Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial.

BACKGROUND: Distinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. OBJECTIVES: We investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. METHODS: This study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 mo after the weight-loss diet intervention. The ASCVD risk estimates were calculated using the validated equations. RESULTS: At baseline, higher concentrations of specific BA subtypes were related to higher concentrations of atherogenic very low-density lipoprotein lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions in triglycerides and total cholesterol [every 1 standard deviation (SD) decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to ß (standard error) -3.3 (1.3), -3.4 (1.3), or -3.8 (1.3) mg/dL, respectively; PFDR < 0.05 for all]. Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 mo; there was ß -4.0 (1.1) mg/dL per 1-SD decrease of glycoursodeoxycholate (PFDR =0.003) for changes in low-density lipoprotein cholesterol. We found significant interactions (P-interaction < 0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet, but not after consuming a low-fat diet. CONCLUSIONS: Decreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk. This trial was registered at clinicaltrials.gov as NCT00072995.

Ready-to-Eat Food Environments and Risk of Incident Heart Failure: A Prospective Cohort Study.

BACKGROUND: Food environments have been linked to cardiovascular diseases; however, few studies have assessed the relationship between food environments and the risk of heart failure (HF). We aimed to evaluate the association between ready-to-eat food environments and incident HF at an individual level in a large prospective cohort. METHODS: Exposure to ready-to-eat food environments, comprising pubs or bars, restaurants or cafeterias, and fast-food outlets, were individually measured as both proximity and density metrics. We also developed a composite ready-to-eat food environment density score by summing the densities of 3 types of food environments. Cox proportional analyses were applied to assess the associations of each single type and the composite food environments with HF risk. RESULTS: Closer proximity to and greater density of ready-to-eat food environments, particularly for pubs and bars and fast-food outlets (P<0.05 for both proximity and density metric) were associated with an elevated risk of incident HF. Compared with those with no exposure to composite ready-to-eat food environments, participants in the highest density score category had a 16% (8%-25%; P<0.0001) higher risk of HF. In addition, we found significant interactions of food environments with education, urbanicity, and density of physical activity facilities on HF risk (all Pinteraction<0.05); the ready-to-eat food environments-associated risk of HF was stronger among participants who were poorly educated, living in urban areas, and without physical activity facilities. CONCLUSIONS: Exposure to ready-to-eat food environments is associated with a higher risk of incident HF, suggesting the potential importance of minimizing unfavorable food environments in the prevention of HF.

Circulating MicroRNA-19 and cardiovascular risk reduction in response to weight-loss diets.

OBJECTIVE: MicroRNA-19 (miR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). We examined whether change in circulating miR-19 was associated with change in CVD risk during weight loss. METHODS: This study included 509 participants with overweight or obesity from the 24-month weight-loss diet intervention study (the POUNDS Lost trial) and with available data on circulating miR-19a-3p and miR-19b-3p at baseline and 6 months. The primary outcome for this analysis was the change in atherosclerotic CVD (ASCVD) risk at 6 and 24 months, which estimates the 10-year probability of hard ASCVD events. Secondary outcomes were the changes in ASCVD risk score components. RESULTS: Circulating miR-19a-3p and miR-19b-3p levels significantly decreased during the initial 6-month dietary intervention period (P = 0.008, 0.0004, respectively). We found that a greater decrease in miR-19a-3p or miR-19b-3p was related to a greater reduction in ASCVD risk (ß[SE] = 0.33 [0.13], P = 0.01 for miR-19a-3p; ß[SE] = 0.3 [0.12], P = 0.017 for miR-19b-3p) over 6 months, independent of concurrent weight loss. Moreover, we found significant interactions between change in miR-19 and sleep disturbance on change in ASCVD risk over 24 months of intervention (P interaction = 0.01 and 0.008 for miR-19a-3p and miR-19b-3p, respectively). Participants with a greater decrease in miR-19 without sleep disturbance had a greater reduction of ASCVD risk than those with slight/moderate/great amounts of sleep disturbance. In addition, change in physical activity significantly modified the associations between change in miR-19 and change in ASCVD risk over 24 months (P interaction = 0.006 and 0.004 for miR-19a-3p and miR-19b-3p, respectively). A greater decrease in miR-19 was significantly associated with a greater reduction in ASCVD risk among participants with an increase in physical activity, while non-significant inverse associations were observed among those without an increase in physical activity. CONCLUSIONS: In conclusion, decreased circulating miR-19 levels during dietary weight-loss interventions were related to a significant reduction in ASCVD risk, and these associations were more evident in people with no sleep disturbance or increase in physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00072995.

Dietary Sodium Intake and Risk of Incident Type 2 Diabetes.

OBJECTIVE: To fill the knowledge gap of the relation between long-term dietary sodium intake and type 2 diabetes (T2D), we evaluate the association between the frequency of adding salt to foods, a surrogate marker for evaluating the long-term sodium intake, and incident T2D risk. METHODS: A total of 402,982 participants from UK Biobank (March 13, 2006 - October 10, 2010) who were free of diabetes, chronic kidney disease, cancer, or cardiovascular disease at baseline, and had completed information on adding salt were analyzed in this study. RESULTS: During a median of 11.9 years of follow-up, 13,120 incident cases of T2D were documented. Compared with participants who "never/rarely" added salt to foods, the adjusted HRs were 1.11 (95% CI, 1.06 to 1.15), 1.18 (95% CI, 1.12 to 1.24), and 1.28 (95% CI, 1.20 to 1.37) across the groups of "sometimes," "usually," and "always," respectively (P-trend<.001). We did not find significant interactions between the frequency of adding salt to foods and baseline hypertension status and other covariates on the risk of incident T2D. The observed positive association was partly mediated by body mass index, waist to hip ratio, and C-reactive protein, with a significant mediation effect of 33.8%, 39.9%, and 8.6%, respectively. The significant mediation effect of body mass index was largely driven by the body fat mass rather than the body fat-free mass. CONCLUSION: Our findings for the first time indicate that higher frequency of adding salt to foods, a surrogate marker for a person's long-term salt taste preference and intake, is associated with a higher T2D risk.

Adherence to a healthy sleep pattern is associated with lower risks of incident falls and fractures during aging.

Background: Autoimmune diseases are more common among people with unhealthy sleep behaviors, and these conditions have been linked to aging-related bone health. However, there have been few studies that examined the correlation between recently developed sleep patterns based on sleep duration, sleepiness, chronotype, snoring, insomnia, and the incidence of falls and fractures. Methods: We used a newly developed sleep pattern with components of sleep 7 to 8 h per day, absence of frequent excessive daytime sleepiness, early chronotype, no snoring, and no frequent insomnia as healthy factors to study their relationship with the incidence of falls and fractures. The analysis was conducted among 289,000 participants from the UK Biobank. Results: The mean follow-up period was 12.3 years (3.5 million person-years of follow-up), and 12,967 cases of falls and 16,121 cases of all fractures were documented. Compared to participants exhibiting an unfavorable sleep pattern, those adhering to a healthy sleep pattern experienced a 17% and 28% reduction in the risks of incident falls (hazard ratio [HR], 0.83; 95% CI, 0.74-0.93) and all fractures (HR, 0.72; 95% CI, 0.66-0.79) during follow-up. In addition, participants exhibiting a healthy sleep pattern, together with a high genetically determined bone mineral density (BMD), showed the lowest risks of falls and fractures. Conclusion: A healthy sleep pattern was significantly linked to decreased risks of incident falls and fractures. The protective association was not modified by genetically determined BMD.

Subtypes of Type 2 Diabetes and Incident Cardiovascular Disease Risk: UK Biobank and All of Us Cohorts.

OBJECTIVE: To characterize and validate the subtypes of type 2 diabetes (T2D) using a novel clustering algorithm and to further assess their associations with the risk of incident cardiovascular disease (CVD) events. METHODS: Unsupervised k-means clustering based on glycated hemoglobin level, age at onset of T2D, body mass index, and estimated glomerular filtration rate was conducted among participants with T2D from the UK Biobank (March 13, 2006, to October 1, 2010) and replicated in the All of Us cohort (May 30, 2017, to April 1, 2021). RESULTS: Five distinct T2D clusters were identified in the UK Biobank and validated in the All of Us cohort, characterizing the phenotypically heterogeneous subtypes. With a median follow-up of 11.69 years for patients with T2D in the UK Biobank, risks of incident CVD events varied considerably between the clusters after adjustment for potential confounders and multiple testing (all P<.001). With cluster 1 characterized by early onset of T2D and mild abnormalities of other variables as the reference, patients in cluster 5 characterized by poor renal function had the highest risk of CVD events (hazard ratio [95% CI], 1.72 [1.45 to 2.03], 2.41 [1.93 to 3.02], and 1.62 [1.35 to 1.94] for composite CVD event, CVD mortality, and CVD incidence, respectively; all P<.001), followed by cluster 4 characterized by poor glycemic control and cluster 3 characterized by severe obesity. No consistently significant difference was found between cluster 2 characterized by late onset of T2D and cluster 1. CONCLUSION: Our study, using a novel clustering algorithm to identify robust subtypes of T2D, found heterogeneous associations with incident CVD risk among patients with diabetes.

Cardiovascular Health and Life Expectancy Among Adults in the United States.

BACKGROUND: Cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)-Life's Essential 8 (LE8) score. We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults. METHODS: We included 23 003 nonpregnant, noninstitutionalized participants aged 20 to 79 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. The overall CVH was evaluated by the LE8 score (range, 0-100), as well as the score for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. Life table method was used to estimate life expectancy by levels of the CVH. RESULTS: During a median of 7.8 years of follow-up, 1359 total deaths occurred. The estimated life expectancy at age 50 years was 27.3 years (95% CI, 26.1-28.4), 32.9 years (95% CI, 32.3-33.4), and 36.2 years (95% CI, 34.2-38.2) in participants with low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80) CVH, respectively. Equivalently, participants with high CVH had an average 8.9 (95% CI, 6.2-11.5) more years of life expectancy at age 50 years compared with those with low CVH. On average, 42.6% of the gained life expectancy at age 50 years from adhering to high CVH was attributable to reduced cardiovascular disease death. Similarly significant associations of CVH with life expectancy were observed in men and women, respectively. Similarly significant associations of CVH with life expectancy were observed in White participants and Black participants but not in Mexican participants. CONCLUSIONS: Adhering to a high CVH, defined as the LE8 score, is related to a considerably increased life expectancy in US adults, but more research needs to be done in other races and ethnicities (eg, Hispanic and Asian).

Circulating thrifty microRNA is related to insulin sensitivity, adiposity, and energy metabolism in adults with overweight and obesity: the POUNDS Lost trial.

BACKGROUND: MicroRNA 128-1 (miR-128-1) was recently linked to the evolutionary adaptation to famine and identified as a thrifty microRNA that controls energy expenditure, contributing to obesity and impaired glucose metabolism. OBJECTIVES: We investigated whether circulating miR-128-1-5p and its temporal changes in response to weight-loss diet interventions were related to regulating insulin resistance, adiposity, and energy expenditure in adults with overweight and obesity. We also examined whether habitual physical activity (PA) and different macronutrient intakes modified associations of changes in miR-128-1-5p with improved metabolic outcomes. METHODS: This study included 495 adults who consumed weight-loss diets with different macronutrient intakes. Circulating levels of miR-128-1-5p were assessed at baseline and 6 mo after the interventions. Outcome measurements included changes in insulin resistance HOMA-IR, adiposity, and resting energy expenditure. RESULTS: We observed significant relations between circulating miR-128-1-5p and the positive selection signals at the 2q21.3 locus assessed by the single nucleotide polymorphisms rs1446585 and rs4988235. Higher miR-128-1-5p levels were associated with greater HOMA-IR (ß per 1 SD: 0.08 [SE 0.03]; P = 0.009), waist circumference (ß, 1.16 [0.55]; P = 0.036), whole-body total % fat mass (ß, 0.75 [0.30]; P = 0.013), and REE (ß, 23 [11]; P = 0.037). In addition, higher miR-128-1-5p level was related to lower total PA index (ß, -0.23 [0.07]; P = 0.001) and interacted with PA (Pinteraction < 0.05) on changes in HOMA-IR and adiposity. We found that greater increases in miR-128-1-5p levels after the interventions were associated with lesser improvements in HOMA-IR and adiposity in participants with no change/decreases in PA. Furthermore, we found that dietary fat (Pinteraction = 0.027) and protein (Pinteraction= 0.055) intakes modified relations between changes in miR-128-1-5p and REE. CONCLUSIONS: Circulating thrifty miRNA was linked to regulating body fat, insulin resistance, and energy metabolism. Temporal changes in circulating miR-128-1-5p were associated with better weight-loss outcomes during the interventions; habitual PA and dietary macronutrient intake may modify such relations. This trial was registered at clinicaltrials.gov as NCT00072995.

DNA Methylation Near CPT1A and Changes in Triglyceride-rich Lipoproteins in Response to Weight-loss Diet Interventions.

CONTEXT: Carnitine palmitoyltransferase-1A, encoded by the CPT1A gene, plays a key role in the oxidation of long-chain fatty acids in the mitochondria and may be important in triglyceride metabolism. Previous work has shown that high fat intake was negatively associated with CPT1A methylation and positively associated with CPT1A expression. OBJECTIVE: We aim to investigate the association of DNA methylation (DNAm) at the CPT1A gene with reductions in triglycerides and triglyceride-rich lipoproteins (TRLs) in response to weight-loss diet interventions. METHODS: The current study included 538 White participants, who were randomly assigned to 1 of 4 diets varying in macronutrient components. We defined the regional DNAm at CPT1A as the average methylation level over CpGs within 500 bp of the 3 triglyceride-related DNAm sites. RESULTS: Dietary fat intake significantly modified the association between baseline DNAm at CPT1A and 2-year changes in total plasma triglycerides, independent of concurrent weight loss. Among participants assigned to a low-fat diet, a higher regional DNAm level at CPT1A was associated with a greater reduction in total plasma triglycerides at 2 years (P = .01), compared with those assigned to a high-fat diet (P = .64) (P interaction = .018). Further investigation on lipids and apolipoproteins in very low-density lipoprotein (VLDL) revealed similar interaction patterns for 2-year changes in VLDL-triglycerides, VLDL-cholesterol, and VLDL-apolipoprotein B (P interaction = .009, .002, and .016, respectively), but not for VLDL-apoC-III (P interaction = .36). CONCLUSION: Participants with a higher regional DNAm level at CPT1A benefit more in long-term improvement in triglycerides, particularly in the TRLs and related apolipoproteins when consuming a low-fat weight-loss diet.

Genetically determined gut microbial abundance and 2-year changes in central adiposity and body composition: The POUNDS lost trial.

BACKGROUND AND AIM: Growing evidence has linked gut microbiota with regulation of adiposity. We aimed to examine whether the genetically determined relative abundance of gut microbial taxa was associated with long-term changes in adiposity and body composition among individuals who were overweight or obese in weight-loss diet interventions. METHODS: The study included 692 participants with overweight or obese from the POUNDS Lost trial. We created a genetic risk score (GRS) for the relevant abundance of gut microbial taxa using 20 single nucleotide polymorphisms identified from a recent genome-wide association study. Body composition was assessed using dual-energy X-ray absorptiometry. RESULTS: Higher GRS for the relative abundance of gut microbial taxa was significantly associated with greater reductions in waist circumference, total fat mass (FM), whole-body total percentage of fat mass (FM%), and percentage of trunk fat (TF%) at 2 years (p = 0.022, 0.034, 0.023, 0.023, respectively). In addition, dietary protein significantly modified the association between GRS for gut microbial abundance and changes in total FM, FM%, and TF% (p-interactions = 0.04, 0.013, and 0.006, respectively) at 6-month, when the maximum weight loss was achieved, even though such interactions were attenuated at 2 years. In the average-protein diet group, a higher microbial abundance GRS was associated with greater reductions in total FM (p = 0.007), FM% (p = 0.002), and TF% (p < 0.001) at 6 months, while no associations were found in the high-protein diet group (p > 0.05). CONCLUSION: Our results suggest that the higher genetically determined relative abundance of gut microbial taxa may be related to long-term improvement of whole-body and central fatness and body composition in response to low-calorie diet interventions.

Adding salt to foods and hazard of premature mortality.

AIMS: We analyzed whether the frequency of adding salt to foods was associated with the hazard of premature mortality and life expectancy. METHODS AND RESULTS: A total of 501 379 participants from UK biobank who completed the questionnaire on the frequency of adding salt to foods at baseline. The information on the frequency of adding salt to foods (do not include salt used in cooking) was collected through a touch-screen questionnaire at baseline. We found graded relationships between higher frequency of adding salt to foods and higher concentrations of spot urinary sodium or estimated 24-h sodium excretion. During a median of 9.0 years of follow-up, 18 474 premature deaths were documented. The multivariable hazard ratios [95% confidence interval (CI)] of all-cause premature mortality across the increasing frequency of adding salt to foods were 1.00 (reference), 1.02 (0.99, 1.06), 1.07 (1.02, 1.11), and 1.28 (1.20, 1.35) (P-trend < 0.001). We found that intakes of fruits and vegetables significantly modified the associations between the frequency of adding salt to foods and all-cause premature mortality, which were more pronounced in participants with low intakes than those with high intakes of these foods (P-interaction = 0.02). In addition, compared with the never/rarely group, always adding salt to foods was related to 1.50 (95% CI, 0.72-2.30) and 2.28 (95% CI, 1.66-2.90) years lower life expectancy at the age of 50 years in women and men, respectively. CONCLUSIONS: Our findings indicate that higher frequency of adding salt to foods is associated with a higher hazard of all-cause premature mortality and lower life expectancy.

Changes in circulating microRNAs-99/100 and reductions of visceral and ectopic fat depots in response to lifestyle interventions: the CENTRAL trial.

BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs and important posttranscriptional regulators of gene expression. Adipose tissue is a major source of circulating miRNAs; adipose-related circulating miRNAs may regulate body fat distribution and glucose metabolism. OBJECTIVES: We investigated how changes in adipose-related circulating microRNAs-99/100 (miR-99/100) in response to lifestyle interventions were associated with improved body fat distribution and reductions of diabetogenic ectopic fat depots among adults with abdominal obesity. METHODS: This study included adults with abdominal obesity from an 18-mo diet and physical activity intervention trial. Circulating miR-99a-5p, miR-99b-5p, and miR-100-5p were measured at baseline and 18 mo; changes in these miRNAs in response to the interventions were evaluated. The primary outcomes were changes in abdominal adipose tissue [visceral (VAT), deep subcutaneous (DSAT), and superficial subcutaneous (SSAT) adipose tissue; cm2] (n = 144). The secondary outcomes were changes in ectopic fat accumulation in the liver (n = 141) and pancreas (n = 143). RESULTS: Greater decreases in miR-100-5p were associated with more reductions of VAT (ß ± SE per 1-SD decrease: -9.63 ± 3.13 cm2; P = 0.0025), DSAT (ß ± SE: -5.48 ± 2.36 cm2; P = 0.0218), SSAT (ß ± SE: -4.64 ± 1.68 cm2; P = 0.0067), and intrahepatic fat percentage (ß ± SE: -1.54% ± 0.49%; P = 0.0023) after the interventions. Similarly, participants with greater decrease in miR-99a-5p had larger 18-mo reductions of VAT (ß ± SE: -10.12 ± 3.31 cm2 per 1-SD decrease; P = 0.0027) and intrahepatic fat percentage (ß ± SE: -1.28% ± 0.52%; P = 0.015). Further, decreases in circulating miR-99b-5p (ß ± SE: per 1-SD decrease: -0.44% ± 0.21%; P = 0.038) and miR-100-5p (ß ± SE: -0.50% ± 0.23%; P = 0.033) were associated with a decrease in pancreatic fat percentage, as well as improved glucose metabolism and insulin secretion at 18 mo. CONCLUSIONS: Decreases in circulating miR-99-5p/100-5p expression induced by lifestyle interventions were related to improved body fat distribution and ectopic fat accumulation. Our study suggests that changes in circulating adipose-related miR-99-5p/100-5p may be linked to reducing diabetogenic fat depots in patients with abdominal obesity.This trial was registered at clinicaltrials.gov as NCT01530724.

Changes in pedometer-measured physical activity are associated with weight loss and changes in body composition and fat distribution in response to reduced-energy diet interventions: The POUNDS Lost trial.

AIMS: To examine whether changes in objectively measured physical activity (PA) are associated with weight loss and changes in body composition and fat distribution in response to weight-loss diet interventions. METHODS: This study included 535 participants with overweight/ obesity, who were randomly assigned to four weight-loss diets varying in macronutrients. PA was measured objectively with pedometers, and body composition and fat distribution were measured using dual-energy X-ray absorptiometry and computed tomography scans at baseline, 6 months and 24 months. RESULTS: From baseline to 6 months, when the maximum weight loss was achieved, each 1000-steps/d increment in PA was associated with a greater reduction in body weight (ß[SE] = -0.48[0.11]) and waist circumference (ß[SE] = -0.49[0.12]). Similar inverse associations were found in changes in body composition and fat distribution (P < 0.05 and false discovery rate qvalue < 0.1 for all). The trajectory of the above adiposity measures across the 24-month intervention period differed between the patterns of PA change. Participants with the largest increase in PA maintained their weight loss from 6 months to 24 months, while those with a smaller increase in PA regained their weight. In addition, dietary fat or protein intake significantly modified the associations between changes in PA and changes in body weight and waist circumference over 24 months (P∆PA*diet < 0.05). CONCLUSIONS: Changes in objectively measured PA were inversely related to changes in body weight, body composition and fat distribution in response to weight-loss diets, and such associations were more evident in people on a high-fat or average-protein diet compared with a low-fat or high-protein diet.

Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial.

BACKGROUND: Thioredoxin Interacting Protein (TXNIP) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes. We hypothesize that baseline DNAm level at TXNIP in blood may be associated with glycemic traits and their changes in response to weight-loss diet interventions. METHODS: We included 639 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss diet intervention. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm level of TXNIP as the average methylation level over CpGs within 500 bp of cg19693031. Generalized linear regression models were used for main analyses. RESULTS: We found that higher regional DNAm at TXNIP was significantly correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (P < 0.05 for all). Significant interactions were observed between dietary protein intake and DNAm on changes in insulin (P-interaction = 0.007) and HOMA-IR (P-interaction = 0.009) at 6 months. In participants with the highest tertile of regional DNAm at TXNIP, average protein (15%) intake was associated with a greater reduction in insulin (ß: -0.14; 95% CI: -0.24, -0.03; P = 0.011) and HOMA-IR (ß: -0.15; 95% CI: -0.26, -0.03; P = 0.014) than high protein (25%) intake, whereas no significant associations were found in those with the lower tertiles (P > 0.05). The interaction was attenuated to be non-significant at 2 years, presumably related to decreasing adherence to the diet intervention. CONCLUSIONS: Our data indicate that higher regional DNAm level at TXNIP was significantly associated with better fasting glucose, HbA1c, and HOMA-IR; and people with higher regional DNAm levels benefited more in insulin and HOMA-IR improvement by taking the average-protein weight-loss diet.

Circulating Levels of microRNA-122 and Hepatic Fat Change in Response to Weight-Loss Interventions: CENTRAL Trial.

PURPOSE: Little is known about the relations between changes in circulating microRNA-122 (miR-122) and liver fat in response to weight-loss interventions. We aimed to investigate the association between miR-122 and changes of hepatic fat content during 18-month diet and physical activity interventions. METHODS: The CENTRAL trial is an 18-month randomized, controlled trial among adults with abdominal obesity or dyslipidemia. Subjects were randomly assigned to a low-fat diet or a Mediterranean/low-carbohydrate diet. After 6 months of dietary intervention, each diet group was further randomized into added physical activity groups or no added physical activity groups for the following 12 months of intervention. The current study included 220 participants at baseline and 134 participants with repeated measurements on serum miR-122 and hepatic fat content over 18 months. RESULTS: Serum miR-122 significantly increased from baseline to 18 months, while no difference was observed across the 4 intervention groups. We found a significant association between miR-122 and hepatic fat content at baseline, as per unit increment in log-transformed miR-122 was associated with 3.79 higher hepatic fat content (P < 0.001). Furthermore, we found that higher elevations in miR-122 were associated with less reductions in hepatic fat percentage during 18-month interventions (ß = 1.56, P = 0.002). We also found a significant interaction between changes in miR-122 and baseline fasting plasma glucose with hepatic fat content changes in 18 months (P interaction = 0.02). CONCLUSIONS: Our data indicate that participants with higher elevation in serum miR-122 may benefit less in reduction of hepatic fat content in response to diet and physical activity interventions.

Adherence to a healthy sleep pattern is associated with lower risks of all-cause, cardiovascular and cancer-specific mortality.

BACKGROUND: Individual unhealthy sleep behaviours have been associated with increased risks of all-cause mortality and deaths due to cardiovascular disease (CVD) or cancer. The evidence regarding the association of sleep patterns with these risks is limited. OBJECTIVE: To examine the associations of sleep patterns with all-cause, CVD and cancer mortality in a large prospective cohort. METHODS: This prospective cohort study included 283,443 adults from UK Biobank without CVD and cancer at baseline. We created a healthy sleep score and sleep patterns combining five individual sleep behaviours. RESULTS: During a mean (standard deviation) of 8.9 (1.1) years (2.5 million person-years) of follow up, a total of 7936 all-cause deaths, 762 CVD-caused deaths, and 4540 cancer-caused deaths occurred during follow up. One point increase of the healthy sleep score was associated with a 4-11% lower risk of all-cause mortality (Hazard Ratio [HR], 0.94; 95% CI, 0.92-0.96), CVD mortality (HR, 0.89; 95% CI, 0.83-0.95) and cancer mortality (HR, 0.96; 95% CI, 0.93-0.99), with adjustment for age, sex, assessment centres, smoking status, alcohol intake status, socioeconomic status and physical activity. Compared with participants with an unfavourable sleep pattern, those with a favourable sleep pattern had 24-42% lower risks of all-cause and CVD mortality. The association with all-cause mortality tended to be stronger among underweight participants and those with insufficient physical activity. CONCLUSIONS: A healthy sleep pattern was associated with lower risks of all-cause mortality and mortality from CVD and cancer. Our findings highlight the importance of improving overall sleep behaviours in lowering mortality.

Curcumin protects against fructose-induced podocyte insulin signaling impairment through upregulation of miR-206.

SCOPE: Fructose consumption can induce insulin resistance and metabolic syndrome, which are associated with glomerular podocyte dysfunction and proteinuria. This study investigated whether fructose caused insulin signaling impairment in podocyte dysfunction and injury, and whether curcumin reduced these disturbances. METHODS AND RESULTS: Rats were fed with 10% fructose for 6 weeks and then orally cotreated with curcumin for next 6 weeks. Metabolic syndrome, podocyte injury, microRNA expression, and insulin signaling were evaluated. Curcumin significantly alleviated fructose-induced podocyte injury and proteinuria, miR-206 low-expression, protein tyrosine phosphatase 1B (PTP1B) overexpression, as well as downregulation of insulin receptor, insulin receptor substrate 1, caveolin-1, protein kinase B, and extracellular signal-regulated kinases 1 and 2 phosphorylation in kidney cortex or glomeruli of fructose-fed rats. These effects were further confirmed in cultured differentiated podocytes exposed to 5 mM fructose in the presence or absence of curcumin, PTP1B siRNA, lentivirus-mediated PTP1B recombinant overexpression, miR-206 mimic, or miR-206 inhibitor transfection, showing that miR-206 upregulation may contribute to improve insulin signaling through regulating PTP1B expression. CONCLUSION: Curcumin is suggested to activate miR-206 expression to downregulate PTP1B, and then improve insulin signaling, protect against fructose-induced glomerular podocyte injury, and proteinuria, which may provide new evidence regarding curcumin's effects on fructose-associated podocyte injury.

Wuling San protects kidney dysfunction by inhibiting renal TLR4/MyD88 signaling and NLRP3 inflammasome activation in high fructose-induced hyperuricemic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuling San, a famous prescription in Chinese medicine, is composed of Polyporus, Poria, Alismatis rhizoma, Cinnamomi cortex and Atractylodis macrocephalae rhizoma, and promotes kidney function and diuresis. The main purpose of this study was to investigate its renal protective effect in high fructose-induced hyperuricemic mice. MATERIALS AND METHODS: ICR mice were fed with 30% fructose in drinking water for 6 weeks to induce hyperuricemia and renal dysfunction. Then mice were orally administrated for other 6 weeks with Wuling San (987, 1316, 1755 and 2340mg/kg), allopurinol (5mg/kg) and water daily, respectively. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Hematoxylin and eosin staining was used to assess renal histological changes. Renal interleukin (IL)-1ß concentrations were measured using ELISA kit. Renal protein levels of organic ion transporters, as well as toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling and pyrin domain containing 3 (NLRP3) inflammasome were determined by Western blot assay. RESULTS: Wuling San significantly decreased serum uric acid, creatinine and BUN levels, increased fractional excretion of uric acid (FEUA) in fructose-fed mice. It restored fructose-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 1 (OAT1), as well as organic cation transporter 1 (OCT1) and OCT2 in mice. Wuling San obviously alleviated infiltration of inflammation cells in kidney glomerulus of fructose-fed mice. Moreover, Wuling San suppressed the activation of TLR4/ MyD88 signaling to inhibit nuclear factor κB (NF-κB) signaling and mitogen-activated protein kinases (MAPKs) activation in fructose-fed mice. Additionally, Wuling San decreased NLRP3 inflammasome activation and IL-1ß secretion in the kidney of fructose-fed mice. CONCLUSION: Wuling San exerts renal protective effect by modulating renal organic ion transporters in fructose-induced hyperuricemic mice. The molecular mechanism of its action may be associated with the suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1ß production in high fructose-induced hyperuricemic mice.