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Background: We aimed to examine the associations between the risk of decreased renal function, obesity, and weight changes in Korean type 2 diabetic patients with normal renal function., Methods: Type 2 diabetic patients (n = 1060) who visited the diabetic clinic at Soonchunhyang University Bucheon Hospital between 2001 and 2007 with follow up surveys completed in 2016 to 2017 were recruited into the study. Decreased renal function was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m 2 . Weight change was calculated between baseline and each follow-up survey. Multivariate analysis was used to evaluate the longitudinal association of baseline obesity and weight changes with the risk of decreased renal function., Results: This study revealed that baseline obesity was associated with the risk of decreased renal function after adjusting for clinical variables in type 2 diabetic patients (odds ratio [OR] 1.40; 95% confidence intervals [CI] 1.08-2.04; p = 0.025). Follow-up (mean = 12 years) revealed that weight gain > 10% was associated with the risk of decreased renal function after adjusting for clinical variables in type 2 diabetic patients with normal renal function at baseline (OR 1.43; CI 1.11-2.00; p = 0.016). Weight loss was not associated with the risk of decreased renal function in type 2 diabetic patients with normal renal function at baseline., Conclusions: Baseline obesity was associated with the increased risk of decreased renal function in Korean type 2 diabetic patients with normal renal function. Weight gain > 10% independently predicted the risk of decreased renal function. Large prospective studies are needed to clarify causal associations between obesity, weight change, and decreased renal function in patients with type 2 diabetes., (© 2021. The Author(s).)

We evaluated the association of metabolic health and obesity phenotypes with the risk of Alzheimer's disease (AD). This study enrolled 136,847 elderly participants aged 60 or above from the Korean National Health Insurance System. At baseline examinations in 2009 and 2010, subjects were categorized into four groups: the metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO) groups. Based on the phenotypic transition after 2 years, the subjects were further categorized into 16 subgroups. They were followed from 2009 to 2015 to monitor for AD development. The MHO phenotype protected subjects from AD, relative to the MHNO phenotype (HR, 0.73; 95% CI, 0.65-0.81). Among subjects initially classified as MHO, 41.8% remained MHO, with a significantly lower risk of AD compared with the stable MHNO group (HR, 0.62; 95% CI, 0.50-0.77). Among MUO subjects at baseline, those who changed phenotype to MUNO were at higher risk of AD (HR, 1.47; 95% CI, 1.28-1.70), and the transition to the MHO phenotype protected subjects from AD (HR, 0.62; 95% CI, 0.50-0.78). The MHO phenotype conferred a decreased risk of AD. Maintenance or recovery of metabolic health might mitigate AD risk among obese individuals.

Background: The enhancement of energy expenditure has attracted attention as a therapeutic target for the management of body weight. Withaferin A (WFA), a major constituent of Withania somnifera extract, has been reported to possess anti-obesity properties, however the underlying mechanism remains unknown., Purpose: To investigate whether WFA exerts anti-obesity effects via increased energy expenditure, and if so, to characterize the underlying pathway., Methods: C57BL/6 J mice were fed a high-fat diet (HFD) for 10 weeks, and WFA was orally administered for 7 days. The oxygen consumption rate of mice was measured at 9 weeks using an OxyletPro™ system. Hematoxylin and eosin (H&E), immunohistochemistry, immunoblotting, and real-time PCR methods were used., Results: Treatment with WFA ameliorated HFD-induced obesity by increasing energy expenditure by improving of mitochondrial activity in brown adipose tissue (BAT) and promotion of subcutaneous white adipose tissue (scWAT) browning via increasing uncoupling protein 1 levels. WFA administration also significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the BAT of obese mice. Additionally, WFA activated mitogen-activated protein kinase (MAPK) signaling, including p38/extracellular signal-regulated kinase MAPK, in both BAT and scWAT., Conclusion: WFA enhances energy expenditure and ameliorates obesity via the induction of AMPK and activating p38/extracellular signal-regulated kinase MAPK, which triggers mitochondrial biogenesis and browning-related gene expression., (Copyright © 2021. Published by Elsevier GmbH.)

As obesity promotes ectopic fat accumulation in skeletal muscle, resulting in impaired skeletal muscle and mitochondria function, it is associated with skeletal muscle loss and dysfunction. This study investigated whether Chrysanthemi zawadskii var. latilobum (CZH) protected mice against obesity-induced skeletal muscle atrophy and the underlying molecular mechanisms. High-fat diet (HFD)-induced obese mice were orally administered either distilled water, low-dose CZH (125 mg/kg), or high-dose CZH (250 mg/kg) for 8 w. CZH reduced obesity-induced increases in inflammatory cytokines levels and skeletal muscle atrophy, which is induced by expression of atrophic genes such as muscle RING-finger protein 1 and muscle atrophy F-box. CZH also improved muscle function according to treadmill running results and increased the muscle fiber size in skeletal muscle. Furthermore, CZH upregulated mRNA and protein levels of protein arginine methyltransferases (PRMT)1 and PRMT7, which subsequently attenuated mitochondrial dysfunction in the skeletal muscle of obese mice. We also observed that CZH significantly decreased PRMT6 mRNA and protein expression, which resulted in decreased muscle atrophy. These results suggest that CZH ameliorated obesity-induced skeletal muscle atrophy in mice via regulation of PRMTs in skeletal muscle.

Background & Aims: Altered microRNA (miRNA) expression is associated with the pathophysiology of obesity; however, little is known about the miRNAs commonly dysregulated in the blood and visceral fat tissue of obese patients. This study compared the circulating and visceral fat miRNA expression in subjects with and without obesity., Methods: For the circulating miRNA study, 20 healthy control and 30 obese subjects were recruited. For the tissue miRNA expression study, omental fat tissue was collected in ten female subjects each in the control and obese groups. MiRNA expression was measured by TaqMan low-density arrays. Metabolic risk factors were measured. Target genes for selected miRNAs were analyzed using informatics tools and a functional network map was constructed., Results: 11 miRNAs were down-regulated (miR-133a, -139-5p, -15b, -26a, -301, -30b, -30c, -374, -451, -570, and -636), and one was up-regulated (miR-155) in both depots in obese subjects. These miRNAs had significant associations with BMI, waist circumference, and fat mass. Among them, miR-15b, miR-26a, miR-301, miR-30b, and miR-30c had more predicted obesity-related target genes than other miRNAs. In particular, miR-15b had numerous target genes associated with adipogenesis, mammalian target of rapamycin (mTOR) signaling, diabetes and insulin resistance, and mitochondrial function., Conclusions: It is suggested that the miRNA alteration in the serum and visceral fat has pathophysiological implications for obesity. Our study identified dysregulated miRNAs that may be novel therapeutic targets to combat obesity., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Context: Metabolically healthy obesity (MHO) is a dynamic condition., Objective: To evaluate the risk of chronic kidney disease (CKD) among people with MHO according to its longitudinal change., Design: Observational study., Setting: A nationwide population-based cohort., Participants: A total of 514 866 people from the Korean National Health Insurance Service-National Sample Cohort., Intervention: The initial presence and changes of obesity (using body mass index [BMI] and waist circumference [WC]) and metabolic health status., Main Outcome Measure: Incident CKD from 2011 to 2015., Results: Of the people classified as MHO at baseline (BMI criteria), 47.6% remained as MHO in 2011 and 2012, whereas 12.1%, 5.5%, and 34.8% were classified as metabolically healthy, non-obese (MHNO), metabolically unhealthy, non-obese, and metabolically unhealthy, obese, respectively. The risk of incident CKD in the baseline MHO group was higher than that in the MHNO group (hazard ratio, 1.23; 95% confidence interval, 1.12-1.36). However, when transition was taken into account, people who converted to MHNO were not at increased risk (hazard ratio, 0.98; 95% confidence interval, 0.72-1.32), whereas the stable MHO group and the groups that evolved to metabolically unhealthy status had a higher risk of incident CKD than the stable MHNO group. When the risk was analyzed using WC criteria, it showed a similar pattern to BMI criteria except for the stable MHO group., Conclusions: MHO was a dynamic condition, and people with MHO constituted a heterogeneous group. Although the MHO phenotype was generally associated with incident CKD, maintenance of metabolic health and weight reduction might alleviate the risk of CKD., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

&nbsp; Withania somnifera (WS), commonly known as ashwagandha, possesses diverse biological functions. WS root has mainly been used as an herbal medicine to treat anxiety and was recently reported to have an anti-obesity effect, however, the mechanisms underlying its action remain to be explored. We hypothesized that WS exerts its anti-obesity effect by enhancing energy expenditure through improving the mitochondrial function of brown/beige adipocytes and skeletal muscle. Male C57BL/6J mice were fed a high-fat diet (HFD) containing 0.25% or 0.5% WS 70% ethanol extract (WSE) for 10 weeks. WSE (0.5%) supplementation significantly suppressed the increases in body weight and serum lipids, and lipid accumulation in the liver and adipose tissue induced by HFD. WSE supplementation increased oxygen consumption and enhanced mitochondrial activity in brown fat and skeletal muscle in the HFD-fed mice. In addition, it promoted browning of subcutaneous fat by increasing mitochondrial uncoupling protein 1 (UCP1) expression. Withaferin A (WFA), a major compound of WS, enhanced the differentiation of pre-adipocytes into beige adipocytes and oxygen consumption in C2C12 murine myoblasts. These results suggest that WSE ameliorates diet-induced obesity by enhancing energy expenditure via promoting mitochondrial function in adipose tissue and skeletal muscle, and WFA is a key regulator in this function., Competing Interests: The authors declare that there are no conflicts of interest.

Aims: We hypothesized that transitions in metabolic health status and obesity affect the cardiovascular (CV) risk and mortality in population with metabolically healthy obesity (MHO)., Methods: This study enrolled 514,866 participants from the Korean National Health Insurance Service-National Sample Cohort. Changes in metabolic health status and obesity from the baseline examination in 2009-2010 to the next biannual health examination in 2011-2012 were determined. Study participants were categorized into four groups: (1) metabolically healthy, non-obese (MHNO), defined as BMI < 25 kg/m 2 and no or one metabolic risk factor; (2) metabolically unhealthy, non-obese (MUNO), defined as BMI < 25 kg/m 2 and ≥2 metabolic risk factors; (3) MHO, defined as BMI ≥ 25 kg/m 2 and no or one metabolic risk factor; and (4) metabolically unhealthy, obese (MUO), defined as BMI ≥ 25 kg/m 2 and ≥2 metabolic risk factors. The study subjects were followed-up from 2011 to 2015 for cardiovascular events, CV mortality and all-cause mortality., Results: Among the subjects classified as MHO in 2009-2010, 45.6% were classified as MHO in 2011-2012, whereas 11.6%, 6.0%, and 36.8% were classified as MHNO, MUNO, and MUO, respectively. The risk of CV events was higher in baseline MHO group than MHNO group (HR, 1.14; 95% CI, 1.05-1.24). However, in baseline MHO group, CV mortality was not increased (HR, 0.85; 95% CI, 0.69-1.06) and all-cause mortality was even lower than that of MHNO group (HR, 0.86; 95% CI, 0.79-0.93). Compared to the stable MHO subjects, the risk of CV events was significantly higher in the subjects who transitioned from MHO to MUO with multivariate-adjusted HRs of 1.24 (95% CI: 1.00-1.54). When weight loss and progression to metabolic unhealthy phenotype occur simultaneously in the MHO population, the all-cause mortality was increased compared to the stable MHO group (HR, 1.96; 95% CI, 1.45-2.65)., Conclusions: Subjects with MHO constitute a heterogeneous group. Our finding supports that evolving to a metabolically unhealthy status and losing weight simultaneously is associated with the adverse outcome in the MHO population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Scope: Obesity and diabetes are major public health problems and are emerging as pandemics. Considerable evidence suggests that pear fruit consumption is associated with a lower risk of obesity-related complications. Thus, the present study is conducted to investigate the therapeutic potential of pear extract (PE) for reversing obesity and associated metabolic complications in high-fat diet-induced obese mice., Methods and Results: Obesity is induced in male C57BL/6 mice fed a high-fat diet for 11 weeks. After the first 6 weeks on the diet, obese mice are administered vehicle or PE for 5 weeks. PE treatment decreases body weight gain, expands white adipose tissue (WAT), and causes hepatic steatosis in obese mice, as well as inhibits adipogenesis and lipogenesis. Impaired glucose tolerance and insulin resistance are improved by PE. In addition, PE reduces macrophage infiltration and expression of pro-inflammatory genes and deactivates mitogen-activated protein kinases in WAT. Finally, malaxinic acid is identified as an active component responsible for the anti-obesity effects of PE in mice., Conclusion: The results demonstrate that PE supplementation ameliorates diet-induced obesity and associated metabolic complications and suggest the health-beneficial effects of both pear fruits and malaxinic acid in counteracting these diseases., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Metabolically healthy individuals are known to be resistant to cardiovascular disease development. However, a considerable fraction of those individuals shows deteriorated metabolic health over time. Although skeletal muscle is the primary insulin-responsive target organ, a longitudinal investigation of the skeletal muscle mass in relation to the development of metabolically unhealthy phenotype has not been performed. We aimed to evaluate whether greater skeletal muscle mass is an independent protective factor for the development of metabolically unhealthy phenotype., Design, Participants and Measurements: We conducted a retrospective cohort study with 9033 metabolically healthy volunteers who underwent routine health examinations in 2012 and a follow-up examination in 2016. Obesity was defined as Asian-Pacific body mass index criterion ≥25 kg/m 2 . Subjects with fewer than two risk factors (elevated blood pressure, triglyceride, glucose, high-sensitivity C-reactive protein, insulin resistance and decreased high-density lipoprotein cholesterol levels) were characterized as metabolically healthy using Wildman criteria., Results: At the 4-year follow-up, approximately one-fourth of the nonobese participants and half of the participants with obesity showed metabolic deterioration. In nonobese men and women, higher appendicular skeletal muscle mass (ASM)/weight at baseline was significantly associated with decreased risk of metabolic deterioration. Compared to the lowest quartile of ASM/weight, the adjusted odds ratios (95% confidence intervals) of the highest quartile were 0.68 (0.52-0.89) in nonobese men and 0.64 (0.46-0.90) in nonobese women. However, this association was not observed in obese subjects., Conclusions: Greater skeletal muscle mass at baseline is significantly associated with maintenance of metabolically healthy status, especially in nonobese individuals., (© 2018 John Wiley & Sons Ltd.)

Inula japonica Thunb. (Asteraceae) is a flowering plant that grows mainly in Korea, Japan, and China and its flower extract has diverse biological effects such as anti-inflammatory and antioxidative activities. However, the effects on obesity and enhancement of endurance capacity have not been explored yet. This study aims to reveal the effects of I. japonica flower ethanol extract (IJE) on obesity and endurance capacity in high-fat diet (HFD) fed C57BL/6J mice and the mechanism. IJE inhibited lipid accumulation in 3T3-L1 adipocytes in vitro. Also, IJE-fed mice showed reduced body weight gain, hepatic lipid, and body fat mass, and increased muscle weight. IJE reduced lipid accumulation in the liver and adipose tissue by decreasing lipogenic and adipogenic gene expression. Additionally, consumption of low-dose IJE significantly enhanced endurance capacity via increasing AMP-activated protein kinase activity and mRNA levels of Myh7 and Myh2. Luteolin and 1β-hydroxyalantolactone (1β-HA), compounds of IJE, are involved in anti-adipogenesis in the 3T3-L cells and only luteolin increased the protein levels of MHC during C2C12 myoblast differentiation. Collectively, our results suggest that consumption of IJE not only helps to prevent obesity but also enhances endurance capacity reduced by HFD., Competing Interests: The authors declare no conflict of interest.

Aims/hypothesis: The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes., Methods: Obese (BMI ≥30 kg/m 2 ) individuals without diabetes (n = 91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant)., Results: There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group (p = 0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles (p < 0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8-36.3] mmol/l × h) and insulin responses (1711 [1476-2223] mmol/l × h) compared with the SSPG-1 group (30.3 [28.8-32.9] mmol/l × h, p = 0.04, and 851 [600-1057] pmol/l × h, p < 0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR (p < 0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41-0.59]; SSPG-2, 0.43 [0.39-0.50]; SSPG-3, 0.34 [0.31-0.40])., Conclusions/interpretation: While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.

Scope: It was investigated whether apigenin (AP) protected against skeletal muscle atrophy induced by obesity., Methods and Results: Mice were fed a high-fat diet (HFD) for 9 weeks to induce obesity, and then were assigned to two groups; the HFD group received a high-fat diet, and the HFD+AP group received a 0.1% AP-containing HFD. After additional feeding of the experimental diet for 8 weeks, mice in the HFD group were highly obese compared with the mice in the standard diet fed mice group. The mice in the AP-treated group showed less fat pad accumulation and less inflammatory cytokines without body weight reduction. The weight of skeletal muscle in the AP group tended to increase as compared with that of the HFD group. Furthermore, AP reduced the expression of atrophic genes, including MuRF1 and Atrogin-1, but increased the exercise capacity. The mitochondrial function and mitochondrial biogenesis were enhanced by AP. In cultured C2C12 cells, AP also suppressed palmitic acid-induced muscle atrophy and mitochondrial dysfunction. In addition, AP activated AMP-activated protein kinase (AMPK) in the C2C12 and the muscle of HFD-induced obese mice., Conclusion: The results suggested that AP ameliorated the obesity-induced skeletal muscle atrophy by attenuating mitochondrial dysfunction., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: Metabolically healthy obese (MHO) phenotype describes an obese state with a favorable metabolic profile. However, the prognosis of this subpopulation remains controversial. We aimed to examine whether MHO phenotype is associated with progression of atherosclerotic activity, reflected as the changes in coronary artery calcification (CAC) over time. If so, we sought to determine the role of fatty liver disease (FLD), the hallmark of hepatic steatosis, in this progression., Methods: We enrolled 1,240 asymptomatic subjects who underwent repeated CAC score measurement during routine health examinations. CAC score progression was defined as either incident CAC in a population free of CAC at baseline, or an increase by ≥2.5 units between the baseline and final square root of CAC scores in participants with detectable CAC at baseline. Subjects were stratified by body mass index (cut-off, 25.0 kg/m2) and metabolic health state using Adult Treatment Panel-III criteria. FLD was assessed via ultrasonography., Results: Over 2.9 years of follow-up, 25.2% of total subjects exhibited CAC score progression. The MHO phenotype was not significantly associated with CAC score progression (multivariate adjusted-odds ratio [OR], 1.45; 95% confidence interval [CI], 0.93-2.25), as compared to the metabolically healthy non-obese (MHNO) phenotype. However, subgroup analysis indicated that the MHO/FLD phenotype was significantly associated with CAC score progression (multivariate adjusted-OR, 2.37; 95% CI, 1.34-4.16), as compared to the MHNO/no FLD phenotype, whereas the MHO/no FLD phenotype was not (multivariate adjusted OR, 1.25; 95% CI, 0.71-2.24)., Conclusions: Obese individuals with FLD have an increased risk of atherosclerosis progression, despite their healthy metabolic profile. Preventive interventions targeting cardiometabolic risk factors should be considered in such individuals, regardless of the weight status.

Background: In contrast to type 2 diabetes, the association of body mass index (BMI) with glycemic control in type 1 diabetes (T1D) remains unclear. We investigated the relationship between BMI and average HbA 1c levels in subjects with T1D., Method: In this multi-centre observational study, we analysed 719 subjects with T1D aged ≥18 years. Average HbA 1c levels over 18 months and other clinical and laboratory parameters were evaluated., Results: The mean age and duration of diabetes at baseline were 41.5 ± 13.9 and 11.3 ± 8.7 years, respectively. A U-shaped correlation between BMI and 18-month average HbA 1c levels was documented by a spline curve. Based on this finding, subjects were divided into three groups according to BMI (group I, <21; group II, 21-23; and group III, ≥23 kg/m 2 ). In group I, the BMI negatively correlated with average HbA 1c (r = -0.172, p = 0.011), while a positive relationship was observed (r = 0.162, p = 0.012) in group III. Average HbA 1c levels were lower and the proportion of individuals with well-controlled glycemia (HbA 1c <7%) were increased in the higher BMI tertile group among subjects with group I as well as in the lower BMI tertile group among subjects with group III BMI. After adjustment with additional covariates in the multiple regression model, these associations between BMI and HbA 1c levels according to the different BMI ranges remained significant., Conclusions: In Korean subjects with T1D, an inverse relationship of BMI with HbA 1c levels was observed in the low BMI group, while a positive correlation was shown in the high BMI group. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

There has been great interest in the browning of fat for the treatment of obesity. Although β-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet. Consistently, BLC-treated mice showed significantly higher energy expenditure compared with control mice. In vitro, BLC increased the expression of brown adipocyte-specific genes in stromal vascular fraction-differentiated adipocytes. BLC also controlled the expression of miR-382, which led to the upregulation of its direct target, Dio2. Upregulation of miR-382 markedly inhibited the differentiation of adipocytes into beige adipocytes, whereas BLC recovered beige adipocyte differentiation and increased the expression of Dio2 and UCP1. Our findings suggest that the BLC-mediated increase in the browning of WAT and the thermogenic capacity of BAT significantly results in increases in energy expenditure. Browning of WAT by BLC was partially controlled via the regulation of miR-382 targeting Dio2 and may lead to the prevention of diet-induced obesity., (© 2016 by the American Diabetes Association.)

Objective: Metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value remains controversial and may partly depend on differences in how the phenotype is defined. We aimed to investigate whether the MHO phenotype is associated with future development of incident hypertension in a Korean population according to various definitions of metabolic health., Subjects and Methods: The study population comprised 31 033 Koreans without hypertension. Participants were stratified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) by body mass index (cut-off value, 25·0 kg/m(2) ) and metabolic health state, using four different definitions: Adult Treatment Panel (ATP)-III, Wildman, Karelis and the homoeostasis model assessment (HOMA) criteria., Results: Over the median follow-up period of 35·0 months (range, 4·5-81·4 months), 4589 of the 31 033 individuals (14·8%) developed incident hypertension. Compared with the MHNO group, the MHO group showed increased association with incident hypertension with multivariate-adjusted odds ratios of 1·56 (95% confidence interval [CI], 1·41-1·72), 1·58 (95% CI 1·42-1·75), 1·52 (95% CI 1·35-1·71) and 1·46 (95% CI 1·33-1·61), when defined by ATP-III, Wildman, Karelis and HOMA criteria, respectively., Conclusion: MUO individuals showed the highest association with the incident hypertension (adjusted odds ratios up to 2·00). MHO subjects showed an approximately 1·5-fold higher association with incident hypertension than their nonobese counterpart regardless of the definition of metabolic health used. Thus, considering both metabolic health and obesity is important for the assessment of potential cardiovascular outcomes., (© 2016 John Wiley & Sons Ltd.)

Objective: This study sought to investigate whether the metabolically healthy obese (MHO) phenotype is associated with an increased risk of incident type 2 diabetes in a Korean population and, if so, whether systemic inflammation affects this risk in MHO individuals., Design and Methods: The study population comprised 36 135 Koreans without type 2 diabetes. Participants were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). High-sensitive C-reactive protein (hsCRP) was used as a surrogate marker of systemic inflammation. Subjects were classified into low (ie, hsCRP < 0.5 mg/L) and high (ie, hsCRP ≥ 0.5 mg/L) systemic inflammation groups., Results: During a median followup of 36.5 months (range, 4.8-81.7 mo), 635 of the 36 135 individuals (1.8%) developed type 2 diabetes. The MHO group had a significantly higher risk of incident type 2 diabetes (multivariate-adjusted hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16-2.11) than the metabolically healthy nonobese (MHNO) group. However, the risk of the MHO group varied according to the degree of systemic inflammation. Compared with the MHNO/low systemic inflammation group, the risk of type 2 diabetes in the MHO/low systemic inflammation group was not significantly elevated (multivariate-adjusted HR, 1.61; 95% CI, 0.77-3.34). However, the MHO/high systemic inflammation group had an elevated risk of incident type 2 diabetes (multivariate-adjusted HR, 3.73; 95% CI 2.36-5.88)., Conclusions: MHO subjects show a substantially higher risk of incident type 2 diabetes than MHNO subjects. The level of systemic inflammation partially explains this increased risk.

Objective: The degree of subclinical coronary atherosclerosis detected by coronary multidetector computed tomography (MDCT) in four groups defined by the state of metabolic health and obesity in an asymptomatic Korean population was compared., Methods: The data of 4009 asymptomatic subjects who participated in a routine health screening examination were collected. Significant coronary artery stenosis defined as >50% stenosis, plaque, and coronary artery calcium scores (CACS) were assessed by MDCT. Participants were stratified by BMI (cut-off value, 25 kg/m(2) ) and metabolically healthy state, which was defined by Wildman criteria., Results: Metabolically healthy obese (MHO) subjects had a significantly higher prevalence of significant subclinical coronary atherosclerotic burden compared with metabolically healthy nonobese (MHNO) subjects. The adjusted odds ratios of the MHO group for various coronary MDCT findings (MHNO group as the reference), such as coronary artery stenosis, any plaque, calcified plaque, mixed plaque, CACS > 0, and CACS > 100, were 1.87 (95% CI 1.15-3.03), 1.31 (1.01-1.71), 1.40 (1.05-1.86), 1.57 (1.01-2.48), 1.38 (1.04-1.82), and 1.69 (1.03-2.78), respectively., Conclusions: Our data illustrate that MHO subjects have substantial subclinical coronary atherosclerotic burden. Thus, it is important to consider the metabolic health state and obesity in evaluating cardiovascular risk., (© 2014 The Obesity Society.)

Scope: Lipid homeostasis in vertebrates is regulated at many levels including synthesis, degradation, and distribution. MicroRNAs (miRNAs) are key regulators of lipid homeostasis. The use of phytochemicals to target miRNA (miR) could provide new therapeutic approaches to human diseases. Thus, we investigated the regulation of lipid metabolism by the flavonoid fisetin during experimental analysis of hepatic miRs in mice., Methods and Results: Mice were separated into three groups. One group was maintained on the normal diet and the other two groups were fed either a high-fat (HF) diet or HF supplemented with fisetin. We found that fisetin lowered hepatic fat accumulation in HF mice and reversed abnormal expressions of lipid metabolism genes. The co-expression of miR-378 and its host gene PGC-1β was significantly induced by HF, whereas fisetin prevented the induction of both genes. We also identified nuclear respiratory factor-1 (NRF-1), a critical regulator of the mitochondrial function, as a direct target of miR-378., Conclusion: Dietary fisetin protects against hepatosteatosis in association with modulation of lipid metabolism genes and miR-378 in mice. These observations suggest that the use of fisetin to target miRs could be an effective prevention or intervention against metabolic diseases., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties. In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis. To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes. Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells. The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner. Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity. Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR. The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling. Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue. We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue. Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice. Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The rapidly increasing prevalence of obesity confers a huge health burden globally. The hypothalamus plays a central role in the regulation of energy homeostasis by integrating multiple metabolic signals from peripheral organs and modulating feeding behavior and energy metabolism. Leptin, a key appetite-regulating hormone derived from the white adipose tissue, primarily acts on hypothalamic neurons to activate catabolic pathway and inhibit anabolic pathway, which can result in anorexia and weight reduction. Despite striking obesity resulting from leptin deficiency, treatment with this hormone in human obesity has been unsuccessful due to leptin resistance. In this review, we describe recent researches extending our understanding of obesity-associated hypothalamic leptin resistance.

To understand the molecular mechanisms underlying the influence of quercetin on the physiological effects of hyperlipidemia, we investigated its role in the prevention of high-fat diet (HFD)-induced obesity and found that it regulated hepatic gene expression related to lipid metabolism. Quercetin supplementation in mice significantly reduced the HFD-induced gains in body weight, liver weight, and white adipose tissue weight compared with the mice fed only with HFD. It also significantly reduced HFD-induced increases in serum lipids, including cholesterol, triglyceride, and thiobarbituric acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic lipid accumulation and the size of lipid droplets in the epididymal fat pads were also reduced by quercetin supplementation. To further investigate how quercetin may reduce obesity, we analyzed lipid metabolism-related genes in the liver. Quercetin supplementation altered expression profiles of several lipid metabolism-related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Acaca, Cd36, Fdft1, and Fasn, relative to those in HFD control mice. The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Collectively, our results indicate that quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be related to the regulation of lipogenesis at the level of transcription., (Copyright © 2012 John Wiley & Sons, Ltd.)

Although Alpinia officinarum has been used in traditional medicine for the treatment of several conditions, such as abdominal pain, emesis, diarrhea, impaired renal function, and dysentery, little is known about its function in obesity. In this study, we investigated the antiobesity effect of A. officinarum ethanol extract (AOE) on lipid accumulation in 3T3-L1 cells and obesity in mice fed a high-fat diet (HFD). AOE dose-dependently suppressed lipid accumulation during differentiation of 3T3-L1 preadipocytes by downregulating CCAAT enhancer binding protein α (C/EBPα), sterol regulatory element binding protein-1 (SREBP-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) genes. Galangin, a major component of A. officinarum, had antiadipogenic effects in 3T3-L1 cells. AOE supplementation in mice fed a HFD revealed that AOE significantly decreased HFD-induced increases in body, liver, and white adipose tissue weights and decreased serum insulin and leptin levels. To elucidate the inhibitory mechanism of AOE in obesity, lipid metabolism-related genes were identified. AOE efficiently suppressed protein expressions of C/EBPα, fatty acid synthase, SREBP-1, and PPAR-γ in the liver and adipose tissue. The protein expression patterns, observed by immunoblot, were confirmed by quantitative real-time polymerase chain reaction. Collectively, these results suggest that AOE prevents obesity by suppressing adipogenic and lipogenic genes. AOE has potential for use as an antiobesity therapeutic agent that can function by regulating lipid metabolism.