure, and regulating lipid metabolism. Orlistat, an anti-obesity drug, inhibits fat absorption in the gastrointestinal tract, but its side effects limits its broader use.

Objectives: The present study aims to investigate the potential synergetic effect of a hybrid combination between orlistat and curcumin. Additionally, we provide a detailed understanding of the molecular mechanisms through which this combination mitigates glucose-induced lipid accumulation in Caenorhabditis elegans, with a focus on the role of the skinhead 1 (SKN-1) transcription factor, an orthologue of NRF2.

Methods: We assessed the lipid accumulation and the changes in skn-1 transcriptional activity in C. elegans using confocal GFP-based detection, alongside mRNA expression analysis of genes from lipid metabolism and oxidative stress response in wild-type, QV225 and LD1 strains. Furthermore, we evaluated locomotion, chemotaxis and mitochondrial dynamics to enhance our understanding of the proposed molecular-based model.

Results: Our findings reveal that the orlistat/curcumin combination exerts an anti-obesogenic effect through SKN-1/NRF2-dependent regulation of conserved genes involved in carbohydrate and lipid metabolism in C. elegans. Moreover, the combination stimulates mitochondrial potential, further contributing to the observed synergistic effects.

Conclusion: The hybrid combination of orlistat and curcumin demonstrates significant anti-obesity activity by regulating nutrient-sensing pathways through SKN-1/NRF-2 modulation. This approach may allow for the reduction of orlistat dosage, thereby minimizing its adverse effects while maintaining its therapeutic efficacy.

Background: Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes.

Methods: We cross-sectionally analyzed hip-worn accelerometry data from 61,116 participants aged 20-75 in the German National Cohort between 2015 and 2019. We divided physical activity into sex- and age-standardized quartiles of total morning (06:00-11:59), afternoon (12:00-17:59), evening (18:00-23:59), and nighttime (00:00-06:00) physical activity. Using multivariable logistic regression, we estimated associations of physical activity timing with obesity (BMI ≥ 30.0 kg/m²) and diabetes (self-reported or HbA1c ≥ 6.5%). We accounted for sex, age, study region, education, employment, risky alcohol use, smoking, night shift work, and sleep duration.

Results: High afternoon (top vs. bottom quartile, OR: 0.36, 95% CI: 0.33-0.38) and evening physical activity (OR: 0.45, 95% CI: 0.42-0.48) showed lower obesity odds than high morning activity (OR: 0.71, 95% CI: 0.66-0.76), whereas nighttime activity increased obesity odds (OR: 1.58, 95% CI: 1.48-1.68). Associations were similar for diabetes, with the lowest odds for afternoon (OR: 0.47, 95% CI: 0.42-0.53), followed by evening (OR: 0.56, 95% CI: 0.50-0.62) and morning activity (OR: 0.80, 95% CI: 0.71-0.89), and higher odds for nighttime activity (OR: 1.43, 95% CI: 1.29-1.58). Findings were not modified by employment status, night shift work, and sleep duration.

Conclusions: Our cross-sectional findings require longitudinal corroboration but suggest afternoon and evening activity provide greater metabolic health benefits than morning activity, while nighttime activity is discouraged.

Objective: Adults living with overweight or obesity do not represent a single homogenous group in terms of mortality and disease risks. The aim of our study was to evaluate how the associations of adulthood overweight and obesity with mortality and incident disease are modified by (i.e., differ according to) self-reported childhood body weight categories.

Methods: The sample comprised 191,181 men and 242,806 women aged 40-69 years (in 2006-2010) in the UK Biobank. The outcomes were all-cause mortality, incident cardiovascular disease (CVD), and incident obesity-related cancer. Cox proportional hazards regression models were used to estimate how the associations with the outcomes of adulthood weight status (normal weight, overweight, obesity) differed according to perceived body weight at age 10 years (about average, thinner, plumper). To triangulate results using an approach that better accounts for confounding, analyses were repeated using previously developed and validated polygenic risk scores (PRSs) for childhood body weight and adulthood BMI, categorised into three-tier variables using the same proportions as in the observational variables.

Results: In both sexes, adulthood obesity was associated with higher hazards of all outcomes. However, the associations of obesity with all-cause mortality and incident CVD were stronger in adults who reported being thinner at 10 years. For example, obesity was associated with a 1.28 (1.21, 1.35) times higher hazard of all-cause mortality in men who reported being an average weight child, but among men who reported being a thinner child this estimate was 1.63 (1.53, 1.75). The ratio between these two estimates was 1.28 (1.17, 1.40). There was also some evidence that the associations of obesity with all-cause mortality and incident CVD were stronger in adults who reported being plumper at 10 years. In genetic analyses, however, there was no evidence that the association of obesity (according to the adult PRS) with mortality or incident CVD differed according to childhood body size (according to the child PRS). For incident obesity-related cancer, the evidence for effect modification was limited and inconsistent between the observational and genetic analyses.

Conclusions: Greater risks for all-cause mortality and incident CVD in adults with obesity who perceive themselves to have been a thinner or plumper than average child may be due to confounding and/or recall bias.

Previous studies have identified G protein-coupled receptor (GPCR) kinase 5 (GRK5) as a genetic factor contributing to obesity pathogenesis, but the underlying mechanism remains unclear. We demonstrate here that Grk5 mRNA is more abundant in stromal vascular fractions of mouse white adipose tissue, the fraction that contains adipose progenitor cells, or committed preadipocytes, than in adipocyte fractions. Thus, we generated a GRK5 knockout (KO) 3T3-L1 preadipocyte to further investigate the mechanistic role of GRK5 in regulating adipocyte differentiation. During adipogenic stimulation, GRK5 KO preadipocytes had decreased lipid accumulation and delayed mature adipocyte development compared to wildtype cells coupled with suppressed adipogenic and lipogenic gene expression. Beside GPCR signaling, RNA sequencing and pathway analysis identified insulin-like growth factor 1 (IGF-1) signaling to be one of the top 5 significantly dysregulated pathways in GRK5 KO cells. GRK5 KO cells also displayed decreased insulin-stimulated ERK phosphorylation, a downstream target of insulin-stimulated IGF-1 receptor activation, suggesting that GRK5 acts through this critical pathway to impact 3T3-L1 adipocyte differentiation. To find a more translational approach, we identified a new small molecule GRK5 inhibitor that was able to reduce 3T3-L1 adipogenesis. These data suggest that GRK5 is required for adipocyte differentiation through IGF-1 receptor/ERK activation and may be a promising translational target for obesity.

Purpose: This study aimed to investigate the validity and applicability of a non-exercise estimation of cardiorespiratory fitness using resting seismocardiography (SCG eV̇O₂peak) in people with overweight and obesity before and after a 14-week lifestyle intervention.

Methods: The study was carried out at a Folk high school that offers 14-week courses on lifestyle changes where participants live at the school and voluntarily participate in daily lectures and activities. Sixty-seven men and women with age and body mass index between 18 and 70 years and 25-50 kg·m^-2 were tested at baseline, and 52 had a follow-up test after 14 weeks. Testing included the determination of anthropometric variables, an SCG eV̇O₂peak at supine rest, and a gold standard V̇O₂peak test on a cycle ergometer until voluntary exhaustion.

Results: Agreement analysis for V̇O₂peak at baseline (n = 67, SCG eV̇O₂peak: 26.9 ± 1.9 ml·min^-1·kg^-1, V̇O₂peak: 26.6 ± 1.6 ml·min^-1·kg^-1, mean ± 95% confidence interval) showed a bias of 0.3 ± 1.0 ml·min^-1·kg^-1 with 95% limits of agreement (LoA) ranging ± 9.8 ml·min^-1·kg^-1. A Pearson's correlation of r = 0.78 (p < 0.0001) and a standard error of estimate (SEE) of 5.0 ml·min^-1·kg^-1 were found between methods. At follow-up (n = 52), body mass was reduced by 6.6 ± 1.4 kg (p < 0.0001). V̇O₂peak increased by 3.3 ± 0.9 ml·min^-1·kg^-1 and 175 ± 78 ml·min^-1 and SCG eV̇O₂peak by 2.6 ± 0.8 ml·min^-1·kg^-1 and 93 ± 76 ml·min^-1 (two-way ANOVA repeated measure: intervention p < 0.0001, method p = 0.939 and interaction p = 0.125, relative V̇O₂peak). A Pearson's correlation of r = 0.37 (p < 0.05) was found between changes in relative V̇O₂peak but not for absolute V̇O₂peak r = 0.10 (p = 0.402).

Conclusions: The SCG method is accurate for estimating V̇O₂peak and appropriate for detecting group changes in both relative and absolute V̇O₂peak following a lifestyle intervention in people with overweight and obesity. Furthermore, the method can detect individual changes in V̇O₂peak but not independently of body mass changes. Yet, the applicability is still limited by the relatively large variation in LoA and SEE.

Background/objectives: Children's biological age does not always correspond to their chronological age. In the case of BMI trajectories, this can appear as phase variation, which can be seen as shift, stretch, or shrinking between trajectories. With maturation thought of as a process moving towards the final state - adult BMI, we assessed whether children can be divided into latent groups reflecting similar maturational age of BMI. The groups were characterised by early factors and time-related features of the trajectories.

Subjects/methods: We used data from two general population birth cohort studies, Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986). Height (n = 6329) and weight (n = 6568) measurements were interpolated in 34 shared time points using B-splines, and BMI values were calculated between 3 months to 16 years. Pairwise phase distances of 2999 females and 3163 males were used as a similarity measure in k-medoids clustering.

Results: We identified three clusters of trajectories in females and males (Type 1: females, n = 1566, males, n = 1669; Type 2: females, n = 1028, males, n = 973; Type 3: females, n = 405, males, n = 521). Similar distinct timing patterns were identified in males and females. The clusters did not differ by sex, or early growth determinants studied.

Conclusions: Trajectory cluster Type 1 reflected to the shape of what is typically illustrated as the childhood BMI trajectory in literature. However, the other two have not been identified previously. Type 2 pattern was more common in the NFBC1966 suggesting a generational shift in BMI maturational patterns.

Background: Several studies have attempted to demonstrate the associations between body mass index (BMI) in early age and cardiovascular diseases (CVDs). However, their findings were inconsistent and inconclusive, indicating the need for further investigation.

Methods: We conducted a systematic review and meta-analysis of studies focusing on BMI in early age (age from 2 to 22) in relation to CVDs in adulthood, including coronary artery disease (CHD), ischemic and hemorrhagic stroke, myocardial infarction and heart failure. Fixed-effects and Random-effects models were used to pool the data. Sex, age, adjustment of socioeconomic status and fatal events specific analysis were conducted to examine their effects on the results.

Results: Thirty-eight studies were eligible for inclusion. BMI in early age was positively related to CVD (HR = 1.18, 95% CI: 1.07-1.30), CHD (HR = 1.13, 95% CI: 1.07-1.19), heart failure (HR = 1.16, 95% CI: 1.11-1.20) but not stroke (HR = 0.99, 95% CI: 0.93-1.05). The results remained consistent after stratified by sex, fatal or non-fatal events and adjustment for socioeconomic status. Further age-specific analysis showed that both childhood and early adulthood group showed positive associations on CHD and HF. While estimates in early adulthood for all CVDs were numerically higher than that for childhood. Category analyses showed a positive association between being overweight or obesity and adulthood CVDs, including stroke.

Conclusion: We found a positive association between early-age BMI and adulthood cardiovascular diseases except for stroke.

Trial registration: Systemic review registration https://www.crd.york.ac.uk/Prospero/ , identifier CRD42023403602.

Background: The effects of time-restricted eating (TRE) with exercise on body composition in adults are not clear.

Objective: This meta-analysis aimed to assess the effects of TRE when followed in combination with various forms of exercise, including aerobic, resistance, and combined aerobic and resistance [concurrent] training on body composition.

Methods: Studies published up to May 2023 were searched in EBSCOhost (MEDLINE, CINAHL, SPORTSDISCUS), PubMed, and SCOPUS databases. Fifteen studies, including 338 participants, that evaluated TRE vs. unrestricted eating in individuals performing exercise were analyzed. A random-effects model was used to calculate the weighted mean effect sizes (ES) with 95% confidence intervals (95% CI's).

Results: According to the pooled results, TRE had a small but significant reduction of fat mass (FM) kg with an effect size of -0.20 (95% CI = -0.28 to -0.13, p < 0.001) and on body fat percent (BF%) with an effect size of -0.23 (95% CI = -0.35 to -0.11, p < 0.001). The prediction interval ranged from -0.48 to 0.08 for FM and from -0.64 to 0.18 for BF%, respectively. TRE did not significantly alter fat-free mass (FFM) kg compared to control (p = 0.07). Furthermore, age, body mass index (BMI), exercise type, study duration, and energy intake did not have a significant impact on the variation in effect sizes according to the subgroup analyses (p > 0.05).

Conclusion: TRE with exercise may reduce fat mass compared to an unrestricted eating window exercise-matched control while preserving FFM. However, more studies are needed.

Background: Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae.

Methods: Eight hundred seventy-seven youth (6-21 years) with overweight/obesity, recruited from the Yale Pediatric Obesity Clinic in New Haven, CT, underwent genetic analysis to screen for functionally damaging, rare variants (MAF < 0.01) in MC4R. Participants were assigned to a Pathogenic Variant or No Pathogenic Variant group and completed a 10-timepoint 180-min oral glucose tolerance test (OGTT) and abdominal MRI.

Results: Compared to the No Pathogenic Variant group, the Pathogenic Variant group demonstrated significantly greater glucose concentrations (AUC_tot: 24.7 ± 1.22 g/dL × 180 min vs. 21.9 ± 1.41 g/dL × 180 min; p = 0.001), insulin levels (AUC_tot: 57.4 ± 11.5 mU/mL × 180 min vs. 35.5 ± 8.90 mU/mL × 180 min; p = 0.002), and lower insulin sensitivity (WBISI: 1.01 ± 0.137 vs. 1.85 ± 0.036; p = 0.0008) during the OGTT. The Pathogenic Variant group also presented with greater visceral adipose tissue (VAT) (85.1 cm² ± 10.3 vs. 56.1 cm² ± 1.64; p = 0.003) and intrahepatic fat content (HFF%) (19.4% ± 4.94 vs. 8.21% ± 0.495; p = 0.012) than the No Pathogenic Variant group despite the two groups having similar BMI z-scores (p = 0.255), subcutaneous adipose tissue (SAT) (p = 0.643), and total body fat (p = 0.225).

Conclusions: Pathogenic variants in MC4R are associated with increased VAT, HFF%, and insulin resistance, independent from the degree of obesity in youth.