Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications.

BACKGROUND: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. METHODS: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. FINDINGS: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). INTERPRETATION: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. FUNDING: Funding acknowledgements for each cohort can be found in the Supplementary Note.

Metabolic syndrome and epigenetic aging: a twin study.

BACKGROUND: Metabolic syndrome (MetS) is associated with premature aging, but whether this association is driven by genetic or lifestyle factors remains unclear. METHODS: Two independent discovery cohorts, consisting of twins and unrelated individuals, were examined (N = 268, aged 23-69 years). The findings were replicated in two cohorts from the same base population. One consisted of unrelated individuals (N = 1 564), and the other of twins (N = 293). Participants' epigenetic age, estimated using blood DNA methylation data, was determined using the epigenetic clocks GrimAge and DunedinPACE. The individual-level linear regression models for investigating the associations of MetS and its components with epigenetic aging were followed by within-twin-pair analyses using fixed-effects regression models to account for genetic factors. RESULTS: In individual-level analyses, GrimAge age acceleration was higher among participants with MetS (N = 56) compared to participants without MetS (N = 212) (mean 2.078 [95% CI = 0.996,3.160] years vs. -0.549 [-1.053,-0.045] years, between-group p = 3.5E-5). Likewise, the DunedinPACE estimate was higher among the participants with MetS compared to the participants without MetS (1.032 [1.002,1.063] years/calendar year vs. 0.911 [0.896,0.927] years/calendar year, p = 4.8E-11). An adverse profile in terms of specific MetS components was associated with accelerated aging. However, adjustments for lifestyle attenuated these associations; nevertheless, for DunedinPACE, they remained statistically significant. The within-twin-pair analyses suggested that genetics explains these associations fully for GrimAge and partly for DunedinPACE. The replication analyses provided additional evidence that the association between MetS components and accelerated aging is independent of the lifestyle factors considered in this study, however, suggesting that genetics is a significant confounder in this association. CONCLUSIONS: The results of this study suggests that MetS is associated with accelerated epigenetic aging, independent of physical activity, smoking or alcohol consumption, and that the association may be explained by genetics.

Age-dependent genes in adipose stem and precursor cells affect regulation of fat cell differentiation and link aging to obesity via cellular and genetic interactions.

BACKGROUND: Age and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation potential, which impacts the capacity to store fat in a metabolically healthy manner. METHODS: We integrated subcutaneous adipose tissue (SAT) bulk (n=435) and large single-nucleus RNA sequencing (n=105) data with the UK Biobank (UKB) (n=391,701) data to study age-obesity interactions originating from ASPCs by performing cell-type decomposition, differential expression testing, cell-cell communication analyses, and construction of polygenic risk scores for body mass index (BMI). RESULTS: We found that the SAT ASPC proportions significantly decrease with age in an obesity-dependent way consistently in two independent cohorts, both showing that the age dependency of ASPC proportions is abolished by obesity. We further identified 76 genes (72 SAT ASPC marker genes and 4 transcription factors regulating ASPC marker genes) that are differentially expressed by age in SAT and functionally enriched for developmental processes and adipocyte differentiation (i.e., adipogenesis). The 76 age-perturbed ASPC genes include multiple negative regulators of adipogenesis, such as RORA, SMAD3, TWIST2, and ZNF521, form tight clusters of longitudinally co-expressed genes during human adipogenesis, and show age-based differences in cellular interactions between ASPCs and adipose cell types. Finally, our genetic data demonstrate that cis-regional variants of these genes interact with age as predictors of BMI in an obesity-dependent way in the large UKB, while no such gene-age interaction on BMI is observed with non-age-dependent ASPC marker genes, thus independently confirming our cellular ASPC results at the biobank level. CONCLUSIONS: Overall, we discover that obesity prematurely induces a decrease in ASPC proportions and identify 76 developmentally important ASPC genes that implicate altered negative regulation of fat cell differentiation as a mechanism for aging and directly link aging to obesity via significant cellular and genetic interactions.

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

Cardiometabolic health in adults born with very low birth weight-a sibling study.

BACKGROUND: Preterm survivors have increased risk for impaired cardiometabolic health. We assessed glucose regulation and cardiometabolic biomarkers in adult very low birth weight (VLBW, <1500 g) survivors, using siblings as controls. METHODS: VLBW-participants were matched with term-born, same-sex siblings. At mean age 29.2 years (SD 3.9), 74 VLBW-adults and 70 siblings underwent a 2-h 75 g oral glucose tolerance test and blood tests for assessment of cardiometabolic biomarkers. RESULTS: Of participants, 23 (31%) VLBW and 11 (16%) sibling-controls met World Health Organization criteria for impaired glucose regulation (OR adjusted for age and sex 2.5, 95% CI: 1.1 to 5.8). Adjusting for age and sex, VLBW-participants showed 9.2% higher 2-h glucose (95% CI: 0.4% to 18.8%) than their siblings. Also, fasting (13.4%, -0.3% to 29.0%) and 2-h free fatty acids (15.6%, -2.4% to 36.9%) were higher in VLBW-participants. These differences were statistically significant only after further adjusting for confounders. No statistically significant differences were found regarding other measured biomarkers, including insulin resistance, atherogenic lipid profiles or liver tests. CONCLUSIONS: VLBW-adults showed more impaired fatty acid metabolism and glucose regulation. Differences in cardiometabolic biomarkers were smaller than in previous non-sibling studies. This may partly be explained by shared familial, genetic, or environmental factors. IMPACT: At young adult age, odds for impaired glucose regulation were 3.4-fold in those born at very low birth weight, compared to same-sex term-born siblings. Taking into consideration possible unmeasured, shared familial confounders, we compared cardiometabolic markers in adults born preterm at very low birth weight with term-born siblings. Prematurity increased risk for impaired glucose regulation, unrelated to current participant characteristics, including body mass index. In contrast to previous studies, differences in insulin resistance were not apparent, suggesting that insulin resistance may partially be explained by factors shared between siblings. Also, common cardiometabolic biomarkers were similar within sibling pairs.

Bone marrow metabolism is affected by body weight and response to exercise training varies according to anatomical location.

AIM: High body weight is a protective factor against osteoporosis, but obesity also suppresses bone metabolism and whole-body insulin sensitivity. However, the impact of body weight and regular training on bone marrow (BM) glucose metabolism is unclear. We studied the effects of regular exercise training on bone and BM metabolism in monozygotic twin pairs discordant for body weight. METHODS: We recruited 12 monozygotic twin pairs (mean ± SD age 40.4 ± 4.5 years; body mass index 32.9 ± 7.6, mean difference between co-twins 7.6 kg/m2 ; eight female pairs). Ten pairs completed the 6-month long training intervention. We measured lumbar vertebral and femoral BM insulin-stimulated glucose uptake (GU) using 18 F-FDG positron emission tomography, lumbar spine bone mineral density and bone turnover markers. RESULTS: At baseline, heavier co-twins had higher lumbar vertebral BM GU (p < .001) and lower bone turnover markers (all p < .01) compared with leaner co-twins but there was no significant difference in femoral BM GU, or bone mineral density. Training improved whole-body insulin sensitivity, aerobic capacity (both p < .05) and femoral BM GU (p = .008). The training response in lumbar vertebral BM GU was different between the groups (time × group, p = .02), as GU tended to decrease in heavier co-twins (p = .06) while there was no change in leaner co-twins. CONCLUSIONS: In this study, regular exercise training increases femoral BM GU regardless of weight and genetics. Interestingly, lumbar vertebral BM GU is higher in participants with higher body weight, and training counteracts this effect in heavier co-twins even without reduction in weight. These data suggest that BM metabolism is altered by physical activity.

Mental, physical, and social well-being and quality of life in healthy young adult twin pairs discordant and concordant for body mass index.

OBJECTIVE: The relationship between obesity and mental health is complex and is moderated by the level of obesity, age, sex, and social and genetic factors. In the current study, we used a unique co-twin control design, with twin pairs discordant for body mass index (BMI), to control for shared genetic and environmental effects between obesity and several dimensions of mental health. METHODS: We studied 74 monozygotic (MZ) twin pairs, of whom 36 were BMI-discordant (intra-pair difference in BMI ≥ 3 kg/m2), and 77 dizygotic (DZ) twin pairs (46 BMI-discordant). We assessed subjective health, especially mental health and mental well-being (depression, anxiety, self-esteem, health-related quality of life, life satisfaction, and social well-being) through questionnaires. RESULTS: Heavier MZ co-twins from BMI-discordant pairs had poorer general health (58.8±3.0 vs. 72.4±3.8, P = 0.001, FDR = 0.017 on a scale from 0 to 100 where higher scores indicate more positive results), physical functioning (90.3±1.1 vs. 95.5±2.2, P = 0.024, FDR = 0.122), energy levels (55.6±3.4 vs. 66.6±3.3, P = 0.013, FDR = 0.109), and emotional well-being (65.9±3.2 vs. 75.4±2.9, P = 0.031, FDR = 0.122), as well as a tendency for depressive symptoms (8.4±1.3 vs. 5.6±0.9, P = 0.071, FDR = 0.166) compared to their leaner co-twins. Heavier DZ co-twins had poorer total physical well-being (91.6±1.9 vs. 95.6±1.0, P = 0.035, FDR = 0.356) and more depressive symptoms (4.3±0.9 vs. 2.4±0.5, P = 0.016, FDR = 0.345 on a scale from 0 to 63 where lower scores indicate fewer depressive symptoms) than their leaner co-twins. Association analyses, using all twin pairs, confirmed that higher BMI within pairs linked to general health, physical functioning and depressive symptoms. No association was found between BMI and anxiety, self-esteem, life satisfaction, or social well-being. CONCLUSIONS: In conclusion, this study underscores the notable association between elevated BMI and physical well-being and to a lesser extent between elevated BMI and depressive symptoms, while revealing no discernible connections with anxiety, self-esteem, life satisfaction, or social well-being.

Development and validation of a weight-loss predictor to assist weight loss management.

This study aims to develop and validate a modeling framework to predict long-term weight change on the basis of self-reported weight data. The aim is to enable focusing resources of health systems on individuals that are at risk of not achieving their goals in weight loss interventions, which would help both health professionals and the individuals in weight loss management. The weight loss prediction models were built on 327 participants, aged 21-78, from a Finnish weight coaching cohort, with at least 9 months of self-reported follow-up weight data during weight loss intervention. With these data, we used six machine learning methods to predict weight loss after 9 months and selected the best performing models for implementation as modeling framework. We trained the models to predict either three classes of weight change (weight loss, insufficient weight loss, weight gain) or five classes (high/moderate/insufficient weight loss, high/low weight gain). Finally, the prediction accuracy was validated with an independent cohort of overweight UK adults (n = 184). Of the six tested modeling approaches, logistic regression performed the best. Most three-class prediction models achieved prediction accuracy of > 50% already with half a month of data and up to 97% with 8 months. The five-class prediction models achieved accuracies from 39% (0.5 months) to 89% (8 months). Our approach provides an accurate prediction method for long-term weight loss, with potential for easier and more efficient management of weight loss interventions in the future. A web application is available: https://elolab.shinyapps.io/WeightChangePredictor/ .The trial is registered at clinicaltrials.gov/ct2/show/NCT04019249 (Clinical Trials Identifier NCT04019249), first posted on 15/07/2019.

Roux-en-Y versus one-anastomosis gastric bypass (RYSA study): weight loss, metabolic improvements, and nutrition at 1 year after surgery, a multicenter randomized controlled trial.

OBJECTIVE: Although it has been suggested that one-anastomosis gastric bypass (OAGB) is metabolically superior to the "gold standard," i.e., Roux-en-Y gastric bypass (RYGB), there is little robust evidence to prove it. Because this result may arise from the typically longer length of bypassed intestine in OAGB, here, the authors standardized the bypass length in RYGB and OAGB and compared weight loss and metabolic outcomes in a randomized controlled trial. METHODS: The authors randomized 121 bariatric patients to RYGB (n = 61) or OAGB (n = 60) in two Finnish University Hospitals and measured weight; body composition; metabolic features (insulin sensitivity, lipids, inflammation, nutrition); and comorbidities before and 6 and 12 months after the operation. RESULTS: Total weight loss was similar in RYGB and OAGB at 6 months (mean: 21.2% [95% CI: 19.4-23.0] vs. 22.8% [95% CI: 21.5-24.1], p = 0.136) and 12 months (25.4% [95% CI: 23.4-27.5] vs. 26.1% [95% CI: 24.2-28.9], p = 0.635). Insulin sensitivity, lipids, and inflammation improved similarly between the groups (p > 0.05). Remission of type 2 diabetes and hypercholesterolemia was marked and similar (p > 0.05) but the use of antihypertensive medications was lower (p = 0.037) and hypertension tended to improve more (p = 0.053) with RYGB versus OAGB at 12 months. Higher rates of vitamin D-25 deficiency (p < 0.05) and lower D-25 levels were observed with OAGB versus RYGB throughout the follow-up (p < 0.001). No differences in adverse effects were observed. CONCLUSIONS: RYGB and OAGB were comparable in weight loss, metabolic improvement, remission of diabetes and hypercholesterolemia, and nutrition at 1-year follow-up. Vitamin D-25 deficiency was more prevalent with OAGB, whereas reduction in antihypertensive medications and hypertension was greater with RYGB. There is no need to change the current practices of RYGB in favor of OAGB.

Polygenic risk of obesity and BMI trajectories over 36 years: A longitudinal study of adult Finnish twins.

OBJECTIVE: This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m2 ). METHODS: Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms. RESULTS: In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8). CONCLUSIONS: Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity.

Human visceral adipose tissue microvascular endothelial cell isolation and establishment of co-culture with white adipocytes to analyze cell-cell communication.

Communication between adipocytes and endothelial cells (EC) is suggested to play an important role in the metabolic function of white adipose tissue. In order to generate tools to investigate in detail the physiology and communication of EC and adipocytes, a method for isolation of adipose microvascular EC from visceral adipose tissue (VAT) biopsies of subjects with obesity was developed. Moreover, mature white adipocytes were isolated from the VAT biopsies by a method adapted from a previously published Membrane aggregate adipocytes culture (MAAC) protocol. The identity and functionality of the cultivated and isolated adipose microvascular EC (AMvEC) was validated by imaging their morphology, analyses of mRNA expression, fluorescence activated cell sorting (FACS), immunostaining, low-density lipoprotein (LDL) uptake, and in vitro angiogenesis assays. Finally, we established a new trans filter co-culture system (membrane aggregate adipocyte and endothelial co-culture, MAAECC) for the analysis of communication between the two cell types. EC-adipocyte communication in this system was validated by omics analyses, revealing several altered proteins belonging to pathways such as metabolism, intracellular transport and signal transduction in adipocytes co-cultured with AMvEC. In reverse experiments, induction of several pathways including endothelial development and functions was found in AMvEC co-cultured with adipocytes. In conclusion, we developed a robust method to isolate EC from small quantities of human VAT. Furthermore, the MAAECC system established during the study enables one to study the communication between primary white adipocytes and EC or vice-versa and could also be employed for drug screening.

Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.

Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.

Cell-Type Composition Affects Adipose Gene Expression Associations With Cardiometabolic Traits.

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA sequencing (RNA-seq) using a reference single-nuclear RNA-seq data set. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower BMI, respectively. We evaluated cell-type proportions and BMI as covariates in tests of association between >25,000 gene expression levels and 22 cardiometabolic traits. For >95% of genes, the optimal, or best-fit, models included BMI as a covariate, and for 79% of associations, the optimal models also included cell type. After adjusting for the optimal covariates, we identified 2,664 significant associations (P ≤ 2e-6) for 1,252 genes and 14 traits. Among genes proposed to affect cardiometabolic traits based on colocalized genome-wide association study and adipose expression quantitative trait locus signals, 25 showed a corresponding association between trait and gene expression levels. Overall, these results suggest the importance of modeling cell-type proportion when identifying gene expression associations with cardiometabolic traits.

Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes.

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions.

Cross-Tissue Single-Nucleus RNA Sequencing Discovers Tissue-Resident Adipocytes Involved in Propanoate Metabolism in the Human Heart.

BACKGROUND: Adipocytes are crucial regulators of cardiovascular health. However, not much is known about gene expression profiles of adipocytes residing in nonfat cardiovascular tissues, their genetic regulation, and contribution to coronary artery disease. Here, we investigated whether and how the gene expression profiles of adipocytes in the subcutaneous adipose tissue differ from adipocytes residing in the heart. METHODS: We used single-nucleus RNA-sequencing data sets of subcutaneous adipose tissue and heart and performed in-depth analysis of tissue-resident adipocytes and their cell-cell interactions. RESULTS: We first discovered tissue-specific features of tissue-resident adipocytes, identified functional pathways involved in their tissue specificity, and found genes with cell type-specific expression enrichment in tissue-resident adipocytes. By following up these results, we discovered the propanoate metabolism pathway as a novel distinct characteristic of the heart-resident adipocytes and found a significant enrichment of coronary artery disease genome-wide association study risk variants among the right atrium-specific adipocyte marker genes. Our cell-cell communication analysis identified 22 specific heart adipocyte-associated ligand-receptor pairs and signaling pathways, including THBS (thrombospondin) and EPHA (ephrin type-A), further supporting the distinct tissue-resident role of heart adipocytes. Our results also suggest chamber-level coordination of heart adipocyte expression profiles as we observed a consistently larger number of adipocyte-associated ligand-receptor interactions and functional pathways in the atriums than ventricles. CONCLUSIONS: Overall, we introduce a new function and genetic link to coronary artery disease for the previously unexplored heart-resident adipocytes.

Associations of obesity phenotypes with weight change, cardiometabolic benefits, and type 2 diabetes incidence during a lifestyle intervention: results from the PREVIEW study.

BACKGROUND/OBJECTIVES: Some individuals with overweight/obesity may be relatively metabolically healthy (MHO) and have a lower risk of cardiovascular disease than those with metabolically unhealthy overweight/obesity (MUO). We aimed to compare changes in body weight and cardiometabolic risk factors and type 2 diabetes incidence during a lifestyle intervention between individuals with MHO vs MUO. METHODS: This post-hoc analysis included 1012 participants with MHO and 1153 participants with MUO at baseline in the randomized trial PREVIEW. Participants underwent an eight-week low-energy diet phase followed by a 148-week lifestyle-based weight-maintenance intervention. Adjusted linear mixed models and Cox proportional hazards regression models were used. RESULTS: There were no statistically significant differences in weight loss (%) between participants with MHO vs MUO over 156 weeks. At the end of the study, weight loss was 2.7% (95% CI, 1.7%-3.6%) in participants with MHO and 3.0% (2.1%-4.0%) in those with MUO. After the low-energy diet phase, participants with MHO had smaller decreases in triglyceride (mean difference between MHO vs MUO 0.08 mmol·L-1 [95% CI, 0.04-0.12]; P < 0.001) but similar reductions in fasting glucose and HOMA-IR than those with MUO. However, at the end of weight maintenance, those with MHO had greater reductions in triglyceride (mean difference -0.08 mmol·L-1 [-0.12--0.04]; P < 0.001), fasting glucose, 2-hour glucose (difference -0.28 mmol·L-1 [-0.41--0.16]; P < 0.001), and HOMA-IR than those with MUO. Participants with MHO had smaller decreases in diastolic blood pressure and HbA1c and greater decreases in HDL cholesterol after weight loss than those with MUO, whereas the statistically significant differences disappeared at the end of weight maintenance. Participants with MHO had lower 3-year type 2 diabetes incidence than those with MUO (adjusted hazard ratio 0.37 [0.20-0.66]; P < 0.001). CONCLUSIONS: Individuals with MUO had greater improvements in some cardiometabolic risk factors during the low-energy diet phase, but had smaller improvements during long-term lifestyle intervention than those with MHO.

The Effectiveness of eHealth Interventions for Weight Loss and Weight Loss Maintenance in Adults with Overweight or Obesity: A Systematic Review of Systematic Reviews.

PURPOSE OF REVIEW: The purpose of this study is to evaluate the effectiveness of eHealth interventions for weight loss and weight loss maintenance among adults with overweight or obesity through a systematic review of systematic reviews. RECENT FINDINGS: This study included 26 systematic reviews, covering a total of 338 original studies, published between 2018 and 2023. The review indicates that eHealth interventions are more effective than control interventions or no care and comparable to face-to-face interventions. The effect sizes remain relatively small when comparing eHealth interventions to any control conditions, with mean differences of weight loss results from - 0.12 kg (95% CI - 0.64 to 0.41 kg) in a review comparing eHealth interventions to face-to-face care to - 4.32 kg (- 5.08 kg to - 3.57 kg) in a review comparing eHealth interventions to no care. The methodological quality of the included studies varies considerably. However, it can be concluded that interventions with human contact work better than those that are fully automated. In conclusion, this systematic review of systematic reviews provides an updated understanding of the development of digital interventions in recent years and their effectiveness for weight loss and weight loss maintenance among adults with overweight or obesity. The findings suggest that eHealth interventions can be a valuable tool for delivering obesity care to more patients economically. Further research is needed to determine which specific types of eHealth interventions are most effective and how to best integrate them into clinical practice.

Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver. METHODS: To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals' subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis. FINDINGS: We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels. INTERPRETATION: Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease. FUNDING: The work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research.

Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure.

Obesity is caused by a prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes is debated3,4. Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.