This article introduced the research design and main results of the article " Effect of Moderate and Vigorous Aerobic Exercise on Incident Diabetes in Adults with Obesity: A 10-Year Follow-up of a Randomized Clinical Trial" recently published in JAMA Internal Medicine, and addressed the scientific significance of the study. The importance of obesity management has been well discussed recently. This study investigated obesity management strategies for obese individuals and their long-term metabolic benefits.

This randomized clinical trial assesses the long-term effect of vigorous and moderate exercise on incident diabetes over a 10-year follow-up after a 12-month exercise intervention.

Previous studies have found microRNA-1 (miR-1) and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) may be involved in the pathogenesis of thyroid hormone (TH) induced cardiac hypertrophy. However, little is known about the role of miR-1 and HCN2 in thyroid stimulation hormone (TSH)-induced cardiac dysfunction. In order to investigate the molecular mechanisms of TSH induced cardiac dysfunction and the role of miR-1/HCN2 in that process, we evaluated the expression of miR-1a/HCN2 in the ventricular myocardium of hypothyroid mice and in TSH-stimulated H9c2 cardiomyocytes. Our data revealed that hypothyroidism mice had smaller hearts, ventricular muscle atrophy, and cardiac contractile dysfunction compared with euthyroid controls. The upregulation of miR-1a and downregulation of HCN2 were found in ventricular myocardium of hypothyroid mice and TSH-stimulated H9c2 cardiomyocytes, indicating that miR-1a and HCN2 may be involved in TSH-induced cardiac dysfunction. We also found that the regulation of miR-1a and HCN2 expression and HCN2 channel activity by TSH requires TSHR, while the regulation of HCN2 expression and HCN2 channel function by TSH requires miR-1a. Thus, our data revealed the potential mechanism of TSH-induced cardiac dysfunction and might shed new light on the pathological role of miR-1a/HCN2 in hypothyroid heart disease.

Background Adipsin has been identified as a secreted adipokine that plays a critical pathogenic role in metabolic disorders. However, it is not clear regarding the association of circulating adipsin with cardiovascular disease (CVD). This study will explore the association between circulating adipsin and asymptomatic carotid atherosclerosis in Chinese obese adults. Methods A total of 483 obese adult subjects (aged 40 years or older) were enrolled in this study. Serum adipsin concentrations and carotid intima-media thickness (CIMT) were measured to determine these associations. Results Individuals with increased CIMT and asymptomatic carotid atherosclerosis had lower levels of circulating adipsin than controls (both p < 0.05). The prevalence of asymptomatic carotid atherosclerosis was significantly higher in subjects with lower levels of serum adipsin than those with higher values (42.5% vs. 36.7%, p < 0.05). Notably, subjects in the lowest quartile of serum adipsin were 1.94 times ( p = 0.059) more likely to have increased CIMT and 2.91 times ( p = 0.03) more likely to have asymptomatic carotid atherosclerosis than those in the highest quartile in multivariable logistic regression analyses, adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, and HOMA-IR. However, such associations with circulating adipsin were not noted for atherosclerotic plaque. Conclusions These findings suggest that circulating adipsin concentrations are a potential marker of risks of increased CIMT and asymptomatic carotid atherosclerosis in obese Chinese adults.

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.

Exercise training can reduce hepatic fat accumulation and cardiovascular risk among patients with non‐alcoholic fatty liver disease ( NAFLD ), but how long these benefits extend beyond the period of active intervention is unclear. Intrahepatic triglyceride ( IHTG ) content, measured by proton magnetic resonance spectroscopy, and metabolic risk factors among 220 obese people with NAFLD , who were randomly assigned to vigorous/moderate exercise, moderate exercise or no exercise (control), were assessed at 1 year after the 12‐month exercise intervention. IHTG content was significantly reduced in the 2 exercise groups compared with the control group over the 12‐month active intervention. It was significantly lower (by −2.39%) in the vigorous/moderate exercise group compared with the control group at the 1‐year follow‐up (95% confidence interval −4.72 to −0.05%; P = .045). Waist circumference and blood pressure remained significantly lower in the vigorous/moderate exercise group and the moderate exercise group compared with the control group at the 1‐year follow‐up. Visceral adipose fat remained significantly reduced, but with no differences among 3 groups. These findings suggest 12‐month exercise intervention induced reductions in hepatic fat accumulation, abdominal obesity and blood pressure for up to 1 year after the active intervention, with some attenuation of the benefits.

Individuals with metabolically healthy obesity (MHO) are at relatively low risk for the development of metabolic abnormalities and subclinical atherosclerosis. This study aims to examine whether hepatic fat accumulation determines metabolic phenotype of obesity and associated with subclinical atherosclerosis. A total of 485 obese adults (aged 40-65 years) who received magnetic resonance spectroscopy were divided into metabolically abnormally obesity (MAO) and MHO groups according to metabolic status. MHO individuals had lower levels of intrahepatic triglyceride (IHTG) content and carotid intima-media thickness (CIMT) than MAO individuals. In multivariable linear regression analyses, IHTG content was independently associated with metabolic syndrome components and CIMT. Based on receiver operating characteristic curve analysis, the IHTG content displayed a higher area under the curve (AUC) for detecting the MAO phenotype (AUC = 0.70, 95% CI = 0.65-0.75) and increased CIMT (AUC = 0.60, 95% CI = 0.54-0.66) than BMI, waist circumference, and body fat percent. MHO individuals were 1.9 times (p < 0.001) more likely to have metabolic syndrome per 1 SD change in IHTG content in multivariable-adjusted models. Likewise, the risk for high CIMT increased 29% per 1 SD change in IHTG content [OR (95% CI): 1.29(1.01-1.64)]. These findings suggest that hepatic fat is a potential predictor of metabolically unhealthy obesity phenotype and subclinical atherosclerosis.

IMPORTANCENonalcoholic fatty liver disease (NAFLD) is a prevalent risk factor for chronic liver disease and cardiovascular disease.OBJECTIVETo compare the effects of moderate and vigorous exercise on intrahepatic triglyceride content and metabolic risk factors among patients with NAFLD.DESIGN, SETTING, AND PARTICIPANTSIn this randomized clinical trial, participants with central obesity and NAFLD were recruited from community-based screening in Xiamen, China, from December 1, 2011, through December 25, 2013. Data analysis was performed from August 28, 2015, through December 15, 2015.INTERVENTIONSParticipants were randomly assigned to vigorous-moderate exercise (jogging 150 minutes per week at 65%-80% of maximum heart rate for 6 months and brisk walking 150 minutes per week at 45%-55% of maximum heart rate for another 6 months), moderate exercise (brisk walking 150 minutes per week for 12 months), or no exercise.MAIN OUTCOMES AND MEASURESPrimary outcome, change in intrahepatic triglyceride content measured by proton magnetic resonance spectroscopy at 6 and 12 months; secondary outcomes, changes in body weight, waist circumference, body fat, and metabolic risk factors.RESULTSA total of 220 individuals (mean [SD] age, 53.9 [7.1] years; 149 woman [67.7%]) were randomly assigned to control (n = 74), moderate exercise (n = 73), and vigorous-moderate exercise (n = 73) groups. Of them, 211 (95.9%) completed the 6-month follow-up visit; 208 (94.5%) completed the 12-month follow-up visit. Intrahepatic triglyceride content was reduced by 5.0% (95% CI, -7.2% to 2.8%; P < .001) in the vigorous-moderate exercise group and 4.2% (95% CI, -6.3% to -2.0%; P < .001) in the moderate exercise group compared with the control group at the 6-month assessment. It was reduced by 3.9% (95% CI, -6.0% to -1.7%; P < .001) in the vigorous-moderate exercise group and 3.5% (95% CI, -5.6% to -1.3%; P = .002) in the moderate exercise group compared with the control group at the 12-month assessment. Changes in intrahepatic triglyceride content were not significantly different between vigorous-moderate and moderate exercise at the 6- or 12-month assessment. Body weight, waist circumference, and blood pressure were significantly reduced in the vigorous-moderate exercise group compared with the moderate exercise and control groups at the 6-month assessment and in the vigorous-moderate and moderate exercise groups compared with the control group at the 12-month assessment. In addition, body fat was significantly reduced in the vigorous-moderate exercise group compared with the moderate exercise and control groups at the 12-month assessment. After adjusting for weight loss, the net changes in intrahepatic triglyceride content were diminished and became nonsignificant between the exercise and control groups (except for the moderate exercise group at the 6-month assessment).CONCLUSIONS AND RELEVANCEVigorous and moderate exercise were equally effective in reducing intrahepatic triglyceride content; the effect appeared to be largely mediated by weight loss.TRIAL REGISTRATIONclinicaltrials.gov Identifier: NCT01418027.

Irisin, an exercise induced myokine, has broad implications for metabolism and energy homeostasis. Available evidence about the association of serum irisin with chronic kidney disease (CKD) is limited.

Background. Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are associated with some common critical cardio-metabolic risk factors. The aim of this study was to explore the association between intrahepatic triglyceride (IHTG) content and CKD in obese subjects.Methods. A total of 1068 obese participants received anthropometric, biochemical measurements and hepatic ultrasonography. Of those, 485 participants received magnetic resonance spectroscopy (H-1-MRS) for the determination of IHTG content. CKD was defined as a urinary albumin:creatinine ratio (UACR) >= 30 mg/g and/or estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m(2).Results. The prevalence of CKD was significantly higher in NAFLD subjects compared to subjects without NAFLD, while the prevalence of CKD was gradually increased as the IHTG content increased by quartiles (P for trend < 0.001). After adjustment for multivariate metabolic factors, the risk of abnormal albuminuria and CKD was increased by 68% [OR (95% CI): 1.68 (1.21-2.33), P < 0.01] and 54% [OR (95% CI): 1.54 (1.14-2.07), P < 0.01] respectively per one standard deviation (SD) increase in IHTG content. The association between IHTG content and CKD was not changed by conventional risk factors, including age, BMI and hypertension (all P < 0.05).Conclusion. IHTG content is independently associated with CKD in obese adults. (C) 2015 Elsevier Inc. All rights reserved.

Corresponding authors: Shu-yu Yang, Xiamen Diabetes Institute, Department of Endocrinology and Metabolism, The First Hospital of Xiamen, Xiamen University, 55 Zhenhai Road, Xiamen 361003, China ( xmyangshuyu@126.com). Jiang He, MD, PhD, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal St, Ste 2000, New Orleans, LA 70112 ( jhe@tulane.edu ). Xiao-Ying Li, MD, PhD, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025 (lixy@sibs.ac.cn). Introduction: Nonalcoholic fatty liver disease (NAFLD) and its cardiovascular complications are common public health problems. Hypothesis: Although the benefit of exercise on NAFLD and cardiometabolic risk factors is documented, the effects of intensive and moderate exercise on these outcomes have not been thoroughly investigated.. Methods: We conducted a randomized controlled trial among 220 individuals aged 40-65 years with a waist circumference of ≥90 cm in men and ≥85 cm in women. NAFLD was defined by proton magnetic resonance spectroscopy (1H-MRS). Participants were randomly assigned to the intensive exercise group (vigorous exercise at 65-80% maximum oxygen consumption by running on a treadmill 30 min/day and 5 days/week for 6 months, followed by moderate exercise by brisk walking 150 min/week for another 6 months), the moderate exercise group (brisk walking 150 min/week for the entire 12 months), or the usual care control (lifestyle counseling for 12 months). The primary outcome was the change of intra-hepatic triglyceride content as determined by 1 H-MRS. Secondary outcomes were metabolic risk factors. Results: At 12 months, the mean change of intra-hepatic triglyceride content from baseline was -6.10% in the intensive exercise, -5.91% in the moderate exercise, and -2.73% in the control groups (P<0.0001). Compared to the control group,the intensive and moderate exercise groups had significant net reductions of intra-hepatic triglyceride content at 6 months (-4.56%, 95% CL-6.71 to -2.42, p<0.001 for intensive and -3.86%, 95% CL-6.01 to -1.71, p<0.001 for moderate) and 12 months (-3.37%, 95% CL-5.52 to -1.22, p<0.001 for intensive, and -3.19%, 95% CL-5.34 to -1.04, p<0.001 for moderate). The net changes of intra-hepatic triglyceride content were not significantly different between the two exercise groups. Both intensive and moderate exercise reduced waist circumference, body weight, and blood pressure; additionally, intensive exercise reduced body fat mass, visceral fat, and body fat percent. Conclusions: Moderate intensity and vigorous intensity exercise were equally effective in improving NAFLD and blood pressure while vigorous exercise produced greater reductions of body fat.

Irisin, a recently identified novel myokine, drives brown-fat-like conversion of white adipose tissues and has been proposed to mediate beneficial effects of exercise on metabolism. Circulating irisin was significantly reduced in type 2 diabetes patients; however, no evidence is available about its association with metabolic syndrome (MetS) and effects of adiposity and muscle mass on circulating irisin have been controversial. Cross-sectional data on socio-demographic, lifestyle, clinical characteristics and serum irisin were collected for 1,115 community-living Chinese adults with central obesity. Associations of serum irisin with MetS (central obesity plus any two of the following four factors (raised blood pressure (BP), raised fasting plasma glucose (FPG), raised triglyceride (TG), and reduced HDL cholesterol) and each component of MetS were analyzed using multivariable logistic regression. Among the 1,115 obese Chinese adults with a mean age of 53.2(±7.2) years, serum irisin levels (log-transformed) were significantly reduced in subjects with MetS and raised FPG than their control groups (p = 0.034 and 0.041, respectively). After adjustment for potential confounders, serum irisin was significantly associated with reduced risks of MetS and raised FPG, with odds ratios (ORs) (95% CI) per standard deviation of log-transformed irisin of 0.796 (0.505-0.959, p = 0.027) and 0.873 (0.764-0.998, p = 0.046), respectively. Associations of irisin with raised BP, raised TG and reduced HDL were not statistically significant ((ORs) (95% CI): 0.733(0.454-1.182, p = 0.202), 0.954(0.838-1.086, p = 0.478) and 1.130(0.980-1.302, p = 0.092), respectively). Stepwise multivariable linear regression analysis showed that fasting insulin, HbA1c and albumin/globulin ratio were negatively associated with serum irisin level with statistical significance (all p-values <0.05) and waist circumference was negatively associated with serum risin with marginally statistical significance (p = 0.055). These results imply that irisin may play an important role in insulin resistance and MetS and should be confirmed in future prospective studies.

Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of fatty acid oxidation, and activation of the JNK signaling pathway. In mouse primary hepatocytes, inhibition of α6β4 integrin prevented activation of JNK and suppression of PPARα in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented RORα binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.

Liver enzymes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) are well recognized as surrogate makers reflecting non-alcoholic fatty liver disease (NAFLD). However, the associations of serum ALT, AST and GGT with hepatic lipid contents are not well established. The aim of this study was to investigate the relationship between liver enzymes and intrahepatic triglyceride (IHTG) contents, and explore the feasibility in using liver enzymes to reflect accumulation of IHTG in obese subjects.

Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor a (PPAR alpha), a master regulator of fatty acid oxidation, and activation of the INK signaling pathway. In mouse primary hepatocytes, inhibition of alpha 6 beta 4 integrin prevented activation of JNK and suppression of PPARa in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented ROR alpha binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.

Background & Aims: Obesity is closely related to non-alcoholic fatty liver disease (NAFLD), which has become an important public health problem because of its high prevalence and association with metabolic syndromes. Irisin was recently identified as a novel peptide to improve obesity and glucose homeostasis, and considered to be therapeutic for human metabolic diseases. The aim of this study was to examine the association of serum irisin concentration and liver triglyceride contents in obese Chinese adults.Methods: Serum irisin levels were measured and liver fat contents determined by H-1 MRS in 296 obese adults. Anthropometric parameters and blood biochemical indexes including liver enzymes, glucose, and lipid profiles were detected. The liver triglyceride contents of subjects were measured by H-1 MRS. The protein levels of irisin were determined by quantitative ELISA.Results: We found that serum irisin levels were reduced in obese adults with NAFLD. By dividing the distribution of intrahepatic triglyceride (IHTG) contents into quartiles, serum irisin levels were reduced gradually with the increase of IHTG contents (p < 0.01). Higher serum irisin levels were associated with preferable TG levels. Serum ALT and AST concentrations were inversely correlated with serum irisin levels. Multivariate linear regression analysis demonstrated that serum irisin levels were independently associated with liver fat (p < 0.01). By logistic regression analysis, the odds ratio for higher IHTG contents was reduced by 12.4% per 1 SD increase in serum irisin concentrations after adjustment for multivariate metabolic factors [OR (95% CI); 0.876 (0.777-0.987)].Conclusions: These results demonstrated that serum irisin concentrations were inversely associated with the triglyceride contents in the liver and liver enzymes in obese Chinese adults. Crown copyright (C) 2013 Published by Elsevier B. V. on behalf of the European Association for the Study of the Liver. All rights reserved.

Objective To investigate the association of serum irisin level with fat mass percentage.Methods A total of 1204 subjects with obesity(waist circumference:male ≥90 cm,female ≥85 cm) were recruited from Lianqian Community in Xiamen city from April,2011 to August,2012.All the participants received questionnaire survey,physical examination,blood chemistry tests and serum irisin levels measurement,and the fat mass percentage was measured by using a bioelectrical impedance analyzer.The data were analyzed using student-t test,ANOVA and logistic regression.Results Total of 807 women and 397 men with central obesity took part in the study,the age was (53 ±7) yrs(35 to 65 yrs).A higher fat mass percentage and serum irisin levels were shown in women as compared with those in men ((39 ± 4) ％ vs (26 ± 4) ％ and 8.9/(4.7-17.2) μg/L vs 7.6 (4.0-14.4) μg/L,t =-53.50,-2.87,both P ＜0.05).Serum irisin levels were correlated with fat mass percentage in total subjects.Fat mass percentage,serum total cholesterol(TC) and low density lipoprotein-cholesterol (LDL-C) levels increased as serum irisin levels increased by tertiles (F =4.49,3.63,4.88,all P for trend ＜ 0.05).Serum irisin levels were increased as fat mass percentage increased by tertiles (F =3.33,P ＜ 0.05).Logistic regression analysis showed that serum irisin levels were increase by 13％ as fat mass percentage increased by one percent after all metabolic markers (such as age,sex,body mass index,waist circumference,physical activity,systolic blood pressure,diastolic blood pressure,current smoking and drinking,triglyceride,TC,LDL-C,high density lipoprotein-cholesterol,glycated hemoglobin A1c,fasting blood glucose and homeostasis model of assessment for insulin resistence index) were adjusted (OR =1.13,95％ CI:1.01-1.25,x2 =4.83,P ＜ 0.05).Conclusions Serum irisin levels in obese adults were associated with fat mass percentage.