Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression.

Genetics is a major determinant of susceptibility to autoimmune disorders. Here, we examined whether genome organization provides resilience or susceptibility to sequence variations, and how this would contribute to the molecular etiology of an autoimmune disease. We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.

WDFY4 deficiency in NOD mice ameliorates autoimmune diabetes and insulitis.

The events that initiate autoimmune diabetes in nonobese diabetic (NOD) mice remain poorly understood. CD4+ and CD8+ T cells are both required to develop disease, but their relative roles in initiating disease are unclear. To test whether CD4+ T cell infiltration into islets requires damage to ß cells induced by autoreactive CD8+ T cells, we inactivated Wdfy4 in nonobese diabetic (NOD) mice (NOD.Wdfy4-/--) using CRISPR/Cas9 targeting to eliminate cross-presentation by type 1 conventional dendritic cells (cDC1s). Similar to C57BL/6 Wdfy4-/- mice, cDC1 in NOD.Wdfy4-/- mice are unable to cross-present cell-associated antigens to prime CD8+ T cells, while cDC1 from heterozygous NOD.Wdfy4+/- mice cross-present normally. Further, NOD.Wdfy4-/- mice fail to develop diabetes while heterozygous NOD.Wdfy4+/- mice develop diabetes similarly to wild-type NOD mice. NOD.Wdfy4-/- mice remain capable of processing and presenting major histocompatibility complex class II (MHC-II)-restricted autoantigens and can activate ß cell-specific CD4+ T cells in lymph nodes. However, disease in these mice does not progress beyond peri-islet inflammation. These results indicate that the priming of autoreactive CD8+ T cells in NOD mice requires cross-presentation by cDC1. Further, autoreactive CD8+ T cells appear to be required not only to develop diabetes, but to recruit autoreactive CD4+ T cells into islets of NOD mice, perhaps in response to progressive ß cell damage.

Oxidative stress in metabolic dysfunction-associated steatotic liver disease (MASLD): How does the animal model resemble human disease?

Despite decades of research, the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is still not completely understood. Based on the evidence from preclinical models, one of the factors proposed as a main driver of disease development is oxidative stress. This study aimed to search for the resemblance between the profiles of oxidative stress and antioxidant defense in the animal model of MASLD and the group of MASLD patients. C57BL/6J mice were fed with the Western diet for up to 24 weeks and served as the animal model of MASLD. The antioxidant profile of mice hepatic tissue was determined by liquid chromatography-MS3 spectrometry (LC-MS/MS). The human cohort consisted of 20 patients, who underwent bariatric surgery, and 6 controls. Based on histological analysis, 4 bariatric patients did not have liver steatosis and as such were also classified as controls. Total antioxidant activity was measured in sera and liver biopsy samples. The hepatic levels of antioxidant enzymes and oxidative damage were determined by Western Blot. The levels of antioxidant enzymes were significantly altered in the hepatic tissue of mice with MASLD. In contrast, there were no significant changes in the antioxidant profile of hepatic tissue of MASLD patients, except for the decreased level of carbonylated proteins. Decreased protein carbonylation together with significant correlations between the thioredoxin system and parameters describing metabolic health suggest alterations in the thiol-redox signaling. Altogether, these data show that even though the phenotype of mice closely resembles human MASLD, the animal-to-human translation of cellular and molecular processes such as oxidative stress may be more challenging.

Association between sex hormones and bone age in boys aged 9-18 years from China.

This study aimed to analyse the association between sex hormones and bone age (BA) in boys aged 9-18 years, both individually and interactively, and further to explore whether nutritional status may influence this association. A retrospective analysis was performed among 1382 Chinese boys with physical measurements, sexual characteristics, BA radiographs and sex hormone indicators from February 2015 to February 2022. A total of 470 (34.0%) boys had advanced BA. BA was positively associated with estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone in both advanced and normal BA groups after adjusting for age, genetic height and body mass index. Multiple logistic regression showed that after adjusting for covariates, estradiol (odds ratio [OR] = 1.66, 95% confidence interval [CI]: 1.14-2.12), LH (OR = 1.43, 95% CI: 1.04-1.96), and testosterone (OR = 1.58, 95% CI: 1.17-2.13) were significantly associated with the increased risk of advanced BA in boys, and the association was reinforced when these hormones were interactively explored. Stratified by nutritional status, the interaction between estradiol, LH, and testosterone showed a strong association with advanced BA in boys with normal weight.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Exercise training and spexin ameliorate thyroid changes in obese type 2 diabetic rats: the possible interlaying mechanisms.

Thyroid dysfunction and diabetes mellitus are prevalent endocrine disorders that often coexist and influence each other. The role of spexin (SPX) in diabetes and obesity is well documented, but its connection to thyroid function is less understood. This study investigates the influence of exercise (EX) and SPX on thyroid hypofunction in obese type 2 diabetic rats. Rats were divided into normal control, obese diabetic sedentary, obese diabetic EX, and obese diabetic SPX groups, with subdivisions for M871 and HT-2157 treatment in the latter two groups. High-fat diet together with streptozotocin (STZ) injection induced obesity and diabetes. The EX group underwent swimming, and the SPX group received SPX injections for 8 wk. Results showed significant improvements in thyroid function and metabolic, oxidative, and inflammatory states with EX and SPX treatment. The study also explored the involvement of galanin receptor isoforms (GALR)2/3 in SPX effects on thyroid function. Blocking GALR2/3 receptors partially attenuated the beneficial effects, indicating their interaction. These findings underscore the importance of EX and SPX in modulating thyroid function in obesity and diabetes. Comprehending this interplay could enable the development of new treatment approaches for thyroid disorders associated with obese type 2 diabetes. Additional research is necessary to clarify the exact mechanisms connecting SPX, EX activity, and thyroid function.NEW & NOTEWORTHY This study proves, for the first time, the beneficial effects of SPX on thyroid dysfunction in obese diabetic rats and suggests that SPX mediates the EX effect on thyroid gland and exerts its effect mainly via GALR2.

Haplotype analysis and linkage disequilibrium of ApoB gene polymorphisms and its relationship with hyperlipidemia in patients with acne vulgaris.

BACKGROUND: Acne vulgaris (AV) is a chronic, multifactorial inflammatory disease of the pilosebaceous unit brought on by hormonal imbalance, excessive sebum production, follicular hyperkeratinization, inflammation and Cutibacterium acne. Acne patients are characterized by alteration of the lipid profile. Apolipoprotein B gene (ApoB) plays an essential role in lipoprotein biosynthesis and multiple single-nucleotide polymorphisms (SNPs) in ApoB are associated with dyslipidemia. AIM: The aim of this study was to estimate the alteration of lipid profiles in AV, determine the genetic association with lipid profile alteration by studying the ApoB gene polymorphisms, and to identify the exact haplotypes associated with acne and lipid profile alteration. SUBJECTS AND METHODS: In a case-control study consisting of 63 non-obese acne patients and 43 healthy controls, all participants underwent biochemical, anthropological assessments, and genetic analysis for ApoB polymorphisms. RESULT: Our results indicate that serum ApoB and the lipid profile were higher in acne patients compared with healthy subject. The most common haplotypes in acne patients were rs562338 A/rs17240441 I/c.12669 A/rs1042034 G, whereas the most common haplotypes in healthy subjects were rs562338 G/rs17240441 D/c.12669 A/rs1042034 G. Patients with mild acne had higher serum ApoB levels p = 0.005. Also, the low-density lipoprotein cholesterol (LDL-C) level was higher in mild acne compared with other acne groups, with a highly significant variation of p ≤ 0.001. CONCLUSION: We found a significant variation between the acne group and healthy controls in serum ApoB, triglycerides, total cholesterol and LDL-C. The most common haplotypes in acne patients are rs562338 A/, rs17240441 I/, c.12669 A/ and rs1042034 G, and there is a linkage disequilibrium between the four selected SNPs.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Single-cell transcriptome analysis reveals immunosuppressive landscape in overweight and obese colorectal cancer.

BACKGROUND: Overweight and obesity are established risk factors for various types of cancers including colorectal cancer (CRC). However the underlying molecular mechanisms remain unclear. An in-depth understanding of the oncologic characteristics of overweight and obese CRC at the single-cell level can provide valuable insights for the development of more effective treatment strategies for CRC. METHODS: We conducted single-cell RNA sequencing (scRNA-seq) analysis on tumor and adjacent normal colorectal samples from 15 overweight/obese and 15 normal-weight CRC patients. Immunological and metabolic differences between overweight/obese CRC and non-obese CRC were characterized. RESULTS: We obtained single-cell transcriptomics data from a total of 192,785 cells across all samples. By evaluating marker gene expression patterns, we annotated nine main cell types in the CRC ecosystem. Specifically, we found that the cytotoxic function of effector T cells and NK cells was impaired in overweight/obese CRC compared with non-obese CRC, relating to its metabolic dysregulation. CD4+T cells in overweight/obese CRC exhibited higher expression of immune checkpoint molecules. The antigen-presenting ability of DCs and B cells is down-regulated in overweight/obese CRC, which may further aggravate the immunosuppression of overweight/obese CRC. Additionally, dysfunctional stromal cells were identified, potentially promoting invasion and metastasis in overweight/obese CRC. Furthermore, we discovered the up-regulated metabolism of glycolysis and lipids of tumor cells in overweight/obese CRC, which may impact the metabolism and function of immune cells. We also identified inhibitory interactions between tumor cells and T cells in overweight/obese CRC. CONCLUSIONS: The study demonstrated that overweight/obese CRC has a more immunosuppressive microenvironment and distinct metabolic reprogramming characterized by increased of glycolysis and lipid metabolism. These findings may have implications for the development of novel therapeutic strategies for overweight/obese CRC patients.

Association between the triglyceride-glucose index and subclinical left ventricular systolic dysfunction in obese patients.

BACKGROUND: The association between the triglyceride-glucose (TyG) index and subclinical left ventricular (LV) systolic dysfunction in obese patients remains unclear. This study aimed to investigate the relationship between the TyG index and LV global longitudinal strain (GLS) in obese patients. METHODS: A total of 1028 obese patients from January 2019 to January 2024 were included in the present study. Clinical parameters and biochemical and echocardiographic data were obtained from the participants. LV GLS was obtained from the GE EchoPAC workstation for evaluating subclinical LV function. The TyG index was calculated as Ln (fasting TG [mg/dL] × fasting glucose [mg/dL]/2). LV GLS was compared between obese patients with a high TyG index and those with a low TyG index. RESULTS: Obese patients with a high TyG index had greater incidences of hypertension, diabetes mellitus and hyperlipidaemia. The LV GLS was significantly lower in the high TyG index group than in the low TyG index group (P = 0.01). After adjusting for sex, age, body mass index, heart rate, hypertension, diabetes mellitus, dyslipidaemia, blood urea nitrogen, serum creatinine, LV mass and LV hypertrophy, the TyG index remained an independent risk indicator related to an LV GLS < 20% (OR: 1.520, 95% CI: 1.040 to 2.221; P = 0.031). CONCLUSIONS: We concluded that an increase in the TyG index is independently associated with subclinical LV systolic dysfunction in obese patients.

Effects of 12-week Circuit Exercise Intervention on Blood Pressure, Vascular Function, and Inflammatory Cytokines in Obese Older Women with Sarcopenia.

Background: This study investigates the effects of a 12-week circuit exercise program on blood pressure, vascular function, and inflammatory cytokines in older obese women with sarcopenia. Methods: Twenty-eight older obese women with sarcopenia (mean age: 78.2 ± 3.7 years) were randomly divided into an exercise group (EG, n = 14) and a control group (CG, n = 14). The EG participated in a 12-week circuit exercise training regimen, conducted three times weekly, with each session lasting between 45 to 75 minutes (progressively increased over time). The CG was advised to maintain their regular daily routines throughout the intervention period. All dependent variables, including blood pressure, vascular function, and inflammation cytokines, were evaluated pre- and post-intervention. Results: Positive changes were observed in the EG in body composition (body fat mass; p < 0.001, body fat percentage; p < 0.01, free-fat mass; p < 0.01), blood pressure (heart rate; p < 0.05, rate pressure product; p < 0.01), vascular function (brachial-ankle pulse wave velocity; p < 0.05, flow-mediated dilation; p < 0.001), and inflammation cytokines (interleukin-6; p < 0.05). In the CG, there was an increase in body fat mass (p < 0.05) and body fat percentage (p < 0.05), while no changes were observed in other variables. Conclusions: The 12-week circuit exercise program significantly reduced blood pressure, improved vascular function, and decreased inflammatory cytokines in obese older women with sarcopenia. However, individual variations in response highlight the need for personalized exercise regimens.

Fat from Hermetia illucens Alters the Cecal Gut Microbiome and Lowers Hepatic Triglyceride Concentration in Comparison to Palm Oil in Obese Zucker Rats.

BACKGROUND: Palm oil (PO) is the most widely utilized plant oil for food production. Owing to the great ecologic problems associated with PO production, sustainably produced fats, such as insect fat, might be a suitable alternative. OBJECTIVES: The hypothesis was tested that fat from Hermetia illucens larvae (HF) compared with PO and soybean oil (SO) has no adverse effects on hepatic lipid metabolism, plasma metabolome, and cecal microbiome in obese Zucker rats. METHODS: Thirty male obese Zucker rats were randomly assigned to 3 groups (SO, PO, HF; n = 10 rats/group) and fed 3 different semisynthetic diets containing either SO, PO, or HF as the main fat source for 4 wk. The effects were evaluated by measurement of liver and plasma lipid concentrations, liver transcriptomics, targeted plasma metabolomics, and cecal microbiomics. RESULTS: Supplementation of HF reduced hepatic triglyceride concentration and messenger ribonucleic acid concentrations of selected genes involved in fatty acid and triglyceride synthesis in comparison to PO (P < 0.05). Pairwise comparison of the Simpson index and Jaccard index showed a higher cecal microbial α- and ß-diversity in rats fed the HF diet than in rats fed the PO diet (P = 0.015 and P = 0.027), but no difference between rats fed the diets with SO or PO. Taxonomic analysis of the cecal microbial community revealed a lower abundance of Clostridium_sensu_stricto_1 and a higher abundance of Blautia, Mucispirillum, Anaerotruncus, Harryflintia, and Peptococcus in rats supplemented with HF than in rats supplemented with PO (P < 0.05). CONCLUSIONS: HF, compared with PO, has liver lipid-lowering effects in obese Zucker rats, which may be caused by a shift in the gut microbial community. Thus, HF might serve as a sustainably produced fat alternative to PO for food production.

Saturation Effect of Lipid Accumulation Product (LAP) Index on Spinal Bone Mineral Density: A Population-Based Study.

Lipid accumulation product (LAP) has a positive effect on spinal bone mineral density (BMD). However, once LAP levels exceed 27.26, the rate of spinal BMD increase slow down or even decline. This indicates a biphasic relationship between lipid metabolism and BMD, suggesting potential benefits within a certain range and possible adverse effects beyond that range. This study aimed to investigate the potential association between LAP index and BMD in US adults, as well as to explore the presence of a potential saturation effect in this relationship. This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018. A multiple stepwise regression model was employed to examine the association between LAP index and total spinal BMD. Additionally, a generalized additive model and a smooth curve fitting algorithm were utilized to examine the relationship, and saturation effect study was conducted to determine the saturation level. The calculation formula of LAP used in the study was: (LAP = (waist circumstances (WC) (cm) - 58) × triglyceride (TG) (mmol/L)) for women, and (LAP = (WC (cm) - 65) × TG (mmol/L)) for men. The study involved a total of 7913 participants aged 20 years or older. Through multiple stepwise regression analysis, it was found that individuals with higher LAP scores exhibited higher total spinal BMD. In both the crude and partially adjusted models, total spinal BMD was significantly higher in the highest LAP quartile (Q4) compared to the lowest LAP quartile (Q1) (P < 0.05). Utilizing a generalized additive model and smooth curve, a nonlinear relationship between LAP and total spinal BMD was observed. Furthermore, the study identified the saturation value of LAP to be 27.26, indicating a saturation effect. This research highlights a nonlinear relationship between LAP and total spinal BMD, along with the presence of a saturation effect.

Association between O-GlcNAc levels and platelet function in obese insulin-resistant subjects.

Obesity is an epidemic associated with platelet and vascular disorders. Platelet O-GlcNAcylation has been poorly studied in obese subjects. We aimed to evaluate O-linked N-acetyl-glucosamine (O-GlcNAc) levels and platelet activity in obese insulin-resistant (ObIR) subjects. Six healthy and six insulin-resistant obese subjects with a body mass index of 22.6 kg/m2 (SD ± 2.2) and 35.6 kg/m2 (SD ± 3.8), respectively, were included. Flow cytometry was used to measure markers of platelet activity, expression of P-selectin (CD62P antibody), glycoprotein IIb/IIIa (integrins αIIbß3 binding to PAC-1 antibody), and thrombin stimulation. O-GlcNAc was determined in the platelets of all test subjects by cytofluometry, intracellular calcium, percentage of platelet aggregation, and immunofluorescence microscopy and Western blot were used to assess O-GlcNAc and OGT (O-GlcNAc transferase) in platelets. Platelets from ObIR subjects had on average 221.4 nM intracellular calcium, 81.89% PAC-1, 22.85% CD62P, 57.48% OGT, and 66.62% O-GlcNAc, while platelets from healthy subjects had on average 719.2 nM intracellular calcium, 4.99% PAC-1, 3.17% CD62P, 18.38% OGT, and 23.41% O-GlcNAc. ObIR subjects showed lower platelet aggregation than healthy subjects, 13.83% and 54%, respectively. The results show that ObIR subjects have increased O-GlcNAc, and increased intraplatelet calcium associated with platelet hyperactivity and compared to healthy subjects, suggesting that changes in platelet protein O-GlcNAcylation and platelet activity might serve as a possible prognostic tool for insulin resistance, prediabetes and its progression to type 2 diabetes mellitus.

Efficacy of noiiglutide injection on body weight in obese Chinese adults without diabetes: A multicentre, randomized, double-blind, placebo-controlled, phase 2 trial.

AIM: To evaluate the effect of noiiglutide as an adjunct to lifestyle intervention on the reduction in body weight and tolerability in obese Chinese adults without diabetes. MATERIALS AND METHODS: In this 24-week, randomized, double-blind, placebo-controlled phase 2 trial, 254 obese adults with a body mass index of 28.0-40.0 kg/m2 and without diabetes were enrolled. Participants were initially randomized in a 1:1:1 ratio to one of three dose levels: 0.12, 0.24, or 0.36 mg of the study treatment. Within each dose level, participants were further randomized in a 3:1 ratio to receive either subcutaneous injection of noiiglutide or a matching placebo. The primary endpoint was the change in body weight from baseline to week 24. RESULTS: Across all noiiglutide dosage levels, least squares mean reductions in body weight from baseline to week 24 ranged from 8.03 to 8.50 kg, compared with 3.65 kg in the placebo group (all p-values <.0001). In the noiiglutide groups (0.12, 0.24, 0.36 mg/day), a significantly higher proportion of participants achieved a weight loss ≥5% (68.8%, 60.0%, 73.0%) and ≥10% (37.5%, 36.9%, 39.7%), compared with the pooled placebo group (≥5%: 29.0%; ≥10%: 8.1%). Gastrointestinal adverse events, such as nausea, diarrhoea and vomiting, were more common in all noiiglutide groups (15.4%-30.2%, 18.8%-22.2%, 15.6%-18.5%) than in the pooled placebo group (8.1%, 6.5%, 0%). CONCLUSIONS: In obese Chinese adults without diabetes, once-daily subcutaneous noiiglutide significantly reduced body week at week 24 compared with placebo, and had a manageable safety profile, primarily involving gastrointestinal disorders.

Accelerated onset of diabetes in non-obese diabetic mice fed a refined high-fat diet.

AIM: Type 1 diabetes results from autoimmune events influenced by environmental variables, including changes in diet. This study investigated how feeding refined versus unrefined (aka 'chow') diets affects the onset and progression of hyperglycaemia in non-obese diabetic (NOD) mice. METHODS: Female NOD mice were fed either unrefined diets or matched refined low- and high-fat diets. The onset of hyperglycaemia, glucose tolerance, food intake, energy expenditure, circulating insulin, liver gene expression and microbiome changes were measured for each dietary group. RESULTS: NOD mice consuming unrefined (chow) diets developed hyperglycaemia at similar frequencies. By contrast, mice consuming the defined high-fat diet had an accelerated onset of hyperglycaemia compared to the matched low-fat diet. There was no change in food intake, energy expenditure, or physical activity within each respective dietary group. Microbiome changes were driven by diet type, with chow diets clustering similarly, while refined low- and high-fat bacterial diversity also grouped closely. In the defined dietary cohort, liver gene expression changes in high-fat-fed mice were consistent with a greater frequency of hyperglycaemia and impaired glucose tolerance. CONCLUSION: Glucose intolerance is associated with an enhanced frequency of hyperglycaemia in female NOD mice fed a defined high-fat diet. Using an appropriate matched control diet is an essential experimental variable when studying changes in microbiome composition and diet as a modifier of disease risk.

Dahuang Huanglian Xiexin Decoction ameliorates obesity via modulating adipocyte differentiation and lipid degradation through inhibiting endoplasmic reticulum stress.

Dahuang Huanglian Xiexin Decoction (DHXD) is the representative clinical formula for treating epigastric oppression. In this study, we aim to explore the effect of DHXD on obesity and attempt to investigate its potential mechanism. 3T3-L1 preadipocytes were differentiated and high-fat diet-induced obese rat model was established. DHXD was used for treatment and tunicamycin, the activator of endoplasmic reticulum (ER) stress, was adopted to investigate the related regulatory mechanism. Cell viability was evaluated using CCK-8 assay. Oil-Red O staining was performed to determine lipid accumulation. Glycerol production and Triglyceride content were measured using their commercial kits. Western blot was conducted to examine the expression of critical proteins. Results indicated that DHXD could greatly reduce intracellular lipid droplets and triglyceride in differentiated 3T3-L1 cells. Moreover, the elevated expression of mature adipocytes markers, PPARγ, aP2, during adipogenesis was decreased by DHXD treatment. In addition, DHXD aggravated the lipolysis in differentiated 3T3-L1 cells, as evidenced by the upregulated ATGL expression and the downregulated HSL expression. Besides, DHXD inhibited endoplasmic reticulum (ER) stress in 3T3-L1 cells. Further experiments indicated that the impacts of DHXD on adipocyte differentiation and lipid degradation were partly abolished by tunicamycin. Finally, DHXD alleviated lipid accumulation and ER stress in obese rats. In conclusion, DHXD ameliorates obesity via modulating adipocyte differentiation and lipid degradation through inhibiting ER stress.

Maternal dietary practices during pregnancy and obesity of neonates: a machine learning approach towards hierarchical and nested relationships in a Tibet Plateau cohort study.

Studies on obesity and risk factors from a life-course perspective among residents in the Tibet Plateau with recent economic growth and increasing obesity are important and urgently needed. The birth cohort in this area provides a unique opportunity to examine the association between maternal dietary practice and neonatal obesity. The study aims to detect the prevalence of obesity among neonates, associated with maternal diet and other factors, supporting life-course strategies for obesity control. A cohort of pregnant women was enrolled in Tibet Plateau and followed till childbirth. Dietary practice during pregnancy was assessed using the Chinese FFQ - Tibet Plateau version, food items and other variables were associated with the risk for obesity of neonates followed by logistic regression, classification and regression trees (CART) and random forest. Of the total 1226 mother-neonate pairs, 40·5 % were Tibetan and 5·4 % of neonates with obesity. Consuming fruits as a protective factor for obesity of neonates with OR (95 % CI) = 0·61 (0·43, 0·87) from logistic regression; as well as OR = 0·20 (0·12, 0·35) for consuming fruits (≥ weekly) from CART. Removing fruit consumption to avoid overshadowing effects of other factors, the following were influential from CART: maternal education (more than middle school, OR = 0·22 (0·13, 0·37)) and consumption of Tibetan food (daily, OR = 3·44 (2·08, 5·69). Obesity among neonates is prevalent in the study population. Promoting healthy diets during pregnancy and strengthening maternal education should be part of the life-course strategies for obesity control.

Impact of non-obese metabolic dysfunction-associated fatty liver disease on risk factors for the recurrence of esophageal squamous cell carcinoma treated with endoscopic submucosal dissection: A multicenter study.

AIM: Metabolic dysfunction is a risk factor for esophageal squamous cell carcinoma (ESCC). We investigated the impact of the recently proposed metabolic dysfunction-associated fatty liver disease (MAFLD) and its subtypes on ESCC recurrence after endoscopic treatment. METHODS: This multicenter observational cohort study enrolled consecutive patients newly diagnosed with ESCC after endoscopic treatment. Patients were classified into MAFLD or non-MAFLD groups. The MAFLD group was further classified into non-obese and obese MAFLD groups with a body mass index cutoff value of 25 kg/m2 . The impact of MAFLD on the recurrence of ESCC was evaluated using a decision tree algorithm and random forest analysis. RESULTS: A total of 147 patients (average age 69 years; male : female, 127:20; observational period, 2.4 years) were enrolled. The 1-, 3-, and 5-year recurrence rates were 2.0%, 21.1%, and 33.7%, respectively. Independent risk factors for the recurrence of ESCC were MAFLD (HR 2.2812; 95% confidence interval 1.0497-4.9571; p = 0.0373), drinking status, and smoking status. Metabolic dysfunction-associated fatty liver disease was identified as the second most important classifier for recurrence, followed by drinking status. The cumulative incidence of ESCC recurrence was higher in the MAFLD group than in the non-MAFLD group. In a subanalysis, the cumulative incidence of recurrence was significantly higher in the non-obese than in the obese MAFLD group among abstainers/non-drinkers. Directed acyclic graphs revealed that MAFLD directly contributes to ESCC recurrence. CONCLUSIONS: MAFLD was independently and directly associated with ESCC recurrence after endoscopic treatment; a high recurrence rate was observed in patients with non-obese MAFLD. Metabolic dysfunction-associated fatty liver disease may identify patients at high risk for ESCC recurrence.

Correlative relationship between body mass index and heart rate variability in psychiatric disorders.

OBJECTIVE: Indicators of heart rate variability (HRV) have been used to assess the autonomic activity. However, the influence of obesity on HRV in these patients remains to be determined. This study aimed to examine how obesity (measured with the body mass index [BMI]) affects HRV and determine whether the effect varies among different psychiatric disorders. We recruited 3159 consecutive patients, including 1744 with schizophrenia, 966 with mood disorders, and 449 with anxiety disorders. Patients were divided into four groups based on BMI: underweight (< 18.5), normal weight (18.5-23.9), overweight (24-27.9), and obese (≥ 28). The cardiovascular status was assessed using several time- and frequency-based HRV indicators, measured via electrocardiogram signals recorded for 5 min. The mean BMI of the participants was 23.6 ± 4.0. The patients in the overweight and obese groups were 29.4% and 13.6% of the total, respectively. The HRV indicators were higher in underweight and normal-weight patients than in the overweight and obese ones. After stratification based on the psychiatric diagnosis, the patients with mood disorders showed lower HRV than those with schizophrenia or anxiety disorder in the normal-weight group. In contrast, in the overweight and obese groups the patients with mood disorders showed higher HRV than those with the other disorders. The HRV variables were significantly associated with BMI, and higher BMI was associated with higher heart rates and lower HRV. These results indicate that weight gain in psychiatric disorders is associated with an imbalance in autonomic nerve activity. However, the relationship between autonomic activity, weight gain, and psychiatric disorders warrants further investigation.