Systematic screening for liver fibrosis using FIB-4 score is recommended in primary care for patients with chronic liver disease risk factors. This study assesses the prevalence and characteristics of patients at risk for advanced fibrosis in a weight loss program. This multicenter retrospective cohort study includes obese and overweight subjects participating in a weight loss program across 110 French centers. 34 510 participants with baseline FIB-4 available were included, predominantly women (78.3%), median age of 54 years, 70% obese. Baseline FIB-4 values were <1.3, 1.3-2.67 or >2.67 in 80.9%, 18.1% and 1% of the participants, respectively. When moving from the lower risk category (<1.3) to the highest (>2.67), the rates of metabolic comorbidities such as diabetes rose (from 3.2% to 13.3%). After 5 (3-7) months, all anthropometric parameters improved. A follow-up FIB-4 value was available in 20.7% participants. Among high-risk, 43% changed classes, 4.6% moving to the lower risk-category.

Introduction Behavioural weight loss programmes are generally accepted as being beneficial in reducing cardiometabolic risk and improving patient-reported outcomes. However, prospective data from large real-world cohorts are scarce concerning the mid-term and long-term impact of such interventions. The objective of this large prospective cohort study (n>10 000 participants) is to demonstrate the effectiveness of the standardised Nutritional and Psycho-Behavioural Rehabilitation programme (RNPC Programme) in reducing the percentage of subjects requiring insulin and/or other diabetes drug therapy, antihypertensive drugs, lipid-lowering therapies and continuous positive airway pressure therapy for obstructive sleep apnoea after the end of the intervention. The rate of remission of hypertension, type 2 diabetes and sleep apnoea will also be prospectively assessed.Methods This is a prospective multicentre observational study carried out in 92 RNPC centres in France. Participants will follow the standardised RNPC Programme. The prospective dataset will include clinical, anthropometric and biochemical data, comorbidities, medications, body composition, patient-reported outcome questionnaire responses, sleep study data with objective measurements of sleep apnoea severity and surrogate markers of cardiovascular risk (ie, blood pressure and arterial stiffness). About 10 000 overweight or obese participants will be included over 2 years with a follow-up duration of up to 5 years.Ethics and dissemination Ethical approval for this study has been granted by the Ethics Committee (Comité de protection des personnes Sud-Est I) of Saint-Etienne University Hospital, France (SI number: 23.00174.000237). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of a future randomised controlled trial in the specific population identified as good responders to the RNPC Programme.Trial registration number NCT05857319.

Systematic screening for liver fibrosis using FIB-4 score is recommended in primary care for patients with chronic liver disease risk factors. This study assesses the prevalence and characteristics of patients at risk for advanced fibrosis in a weight loss program. This multicenter retrospective cohort study includes obese and overweight subjects participating in a weight loss program across 100 French centers. 27 643 participants with baseline FIB-4 available were included, predominantly women (78.3%), median age of 54 years, 70% obese. Baseline FIB-4 values were < 1.3, 1.3–2.67 or > 2.67 in 80.9%, 18.1% and 1% of the participants, respectively. When moving from the lower risk category (< 1.3) to the highest (> 2.67), the rates of metabolic comorbidities such as diabetes rose (from 3.2–13.3%). After 5 [3–7] months, all anthropometric parameters improved. A follow-up FIB-4 value was available in 20,7% participants. Among high-risk, 43% changed classes, 4.6% moving to the lower risk-category. Prevalence of patients at risk for advanced fibrosis according to initial FIB-4 was 19.1%, with higher rates of metabolic comorbidities in higher-risk participants. General practitioners and nutrition professionals play crucial role for implementing the two-step algorithm to screen for advanced fibrosis in patients at risk.

Le syndrome d’apnées obstructives du sommeil (SAS) est associé au surpoids et à l’obésité dans 60 % des cas. Nous avons estimé prospectivement l’impact d’un programme de réduction pondérale et psychocomportemental sur le risque de SAS et la somnolence chez des patients sans SAS diagnostiqué. Étude de cohorte prospective multicentrique. Le risque de SAS est mesuré avec le questionnaire Berlin et la somnolence diurne avec le score de somnolence d’Epworth. Les questionnaires ont été administrés avant et après le programme. Cent vingt-sept patients ont été inclus : 85,2 % de femmes, âge médian 52 ans, IQR [44 ; 61]. Le programme a entraîné une diminution médiane d’indice de masse corporelle (IMC) de −3,7 kg/m2 [−5 ; −2,8] sur une période de 5,6 mois [3,8 ; 8,4]. Au début du programme, 46 patients (36 %) avaient un risque de SAS (Berlin ≥ 2). On observe une diminution significative de poids, d’IMC et de pression artérielle diastolique dans le groupe de patients à risque de SAS par rapport au groupe sans risque de SAS au démarrage du programme. À la fin du suivi, la proportion de patients ayant un risque de SAS est passé de 36 % à 7 % (p < 0,01) et la proportion de patients avec une somnolence diurne excessive (Epworth > 10) est passée de 17 % à 4 %, p < 0,01. Ces résultats confirment qu’un programme de perte de poids est associé à une diminution significative du risque de SAS et de somnolence diurne chez les patients en surpoids/obèses.

Although high-protein diets appear to be the most efficient way to lose weight, concerns may arise about their innocuity on renal function. The objective of this study is to assess the impact of a weight loss program on renal function. A multicentric cohort-based study was performed using the RNPC© French national weight loss program. Patients with at least two creatinine measurements at the beginning of the program and at the end of the weight loss phase between 1 January 2016 and 1 July 2021 were included. Renal function was assessed by Modification of Diet in Renal Disease (MDRD) equation-based estimated glomerular filtration rate (eGFR). From 4394 patients with two creatinine measurements included, 1579 (35.9%) had normal eGFR (MDRD 90–120 mL/min/1.73 m2), 210 (4.8%) had hyperfiltration (MDRD > 120 mL/min/1.73 m2), 2383 (54.2%) had chronic kidney disease (CKD) grade 2 (MDRD 60–90 mL/min/1.73 m2), and 221 (5.0%) had CKD grade 3 (MDRD 30–60 mL/min/1.73 m2). Multivariable analyses showed no eGFR change for patients in initial CKD grade 2, normal eGFR and hyperfiltration, and a significant increase in CKD grade 3. The RNPC© program avoids renal function impairment during the two first phases, regardless of the initial eGFR.

Background: Dietary intervention is a cornerstone of weight loss therapies. In obesity, a dysbiotic gut microbiota (GM) is characterized by high levels of Bacteroides lineages and low diversity. We examined the GM composition changes, including the Bacteroides 2 enterotype (Bact2), in a real-world weight loss study in subjects following a high-protein hypocaloric diet with or without a live microorganisms (LMP) supplement. Method: 263 volunteers were part of this real-world weight loss program. The first phase was a high-protein low-carbohydrate calorie restriction diet with or without LMP supplements. Fecal samples were obtained at baseline and after 10% weight loss for 163 subjects. Metagenomic profiling was obtained by shotgun sequencing. Results: At baseline, the Bact2 enterotype was more prevalent in subjects with aggravated obesity and metabolic alterations. After weight loss, diversity increased and Bact2 prevalence decreased in subjects with lower GM diversity at baseline, notably in LMP consumers. Significant increases in Akkermansia muciniphila and Parabacteroides distasonis and significant decreases of Eubacterium rectale, Streptococcus thermophilus and Bifidobacterial lineages were observed after weight loss. Conclusions: Baseline microbiome composition is associated with differential changes in GM diversity and Bact2 enterotype prevalence after weight loss. Examining these signatures could drive future personalized nutrition efforts towards more favorable microbiome compositions.

Obstructive sleep apnea (OSA) is one of the most frequent chronic diseases, and comorbid obesity occurs in more than 60% of cases. Variations in body weight influence both OSA severity and OSA-related symptoms. We prospectively assessed the impact of a weight-loss program using the Berlin score to reflect OSA risk, and we also used the Epworth Sleepiness Scale (ESS) to assess daytime sleepiness. DietSleep was a prospective multicentric cohort study investigating OSA risk and daytime sleepiness before and after weight-loss intervention. One hundred and twenty-seven patients were included (initial OSA risk 36%), most of whom were women (85.8%) with a median body mass index (BMI) of 29.7 kg/m2, and the interquartile range was (27.6; 34). The diet-based weight-loss program induced a median decrease in BMI of 3.7 kg/m2 (−5; −2.9) (body weight~12.1% (−16.0; −8.8)) over a period of 171 days (114; 269). Changes in anthropometric values were similar regarding OSA risk after adjusting for initial values. Berlin scores significantly improved from 3 (1; 5) to 1 (0; 2), p < 0.01; the proportion of patients with a Berlin score ≥2 decreased from 36% to 7% after the intervention. The proportion of patients with ESS ≥11 decreased from 13% to 2%. These results confirm that a weight-loss program produces clinically relevant weight loss and a significant improvement in both OSA and subjective daytime sleepiness.

Perinatal smoke/nicotine exposure alters lung development and causes asthma in exposed offspring, transmitted transgenerationally. The mechanism underlying the transgenerational inheritance of perinatal smoke/nicotine-induced asthma remains unknown, but germline epigenetic modulations may play a role. Using a well-established rat model of perinatal nicotine-induced asthma, we determined the DNA methylation pattern of spermatozoa of F1 rats exposed perinatally to nicotine in F0 gestation. To identify differentially methylated regions (DMRs), reduced representation bisulfite sequencing was performed on spermatozoa of F1 litters. The top regulated gene body and promoter DMRs were tested for lung gene expression levels, and key proteins involved in lung development and repair were determined. The overall CpG methylation in F1 sperms across gene bodies, promoters, 5'-UTRs, exons, introns, and 3'-UTRs was not affected by nicotine exposure. However, the methylation levels were different between the different genomic regions. Eighty one CpG sites, 16 gene bodies, and 3 promoter regions were differentially methylated. Gene enrichment analysis of DMRs revealed pathways involved in oxidative stress, nicotine response, alveolar and brain development, and cellular signaling. Among the DMRs, Dio1 and Nmu were the most hypermethylated and hypomethylated genes, respectively. Gene expression analysis showed that the mRNA expression and DNA methylation were incongruous. Key proteins involved in lung development and repair were significantly different (FDR < 0.05) between the nicotine and placebo-treated groups. Our data show that DNA methylation is remodeled in offspring spermatozoa upon perinatal nicotine exposure. These epigenetic alterations may play a role in transgenerational inheritance of perinatal smoke/nicotine induced asthma.

The aim of this study was to assess the impact of the nationwide total lockdown (LD) in France on weight loss and body composition modifications in subjects participating in a weight loss program and to evaluate the impact of remote consultations on participants’ adherence to the weight loss program. The CO-RNPC study was a prospective multicentre cohort study including participants undergoing a two to six months program. The rate of weight loss in kg/week was computed before (15 days), during (99 days) and after LD (15 days). In the 1550 completing participants, body weight decreased from 87.1 kg [IQR 77.0; 100.2] to 82.3 kg [72.1; 94.3] resulting in a difference of −4.79 kg [−4.48; −5.10] (p < 0.01), with a corresponding reduction in waist circumference by 4 cm ([0; 9], p < 0.01). The median weight loss was 4.4 kg [0.5; 9.4] in those who used remote consultations, and 1.4 kg [0.8; 5.7] in the no remote consultation group (p < 0.01). In this large prospective cohort, we observed that the rate of weight loss was reduced during LD. This reduction was counterbalanced in participants involved in a remote consultation follow-up with a dose-effect response based on the number of remote consultations.

The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β 3 -adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

Exercise training improves skeletal muscle function, notably through tissue regeneration by muscle stem cells. Here, we hypothesized that exercise training reprograms the epigenome of muscle cell, which could account for better muscle function. Genome-wide DNA methylation of myotube cultures established from middle-aged obese men before and after endurance exercise training identified a differentially methylated region (DMR) located downstream of Gremlin 1 ( GREM1 ), which was associated with increased GREM1 expression. GREM1 expression was lower in muscle satellite cells from obese, compared to lean mice, and exercise training restored GREM1 levels to those of control animals. We show that GREM1 regulates muscle differentiation through the negative control of satellite cell self-renewal, and that GREM1 controls muscle lineage commitment and lipid oxidation through the AMPK pathway. Our study identifies novel functions of GREM1 and reveals an epigenetic mechanism by which exercise training reprograms muscle stem cells to improve skeletal muscle function.

Bariatric surgery is the most effective treatment for obesity. However, less than 1% of eligible patients undergo bariatric surgery annually. Here we evaluated the weight loss effectiveness of an intensive non-surgical weight loss program in patients that would qualify for bariatric surgery. Patients eligible for bariatric surgery (n = 1460) (BMI≥40 or BMI≥35 kg/m2 plus comorbidities) who were enrolled in a dietary weight loss intervention, the RNPC® program, were compared to a cohort of bariatric surgery patients in terms of weight loss outcome. The 663 patients completing the RNPC® program (35% dropout and 20% ongoing) lost 20.2 ± 11.8 kg corresponding to a reduction of 47% of the excess weight and a percentage weight loss from the initial weight of 18% after a mean period of 18.6 ± 9.1 months. Weight loss 18 months after bariatric surgery (n = 61) was 42.5 ± 15.8 kg corresponding to a reduction of 74% of excess weight and a percentage weight loss from the initial weight of 32%. Although bariatric surgery results in a more pronounced weight loss, a clinically important weight loss can be obtained in patients that would qualify for bariatric surgery following an intensive non-surgical weight loss program. This retrospective analysis calls for randomized trials that compare the long-term cost-effectiveness between the RNPC® program and bariatric surgery.

Body weight loss is essential to lower risk factors for type 2 diabetes and cardiovascular diseases in overweight patients. Therefore, we examined the effectiveness of the Rééducation Nutritionnelle et Psycho-Comportementale (RNPC®) program, designed to improve metabolic parameters during weight loss, among different patient groups. The RNPC® program, used in 54 French centers, starts with an energy-restricted 800–1000 kcaL/day high-protein, low-carbohydrate, and low-fat diet comprising real foods and meal replacement products. The 89% (n = 10,809) of the patients completing the ∼15-week weight loss phase had a median 11% of initial body weight loss and was included in the study. The weight stabilization phases of the program were not included as metabolic risk markers were only sporadically measured in those phases. A total of 70.3% were obese and 30.3% classified as having the metabolic syndrome. Without differences in weight loss, improvements in fasting glucose were 0.1 mmoL/L (95% CI -0.2; -0.03, P < 0.05), 0.6 mmoL/L (95% CI -0.7; -0.5, P < 0.001), 3.0 mmoL/L (95% CI -3.6; -2.5, P < 0.001) and 2.0 mmoL/L (95% CI -3.1; -0.8, P < 0.05) for men with pretreatment fasting glucose of <5.6, 5.6–6.9, ≥7.0, or receiving diabetic medication, respectively. Similarly, the largest improvements in triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and alanine transaminase levels were found among male patients with the worst baseline level. Comparable results were obtained for females. Weight loss during the RNPC® program is followed by overall metabolic improvement that is mainly driven by substantial improvements in specific metabolic risk markers among those with highest baseline values.

Separately, polyphenols and exercise are known to prevent insulin resistance (IR) but their combined curative effects on established obesity and IR require further investigation. Therefore, we compared the metabolic effects of a combination of exercise and grape polyphenols supplementation in obese IR rats with high-fat diet (EXOPP) to the effect of high-fat diet alone (HF) or with a nutritional supplementation of grape polyphenols (PP) or with endurance exercise (EXO) during 8 wks. We observed an improvement of systemic and skeletal muscle insulin sensitivity in EXO and EXOPP rats. EXOPP rats compared to HF rats presented a lower insulinemia and HOMA-IR with higher liver and muscle glycogen contents. Interestingly, EXOPP rats had a 68% enhanced endurance capacity compared to EXO rats with also a higher activation of AMPK compared to sedentary and EXO rats with increased lipid oxidation. Together, our results suggest that grape polyphenols supplementation combined with exercise has a synergistic effect by increasing muscle lipid oxidation and sparing glycogen utilization which thus enhances endurance capacity. Our data highlight that in cases of established obesity and IR, the combination of nutritional grape polyphenols supplementation and exercise heighten and intensify their individual metabolic effects.

Bodyweight loss is essential to lower risk factors for type 2 diabetes and cardiovascular disease in overweight patients. Therefore, we examined the effectiveness of the RNPC® program for short and long term bodyweight reduction. The RNPC® program is a novel weight loss and maintenance program achieving weight loss by an energy-restricted 800–1000 kcal/day high-protein low-glycemic diet (weight loss phase), followed by an intensive follow-up with a step-wise increase in energy intake to reach energy balance (weight stabilization phases). The analysis included 12,179 overweight or obese patients treated in 54 RNPC® weight loss clinics in France. A total of 10,809 (89%) patients completed the initial weight loss phase and 2996 (25%) completed the full program. Median weight loss percentage was 10.7% (Interquartile range [IQR]: 5.8; 16.5) after a median of 105 days (IQR: 56; 175) during the weight loss phase, and a median of 17.5% (IQR: 12.7; 24.2) after a median of 251 days (IQR: 187; 350) at program completion. The RNPC® program is cost-effective and well tolerated for short-term body weight loss as well as effective in the long term among the patients completing the program. The program might be particularly effective among patient with elevated fasting glucose.

Aim: To determine the genomic mechanisms by which adipose tissue responds to acute and chronic exercise. Methods: We profiled the transcriptomic and epigenetic response to acute exercise in human adipose tissue collected before and after endurance training. Results: Although acute exercises were performed at same relative intensities, the magnitude of transcriptomic changes after acute exercise was reduced by endurance training. DNA methylation remodeling induced by acute exercise was more prominent in trained versus untrained state. We found an overlap between gene expression and DNA methylation changes after acute exercise for 32 genes pre-training and six post-training, notably at adipocyte-specific genes. Conclusion: Training status differentially affects the epigenetic and transcriptomic response to acute exercise in human adipose tissue.

One of the major insulin resistance instigators is excessive adiposity and visceral fat depots. Individually, exercise training and polyphenol intake are known to exert health benefits as improving insulin sensitivity. However, their combined curative effects on established obesity and insulin resistance need further investigation particularly on white adipose tissue alterations. Therefore, we compared the effects on different white adipose tissue depot alterations of a combination of exercise and grape polyphenol supplementation in obese insulin-resistant rats fed a high-fat diet to the effects of a high-fat diet alone or a nutritional supplementation of grape polyphenols (50 mg/kg/day) or exercise training (1 hr/day to 5 days/wk consisting of treadmill running at 32 m/min for a 10% slope), for a total duration of 8 weeks. Separately, polyphenol supplementation and exercise decreased the quantity of all adipose tissue depots and mesenteric inflammation. Exercise reduced adipocytes' size in all fat stores. Interestingly, combining exercise to polyphenol intake presents no more cumulative benefit on adipose tissue alterations than exercise alone. Insulin sensitivity was improved at systemic, epididymal, and inguinal adipose tissues levels in trained rats thus indicating that despite their effects on adipocyte morphological/metabolic changes, polyphenols at nutritional doses remain less effective than exercise in fighting insulin resistance.

BackgroundCancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. We hypothesize that cancer treatments could lead to long-term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory diseases in cancer survivors.ResultsTo test this hypothesis, we established the epigenetic and transcriptomic profiles of immune cells from 44 childhood cancer survivors (CCS, >16years old) on full remission (>5years) who had received chemotherapy alone or in combination with total body irradiation (TBI) and hematopoietic stem cell transplant (HSCT). We found that more than 10years post-treatment, CCS treated with TBI/HSCT showed an altered DNA methylation signature in T cell, particularly at genes controlling immune and inflammatory processes and oxidative stress. DNA methylation remodeling in T cell was partially associated with chronic expression changes of nearby genes, increased frequency of type 1 cytokine-producing T cell, elevated systemic levels of these cytokines, and over-activation of related signaling pathways. Survivors exposed to TBI/HSCT were further characterized by an Epigenetic-Aging-Signature of T cell consistent with accelerated epigenetic aging. To investigate the potential contribution of irradiation to these changes, we established two cell culture models. We identified that radiation partially recapitulated the immune changes observed in survivors through a bystander effect that could be mediated by circulating factors.ConclusionCancer treatments, in particular TBI/HSCT, are associated with long-term immune disturbances. We propose that epigenetic remodeling of immune cells following cancer therapy augments inflammatory- and age-related diseases, including metabolic complications, in childhood cancer survivors.

Differences in methylation in the spermatozoa between the Untrained, Trained and Detrained state. S5 Table shows results for the FDR 10% cut-off and S6 Table shows results for the FDR 5% cut-off. Regions differentially methylated between, Untrained and Trained as well as Untrained and Detrained. median.p: median P-value in DMR; median.meth.untrained/trained/detrained: median methylation of CpGs in DMR; median.meth.diff: median methylation difference between conditions; annotation: location relative to nearest gene. (ZIP 198Â kb)