A gut-derived hormone regulates cholesterol metabolism.

The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.

Calorie Restriction with or without Time-Restricted Eating in Weight Loss.

BACKGROUND: The long-term efficacy and safety of time-restricted eating for weight loss are not clear. METHODS: We randomly assigned 139 patients with obesity to time-restricted eating (eating only between 8:00 a.m. and 4:00 p.m.) with calorie restriction or daily calorie restriction alone. For 12 months, all the participants were instructed to follow a calorie-restricted diet that consisted of 1500 to 1800 kcal per day for men and 1200 to 1500 kcal per day for women. The primary outcome was the difference between the two groups in the change from baseline in body weight; secondary outcomes included changes in waist circumference, body-mass index (BMI), amount of body fat, and measures of metabolic risk factors. RESULTS: Of the total 139 participants who underwent randomization, 118 (84.9%) completed the 12-month follow-up visit. The mean weight loss from baseline at 12 months was -8.0 kg (95% confidence interval [CI], -9.6 to -6.4) in the time-restriction group and -6.3 kg (95% CI, -7.8 to -4.7) in the daily-calorie-restriction group. Changes in weight were not significantly different in the two groups at the 12-month assessment (net difference, -1.8 kg; 95% CI, -4.0 to 0.4; P = 0.11). Results of analyses of waist circumferences, BMI, body fat, body lean mass, blood pressure, and metabolic risk factors were consistent with the results of the primary outcome. In addition, there were no substantial differences between the groups in the numbers of adverse events. CONCLUSIONS: Among patients with obesity, a regimen of time-restricted eating was not more beneficial with regard to reduction in body weight, body fat, or metabolic risk factors than daily calorie restriction. (Funded by the National Key Research and Development Project [No. 2018YFA0800404] and others; ClinicalTrials.gov number, NCT03745612.).

Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study.

INTRODUCTION: The association of serum sex hormone-binding globulin (SHBG) concentrations with dementia risk remains uncertain in middle-aged to older women. We examined associations of serum SHBG levels with incidence of all-cause dementia and its subtypes in middle-aged to older women from the large population-based UK Biobank cohort study. METHODS: Serum total SHBG levels were measured by immunoassay. The incidence of all-cause dementia and its subtypes was recorded. Cox proportional hazards models were used to calculate hazard ratios (HR) for main outcomes. RESULTS: Among 171,482 community-dwelling women (mean [SD] age was 59.9 [5.4] years, median follow-up of 11.8 years), 2,368 developed dementia, including 1,088 from Alzheimer's disease (AD), 451 from vascular dementia (VAD), and 1,609 from other dementia. After multivariable adjustments, higher serum SHBG levels were significantly associated with higher risks of all-cause dementia, AD, and other dementia (all p < 0.05). Compared to those in the lowest quartile of SHBG levels, participants in the highest quartile of SHBG levels had a higher risk of all-cause dementia (HR: 1.34; 95% confidence interval [CI]: 1.16-1.53), AD (HR: 1.32; 95% CI: 1.07-1.62), and other dementia (HR: 1.44; 95% CI: 1.21-1.70). However, this relationship was not significant for VAD (HR: 1.16; 95% CI: 0.86-1.56). CONCLUSION: These findings indicated that higher serum SHBG concentrations were independently associated with higher risks of incident all-cause dementia, as well as AD and other dementia among middle-aged to older women. No association was found for VAD.

Circulating galectin-3 levels are inversely associated with subclinical cardiovascular disease in obese adults.

BACKGROUND: Galectin-3 is a new cytokine that is mainly secreted by activated macrophages. It is involved in apoptosis, inflammation and may play a role in the development of cardiovascular disease (CVD). However, there is little information about the association between circulating galectin-3 and subclinical atherosclerosis in humans. METHODS AND RESULTS: We measured serum galectin-3 in 483 obese adult subjects (aged 40 years and over) who had the measurement of carotid intima-media thickness (CIMT) recruited from the community. Adults with lower levels of circulating galectin-3 had increased CIMT (p < 0.05). In multivariable linear regression analyses, circulating galectin-3 was independently associated with CIMT. The risks of increased CIMT were significantly decreased by 65.1% (OR (95% CI): 0.349 (0.165-0.739)), adjusting for possible confounding factors. Notably, individuals in the lowest quartile of serum galectin-3 were 1.80 times (p < 0.05) more likely to have increased CIMT than those in the highest quartile in multivariable logistic regression analyses; however, such associations with circulating galectin-3 were not noted for carotid plague. CONCLUSIONS: These findings propose that circulating galectin-3 concentrations are inversely associated with increased CIMT in obese adults, which may be a potential biomarker of CVD.

Association of circulating adipsin with nonalcoholic fatty liver disease in obese adults: a cross-sectional study.

BACKGROUND: As a secreted adipokine, adipsin has been recently shown to play a pivotal role in metabolic disorders. However, information regarding the association of circulating adipsin with non-alcoholic fatty liver disease (NAFLD) in humans is scant. METHODS: We recruited 1163 obese adult subjects with waist circumference at least 90 cm in men and 80 cm in women from the community. Circulating adipsin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Circulating adipsin levels of NAFLD subjects was decreased compared to those in non-NAFLD (p < 0.05). The prevalence of NAFLD with lower levels of serum adipsin was significantly higher than those with higher values (57.6% vs. 50.9%, p < 0.05). Circulating adipsin levels were significantly associated with decreasing levels of fasting glucose and postprandial glucose (both p < 0.001 for interaction) in NAFLD subjects but not in non-NAFLD subjects. The risk of NAFLD was significantly decreased by 21.7% [OR (95% CI): 0.783 (0.679-0.902), p < 0.001], adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, HOMA-IR, and body fat mass. Importantly, subjects in the lowest quartile of circulating adipsin were 1.88 times more likely to have NAFLD than those in the highest quartile in multivariable logistic regression analyses. However, such associations with circulating adipsin were not noted for metabolic syndrome, abnormal liver enzyme and significant liver fibrosis. CONCLUSIONS: These results demonstrate that circulating adipsin levels in Chinese obese adults are negatively associated with risk of NAFLD, implying that serum adipsin levels may be a potential protective factor in NAFLD.

Preparation of MIL-101(Cr)-NH2@TAPB-DVA-COF based membrane solid-phase extraction for efficient enrichment and sensitive determination of trace aromatic disinfection by-products in juice drinks.

Aromatic disinfection by-products (DBPs) have garnered considerable interest in recent years for their potential carcinogenicity. However, efficient separation and enrichment of DBPs in complex samples is a challenge due to the extremely low content of aromatic DBPs and the complexity of sample matrices. In this study, a MIL-101(Cr)-NH2@TAPB-DVA-COF hybrid material was prepared as the enrichment medium of membrane solid-phase extraction (M-SPE) to efficiently determine trace emerging aromatic DBPs. This medium exhibited excellent enrichment capacity and selectivity for aromatic DBPs because of the strong hydrogen bonding, π-π stacking and hydrophobic interactions. An efficient analytical method for five aromatic DBPs in juice drinks was successfully established by use of this hybrid material as the enrichment medium for M-SPE in combination with liquid chromatography tandem mass spectrometry (LC-MS/MS). The limits of detection of the established method were from 0.50 to 3.00 ng/L. Moreover, the method had been successfully used in real juice drinks to determine trace five aromatic DBPs with the spiked recoveries ranging from 84.1% to 125%. The method possessed high analytical sensitivity and accuracy for these five aromatic DBPs in juice drinks with the aid of the efficient M-SPE technology proposed.

Associations of Serum Testosterone and Sex Hormone-binding Globulin With Incident Arrhythmias in Men From UK Biobank.

CONTEXT: Sex hormones have been identified as cardiovascular risk factors, whereas the relationship between sex hormones and the risk of arrhythmias in men has not yet been well studied in the prospective cohort study. OBJECTIVE: To analyze associations of serum testosterone and SHBG concentrations and calculate free testosterone (cFT) with arrhythmias in men. METHODS: Sex hormones were measured at baseline from UK Biobank. Main outcomes were incidence of atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia (BA). RESULTS: Of 173 498 men (aged 37-73 years, followed for 11 years), 11 368 had incident AF, 1646 had incident VA, and 4788 had incident BA. Compared with the third quartiles, the lowest category of serum testosterone was associated with increased risks of AF (hazard ratio [HR], 1.06; 95% CI, 1.00-1.12) and BA (HR, 1.11; 95% CI, 1.02-1.20) after multivariable adjustment, but no VA. Likewise, similar associations were found between cFT values and AF and BA events. Furthermore, higher levels of cFT were associated with increased risks of AF (HR, 1.07; 95% CI, 1.02-1.13) and VA (HR, 1.18; 95% CI, 1.01-1.37). Higher SHBG concentrations were associated with increased risks of AF (HR, 1.44; 95% CI, 1.34-1.54), VA (HR, 1.27; 95% CI, 1.07-1.52), and BA (HR, 1.17; 95% CI ,1.05-1.29). CONCLUSIONS: Lower levels of testosterone and cFT were associated with increased risk of AF and BA. Higher cFT levels were associated with increased risk of AF and VA. Higher SHBG levels were associated with increased risk of AF, VA, and BA.

Effect of time-restricted eating regimen on weight loss is mediated by gut microbiome.

Time-restricted eating (TRE) is a promising obesity management strategy, but weight-loss efficacy varies among participants, and the underlying mechanism is unclear. The study aimed to investigate the role of gut microbiota in weight-loss response during long-term TRE intervention. We analyzed data from 51 obese adults in a 12-month TRE program, categorizing them into distinct weight loss groups (DG) and moderate weight loss groups (MG) based on their TRE responses. Shotgun metagenomic sequencing analysis revealed a significant increase in species closely associated with weight loss effectiveness and metabolic parameter changes in the DG group. Pathways related to fatty acid biosynthesis, glycogen biosynthesis, and nucleotide metabolism were reduced in the DG group and enhanced in the MG group. Next, we identified nine specific species at baseline that contributed better responses to TRE intervention and significant weight loss. Collectively, gut microbiota contributes to responsiveness heterogeneity in TRE and can predict weight-loss effectiveness.

Insulin-Like Growth Factor 1 and Risk of Cardiovascular Disease: Results From the UK Biobank Cohort Study.

CONTEXT: Relationships between insulin-like growth factor 1 (IGF-1) levels and cardiovascular disease (CVD) in the general population remain unclear. OBJECTIVE: This study aims to investigate the association of circulating IGF-1 concentrations with CVD from a population-based cohort study. METHODS: A total of 394 082 participants without CVD and cancer at baseline from UK Biobank were included with measurements of serum IGF-1 at baseline. Main outcomes were incidence of CVD, including CVD mortality, coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and stroke. RESULTS: Over a median 11.6 years of follow-up, UK Biobank documented 35 803 incident CVD cases, including 4231 from CVD-related death, 27 051 from CHD, 10 014 from MI, 7661 from HF, and 6802 from stroke. Dose-response analysis showed a U-shaped relationship between IGF-1 levels and cardiovascular events. Compared with the third quintile of IGF-1, the lowest category of IGF-1 was associated with increased risk of CVD (hazard ratio 1.128; 95% CI, 1.093 to 1.164), CVD mortality (1.294; 1.181 to 1.418), CHD (1.118; 1.078 to 1.159), MI (1.071; 1.008 to 1.139), HF (1.185; 1.107 to 1.268), and stroke (1.149, 1.070 to 1.235); also, the highest category was associated with increased risk of CVD (1.056; 1.020 to 1.094), CVD mortality (1.111; 1.000 to 1.236), CHD (1.070; 1.028 to 1.114), MI (1.111; 1.041 to 1.187) and HF (1.098; 1.015 to 1.188) after multivariable adjustment. CONCLUSION: This study indicates that both low and high levels of circulating IGF-1 are associated with increased risk of CVD in general population. These results highlight the importance of monitoring IGF-1 status on cardiovascular health.

Effects of Time-Restricted Eating on Nonalcoholic Fatty Liver Disease: The TREATY-FLD Randomized Clinical Trial.

Importance: The efficacy and safety of time-restricted eating (TRE) on nonalcoholic fatty liver disease (NAFLD) remain uncertain. Objective: To compare the effects of TRE vs daily calorie restriction (DCR) on intrahepatic triglyceride (IHTG) content and metabolic risk factors among patients with obesity and NAFLD. Design, Setting, and Participants: This 12-month randomized clinical trial including participants with obesity and NAFLD was conducted at the Nanfang Hospital in Guangzhou, China, between April 9, 2019, and August 28, 2021. Interventions: Participants with obesity and NAFLD were randomly assigned to TRE (eating only between 8:00 am and 4:00 pm) or DCR (habitual meal timing). All participants were instructed to maintain a diet of 1500 to 1800 kcal/d for men and 1200 to 1500 kcal/d for women for 12 months. Main Outcomes and Measures: The primary outcome was change in IHTG content measured by magnetic resonance imaging; secondary outcomes were changes in body weight, waist circumference, body fat, and metabolic risk factors. Intention-to-treat analysis was used. Results: A total of 88 eligible patients with obesity and NAFLD (mean [SD] age, 32.0 [9.5] years; 49 men [56%]; and mean [SD] body mass index, 32.2 [3.3]) were randomly assigned to the TRE (n = 45) or DCR (n = 43) group. The IHTG content was reduced by 8.3% (95% CI, -10.0% to -6.6%) in the TRE group and 8.1% (95% CI, -9.8% to -6.4%) in the DCR group at the 6-month assessment. The IHTG content was reduced by 6.9% (95% CI, -8.8% to -5.1%) in the TRE group and 7.9% (95% CI, -9.7% to -6.2%) in the DCR group at the 12-month assessment. Changes in IHTG content were comparable between the 2 groups at 6 months (percentage point difference: -0.2; 95% CI, -2.7 to 2.2; P = .86) and 12 months (percentage point difference: 1.0; 95% CI, -1.6 to 3.5; P = .45). In addition, liver stiffness, body weight, and metabolic risk factors were significantly and comparably reduced in both groups. Conclusions and Relevance: Among adults with obesity and NAFLD, TRE did not produce additional benefits for reducing IHTG content, body fat, and metabolic risk factors compared with DCR. These findings support the importance of caloric intake restriction when adhering to a regimen of TRE for the management of NAFLD. Trial Registration: ClinicalTrials.gov Identifiers: NCT03786523 and NCT04988230.

Associations of Menstrual Cycle Regularity and Length With Cardiovascular Diseases: A Prospective Study From UK Biobank.

Background The association between menstrual cycle characteristics and cardiovascular outcomes remains unclear. This study was undertaken to evaluate whether menstrual cycle regularity and length throughout the life course are associated with cardiovascular outcomes. Methods and Results This cohort study included 58 056 women who had no cardiovascular disease (CVD) at baseline and reported their menstrual cycle regularity and length. Hazard ratios (HRs) and 95% CIs for CVD events were estimated using Cox proportional hazards models. During the median 11.8 years of follow-up, 1623 incident CVD cases were documented, including 827 incident cases of coronary heart disease, 199 myocardial infarctions, 271 strokes, 174 cases of heart failure, and 393 cases of atrial fibrillations. Compared with women with regular menstrual cycles, the HRs for women with irregular menstrual cycles were 1.19 (95% CI, 1.07-1.31) for CVD events and 1.40 (95% CI, 1.14-1.72) for atrial fibrillation. The multivariable-adjusted HRs for short (≤21 days) or long (35 days) menstrual cycles during follow-up were 1.29 (95% CI, 1.11-1.50) and 1.11 (95% CI, 0.98-1.56) for CVD events, respectively. Similarly, long or short cycle length were more likely to be associated with increased risk of atrial fibrillation (HR, 1.30 [95% CI, 1.01-1.66]; and HR, 1.38 [95% CI, 1.02-1.87]), and short cycle length was more likely to be associated with increased risk of coronary heart disease and myocardial infarction. However, these associations for stroke and heart failure were not significant. Conclusions Long or short menstrual cycle length was associated with increased risks of CVD and atrial fibrillation but not myocardial infarction, heart failure, or stroke. Short cycle length was associated with a greater risk of coronary heart disease and myocardial infarction.

Association of Serum 25-Hydroxyvitamin D With Cardiovascular Outcomes and All-Cause Mortality in Individuals With Prediabetes and Diabetes: Results From the UK Biobank Prospective Cohort Study.

OBJECTIVE: To examine the associations of circulating 25-hydroxyvitamin D (25[OH]D) concentrations with cardiovascular disease (CVD) and all-cause mortality in individuals with prediabetes and diabetes from the large population-based UK Biobank cohort study. RESEARCH DESIGN AND METHODS: A total of 67,789 individuals diagnosed with prediabetes and 24,311 with diabetes who had no CVD or cancer at baseline were included in the current study. Serum 25(OH)D concentrations were measured at baseline. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for cardiovascular outcomes and mortality after 10-14 years. RESULTS: After multivariable adjustment, higher serum 25(OH)D levels were significantly and nonlinearly associated with lower risk of cardiovascular outcomes and all-cause mortality among participants with prediabetes and diabetes (all P nonlinearity < 0.05). Compared with those in the lowest category of 25(OH)D levels (<25 nmol/L), participants with prediabetes in the highest category of 25(OH)D levels (≥75 nmol/L) had a significant association with lower risk of cardiovascular events (HR 0.78; 95% CI 0.71-0.86), coronary heart disease (CHD) (HR 0.79; 95% CI 0.71-0.89), heart failure (HR 0.66; 95% CI 0.54-0.81), stroke (HR 0.75; 95% CI 0.61-0.93), CVD mortality (HR 0.43; 95% CI 0.32-0.59), and all-cause mortality (HR 0.66; 95% CI 0.58-0.75). Likewise, these associations with cardiovascular events, CHD, heart failure, CVD mortality, and all-cause mortality were observed among participants with diabetes, except for stroke. CONCLUSIONS: These findings highlight the importance of monitoring and correcting vitamin D deficiency in the prevention of CVD and mortality among adults with prediabetes and diabetes.

Adiposity Measurements and Metabolic Syndrome Are Linked Through Circulating Neuregulin 4 and Adipsin Levels in Obese Adults.

BACKGROUND: Adiposity and adipokines are associated with metabolic disorders, but little is known regarding that whether adiposity measurements link metabolic syndrome (MetS) through circulating neuregulin 4 (Nrg4) and adipsin levels. MATERIALS AND METHODS: A total of 1212 subjects with a waist circumference greater than 90 cm for men or 80 cm for women were enrolled from a Chinese community. Circulating Nrg4 and adipsin levels were measured using commercial kits. Mediation analyses of circulating Nrg4 and adipsin were performed in the study using linear and logistic regression. RESULTS: Subjects with MetS had higher waist circumference, visceral fat level, and circulating adipsin level, and lower levels of circulating Nrg4 and muscle mass to visceral fat (MVF) ratio (all P < 0.05). In multivariable logistic regression analyses, after adjusting for confounding variables, per standard deviation (SD) increase in waist circumference and visceral fat level were significantly associated with increased odds of MetS [OR (95% CI), 1.42 (1.22-1.64); 2.20 (1.62-2.99); respectively]; and per SD reduction in MVF ratio was significantly associated with reduced odds of MetS [OR (95% CI), 0.65 (0.55-0.77)]. In the mediation analyses, both circulating Nrg4 and adipsin levels mediated the association between waist circumference (8.31% and 18.35%, respectively), visceral fat level (7.50% and 9.98%, respectively), and MVF ratio (5.80% and 9.86%, respectively) and MetS after adjustments. CONCLUSION: These findings indicate that adiposity measurements and MetS are linked through circulating Nrg4 and adipsin levels in obese adults, suggesting that circulating Nrg4 and adipsin levels might be potential predictors for management of MetS.

Elevated circulating Gpnmb levels are associated with hyperthyroidism.

BACKGROUND: Glycoprotein non-metastatic protein B (Gpnmb) has been identified as a new cytokine secreted by hepatocyte that plays an important role in balancing lipid homeostasis and development of obesity and metabolic disorders. However, information is not available regarding the association between circulating Gpnmb and hyperthyroid in humans. METHODS: We measured serum Gpnmb in 180 hyperthyroid patients and 82 healthy subjects that were recruited from the clinic. Of them, 46 hyperthyroid patients received thionamide treatment for 3 months. RESULTS: Hyperthyroid subjects had higher levels of circulating Gpnmb than healthy controls (47.8 ± 10.1 ng/mL vs 31.0 ± 4.9 ng/mL, P < 0.001). Subjects with higher levels of serum free triiodothyronine (T3) and free thyroxine (T4) had higher levels of circulating Gpnmb. After thionamide treatment, levels of circulating Gpnmb in hyperthyroid subjects remarkably declined with significant improvement of thyroid function (P < 0.001). Furthermore, the change of circulating Gpnmb levels was significantly associated with basal metabolic rate (BMR) and thyroid hormones, including free T3 and free T4, adjusting for age, gender, smoking and BMI before thionamide treatment. In multivariable logistic regression analyses, circulating Gpnmb was significantly associated with risks of hyperthyroidism (OR (95% CI): 1.44 (1.20-1.74), P < 0.001), adjusted for age, gender, BMI, fasting glucose, HOMA-IR, LDL-cholesterol, ALT and AST. CONCLUSIONS: These findings indicate that circulating Gpnmb concentrations are independently associated with hyperthyroid, suggesting that circulating Gpnmb may be a predictor of risk for hyperthyroidism and can be used for therapeutic monitoring.

Elevated Serum Tsukushi Levels in Patients With Hyperthyroidism.

Background: Tsukushi (TSK) is a secreted hepatokine recently identified as playing an important role in modulating glucose and lipid metabolism, and systemic energy homeostasis. However, information is not available regarding the association between circulating TSK and hyperthyroidism in humans. Methods: We measured serum TSK levels in 180 patients with hyperthyroidism and 82 healthy controls recruited from the clinic. Of them, 46 hyperthyroid patients received thionamide treatment for 3 months. Results: Hyperthyroid patients had higher levels of circulating TSK than healthy controls [186.67 (133.63-280.59) ng/ml vs. 97.27 (77.87-146.96) ng/ml, P < 0.001]. Subjects with higher level of serum free triiodothyronine (T3) and free thyroxine (T4) had higher levels of circulating TSK. In addition, serum TSK levels markedly declined with the improvement of thyroid function after thionamide treatment. In multivariable linear regression analyses, circulating TSK concentrations were significantly associated with serum free T3, free T4, thyroid stimulating hormone, thyrotropin receptor antibody, total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), and basal metabolic rate (all P < 0.01), adjusting for age, gender, smoking, and body mass index (BMI). Importantly, circulating TSK was significantly associated with risks of hyperthyroidism in multivariable logistic regression analyses, adjusting for age, gender, smoking, BMI, fasting glucose, LDL-cholesterol, and insulin resistance (HOMA-IR) [OR (95% CI), 1.012(1.005-1.019), P = 0.001]. Conclusion: These findings indicate that circulating TSK concentrations are independently associated with hyperthyroidism, suggesting that circulating TSK may be a predictive factor of hyperthyroidism and can be used for therapeutic monitoring.