Obesity,metabolic health and omics:Current status and future directions

The growing obesity epidemic is becoming a major public health concern,and the associated costs represent a considerable burden on societies.Among the most common complications of severe obesity are the development of hypertension,dyslipidemia,type 2 diabetes,cardiovascular disease,and various types of cancer.Interestingly,some obese individuals have a favorable metabolic profile and appear to be somehow protected from the detrimental effects of excessive adipose tissue accumulation.These individuals remain normoglycemic,insulin sensitive,and hypotensive with proper blood lipid levels,despite their high body mass index and/or waist circumference.Multiple independent observations have led to the concept of the metabolically healthy obese(MHO) phenotype,yet no consensus has been reached to date regarding a universal definition or the main mechanism behind this phenomenon.Recent technological advances and the use of high-throughput analysis techniques have revolutionized different areas of biomedical research.A multi-omics approach,which is used to investigate changes at different molecular levels in an organism or tissue,may provide valuable insights into the interplay between the molecules or pathways and the roles of different factors involved in the mechanisms underlying metabolic health deterioration.The aim of this review is to present the current status regarding the use of omics technologies to investigate the MHO phenotype,as well as the results of targeted analyses conducted in MHO individuals.

Metabolically healthy obesity:Is it really healthy for type 2 diabetes mellitus?

Metabolically healthy obese(MHO)individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome.However,the association between MHO and type 2 diabetes(T2DM)is still controversial.Some studies indicated that MHO is a favorable phenotype for T2DM,but more studies showed that MHO individuals have an increased risk of developing T2DM compared with metabolically healthy normalweight individuals,especially among those who would acquire metabolically unhealthy obesity.This has been supported by finding insulin resistance and lowgrade inflammatory responses in MHO individuals with a tendency for impaired beta-cell dysfunction.Studies also showed that liver fat accumulation increased the risk of incidence of T2DM in MHO.Here,we reviewed current literature on the relationship between MHO and T2DM,discussed the determinants for the development of diabetes in MHO,and summarized the measures for the prevention of T2DM in MHO.

Comparative Study of Inflammatory and Oxidative Stress Biomarkers in Different Metabolically Healthy Obesity Phenotypes

Aims: Obesity is the major contributor of the metabolic syndrome (MetS), but a unique phenotype of obesity known as metabolically healthy obese (MHO) shows healthier metabolic profile; however understanding of their biochemical correlates is poorly understood. Obesity is defined by Body mass index (BMI), but controversy exists regarding ethnic-specific BMI cut-offs. The present study used the Asian Indian BMI cut-offs to assess relationships of MHO phenotypes with oxidative stress (OS) and inflammation. Methods: In this case-control study, 299 metabolically-healthy (MH) respondents were divided into four groups as per Asian criteria for obesity: MH non-obese (MHNO), MH overweight (MHOW), MHO and MH severely obese (MHSO). Their oxidative stress and pro-inflammatory markers were measured. Results: Levels of hydroxyl radicals (·OH), fluorescent oxidation products (FLOP), MDA, PCO and inflammatory markers CRP, TNF-α, IL-6 were highest in MHSO phenotype followed by the MHO, MHOW and MHNO groups (p > 0.0001), whereas antioxidant markers, CuZn-SOD, catalase, glutathione peroxidase and total antioxidant activity followed the reverse trend. The MHNO and MHOW groups showed significant difference with regard to (·OH) radicals and FLOP. Moreover, ·OH radicals, FLOP and inflammatory markers were significantly correlated to BMI in MHSO and MHO but not in MHNO and MHOW group. Conclusion: The MHO and MHSO phenotype display differences in terms of OS and inflammatory markers at lower BMI cut-offs, indicating that they may be on the way to becoming “unhealthy” obese. The lower BMI cut-offs proposed by Indian Consensus Group would help in understanding of manifestation of metabolic syndrome.

Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders

Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders.These people store fat in subcutaneous adipose tissue(SAT)rather than in visceral adipose tissue(VAT).However,the molecules participating in this specific scenario remain elusive.Rab18,a lipid droplet(LD)-associated protein,mediates the contact between the endoplasmic reticulum(ER)and LDs to facilitate LD growth and maturation.In the present study,we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice.Rab18 adipocyte-specific knockout(Rab18 AKO)mice had a decreased volume ratio of SAT to VAT compared with wildtype mice.When subjected to high-fat diet(HFD),Rab18 AKO mice had increased ER stress and inflammation,reduced adiponectin,and decreased triacylglycerol(TAG)accumulation in SAT.In contrast,TAG accumulation in VAT,brown adipose tissue(BAT)or liver of Rab18AKO mice had a moderate increase without ER stress stimulation.Rab18 AKO mice developed insulin resistance and systematic inflammation.Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT,similar to the counterpart mice.Furthermore,Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress,indicating the involvement of Rab18 in alleviating lipid toxicity.Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT.In conclusion,our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

Elevated thyroid stimulating hormone levels are associated with metabolic syndrome in a Chinese community-based population of euthyroid people aged 40 years and older

This study investigated whether high-normal thyrotropin（TSH） levels are associated with metabolic syndrome in euthyroid Chinese people≥40 years old.Clinical and metabolic factors were assessed in 2,356 subjects（40-77 years old） with TSH levels in the normal range（0.35-5.00 mU/L）.Using 2.50 mU/L as the cut-off point of TSH level within the normal range,we divided subjects into the high-TSH（2.50-5.00 mU/L;n= 1,064） and low-TSH（0.35-2.50mU/L;n= 1,292） group.The results showed that the mean levels of body mass index（BMI）,total cholesterol（TC）,low density lipoprotein cholesterol（LDL-C）,and fasting plasma glucose（FPG） were higher in the high-TSH group and TSH levels were significantly positively con-elated with BMI,LDL-C,TC,and FPG.The prevalence of central obesity,hypertriglyceridemia,low high density lipoprotein cholesterol（HDL-C）,and high FPG（〉5.60 mmol/L） was significantly higher in females and subjects with high-TSH levels.Metabolic syndrome was also more prevalent in the high-TSH group.People over the age of 40 years with high-normal TSH levels had a 1.2-fold increased risk of metabolic syndrome,compared with those with low-normal TSII levels,after adjusting for age and gender.In conclusion,high normal TSH is a risk factor for metabolic syndrome in people ≥40 years old.

White adipose tissue browning and obesity

Obesity and metabolic disorders are major health concems worldwide. Although a range of therapies have been developed, these pharmaceutical treatments often have adverse side effects or limited efficacy. Therefore, there is a growing need of novel therapeutics to prevent or treat obesity. Obesity is thought to be caused by an imbalance between energy intake and energy consumption. Increasing energy consumption is considered as a potential therapeutic strategy to treat obesity and its related disorders.

Prevalence of Metabolic Obese Normal Weight and Related Risk Factors in South China

[Objectives]Metabolic obese normal weight(MONW)is becoming one of the pubic problems which are threatening human health.Whereas,MONW was facing a great challenge for limited attention,especially for the female in China.The aim of this research was to estimate the prevalence of MONW and its related risk components in South China.[Methods]A community-based cross-sectional study was performed on 3349 residents aged 18-93 years in The First Affiliated Hospital of Jinan University,Guangzhou,China,in 2019.Data was collected by physical examination data which included physical measurements and laboratory examinations.[Results]In all subjects,55%were females(M/F=1509/1840).The prevalence of MONW was 16.09%(0.04%for male,16.05%for female,P<0.001).The prevalence increased significantly with increasing age in both genders(P<0.001).The binary logistic regression analysis shows that among the risk factors with MONW,age,BMI,gender,systolic pressure,hypertension[Male:ORs=2.56,95%CI(1.23,5.32);Female:ORs=2.88,95%CI(1.76,4.71)]and hypertriglyceridemia[Male:ORs=3.23,95%CI(1.67,6.19);Female:ORs=2.57,95%CI(1.64,4.03)]were found to be statistically significant.The level of ALT in MONW group was(27.88±15.85)in male and(24.33±15.75)in female,which were significantly higher than those in the non-MetS group.[Conclusions]The prevalence of MONW was pretty high.We considered MONW be significantly associated with the increase of ALT.Female gender,advanced age,and elevated ALT were independent risk factors for MONW.It was high time that the government should raise the public attention toward metabolic function in normal weight population.Effective prevention and treatment strategies for MONW and its risk factors should be developed targeting different ages and genders.

Opposite fates of fructose in the development of metabolic syndrome

This short review comments on the recently published work of Ishimoto et al regarding the opposing effects of fructokinase C and A isoforms on fructoseinduced metabolic syndrome in mice. The framework for the commentary is the preexisting background of epidemiological and experimental data regarding the association between ingestion of fructose, as present in sweetened beverages, and the development of metabolic syndrome. The work of Ishimoto et al clearly confirms the negative effect of fructose on lipid and glucose metabolism, independently from the amount of energy provided by the ingested sugar. It also confirms the absolute requirement of liver fructose metabolism, driven by fructokinase activity, in order to develop the full spectrum of metabolic syndrome alterations.

Effects of Maternal Linseed Oil Supplementation on Metabolic Parameters in Cafeteria Diet-induced Obese Rats

Because linseed oil may influence maternal and fetal metabolisms, we investigated its role in the modulation of lipid metabolism in cafeteria diet-induced obese rats and their offspring. Female Wistar rats were fed control or cafeteria food, which were either supplemented or not supplemented with linseed oil （5%） for I month before and during gestation. At parturition, serum and tissue lipids and enzyme activities were analyzed. Cafeteria diet induced adverse metabolic alterations in both mothers and offspring. Linseed oil improved metabolic status. In conclusion, linseed oil displayed health benefits by modulating tissue enzyme activities in both obese mothers and their newborns.

Apolipoprotein E in diet-induced obesity:a paradigm shift from conventional perception

Apolipoprotein E（APOE） is a major protein component of peripheral and brain lipoprotein transport systems.APOE in peripheral circulation does not cross the blood brain barrier or blood cerebrospinal fluid barrier. As a result,peripheral APOE expression does not affect brain APOE levels and vice versa. Numerous epidemiological studies suggest a key role of peripherally expressed APOE in the development and progression of coronary heart disease while brain APOE has been associated with dementia and Alzheimer＇s disease. More recent studies, mainly in experimental mice, suggested a link between Apoe and morbid obesity. According to the latest findings, expression of human apolipoprotein E3（APOE3） isoform in the brain of mice is associated with a potent inhibition of visceral white adipose tissue（WAT） mitochondrial oxidative phosphorylation leading to significantly reduced substrate oxidation,increased fat accumulation and obesity. In contrast, hepatically expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. These novel findings constitute a major paradigm shift from the widely accepted perception that APOE promotes obesity via receptor-mediated postprandial lipid delivery to WAT. Here, we provide a critical review of the latest facts on the role of APOE in morbid obesity.

Increased BMR in Overweight and Obese Patients with Type 2 Diabetes may Result from an Increased Fat-free Mass

The study aimed to determine the relationships between the basal metabolic rate（BMR） and body composition of overweight and obese Chinese adults with type 2 diabetes mellitus（DM）. This cross-sectional clinical study enrolled 193 Chinese adults with type 2 DM who were overweight（24 kg/m2≤BMI〈28 kg/m2, n=99）, or obese（BMI ≥28 kg/m2, n=94）. Ninety-seven adults with normal BMIs, including 50 DM patients and 47 healthy adults, were recruited as a control group. BMR was measured by indirect calorimetry; predicted BMR was calculated according to the Schofield equation; and the relationships between BMR, body composition, and biochemical results were determined by the Pearson correlation. The results showed that obese DM patients had significantly higher BMRs than both overweight patients（P〈0.05） and patients with normal BMI did（P〈0.05）. The measured BMR was significantly lower than the predicted BMR（P〈0.05） in all groups. Obese and overweight DM patients had significantly greater weight, waist circumference, hip circumference, BMI, body surface area, body fat percentage, fat mass, and fat-free mass than patients with normal BMI. Except for waist circumference, these body composition measurements were significantly increased in obese DM patients when compared with those in overweight DM patients（P〈0.05）. Fat-free mass was closely correlated with BMR in both DM patients（r=0.874, P〈0.01） and in healthy controls（r=0.902, P〈0.01）. It was concluded that overweight and obese Chinese adults with type 2 DM had increased BMRs compared with normal-weight controls, which may result from the difference in fat-free mass.

Comparison of efficacy of treating obese patients with endocrine-metabolic abnormity by electroacupuncture of different types of wave modes

Objective To compare the efficacy of treating obese patients with abnormity of lipids and serum leptin by dilatational wave or continuous wave of electroacupuncture combined with thunder-fire moxibustion in order to provide a clinical basis for selecting wave types of electroacupuncture for different patterns of obesity. Methods Sixty obese patients with abnormal lipids and serum leptin were randomly divided into a dilatational wave group and a continuous wave group via random number table, with 30 cases in each group. They were divided by TCM differentiation into three types： stomachintestine excessive heat, weakness of the spleen-stomach and spleen-kidney yang deficiency, treated by electroacupuncture on Tianshu （天枢 ST 25）, Daheng （大横 SP 15）, Zusanli （足三里ST 36）, Shangjuxu （上巨虚 ST 37）, Fanglong （丰隆 ST 40）, Yinlingquan （阴陵泉 SP 9）, Quchi （曲池 LI 11）, Zhigou （支沟 TE 6） and Hegu （合谷 LI 4） along with thunder-fire moxibustion. The frequency of electro-acupuncture in the dilatational wave group and the continuous wave group was 2 Hz/100 Hz and 2 Hz, respectively. Patients in the two groups were treated once a day, six times a week. The treatment lasted for 4 weeks with 3-month follow-up. Body mass and body fat percentage before and after the treatment, as well as during the follow-up, were compared. The effectiveness rates in the two groups were compared, and the efficacy statistics of patients with different TCM patterns in the dilatational wave group were also analyzed. Lipid levels of the patients in two groups before and after the treatment were measured with an automatic biochemical analyzer, and serum leptin levels were detected with flow cytometry system. Results After the treatment, the patients＇ blood lipids, serum leptin levels, body mass and body fat percentage were effectively reduced in the two groups; three months＇ follow-up witnessed continuous decline of obesity indicators （P〈0.01 or P〈0.05）, and patients in the dilatat-ional wave group improved more significantly than those in continuous wave group （P〈0.05 or P〈0.01）. The efficacy in the dilatational wave group was superior to that in the continuous wave group （P〈0.01）. The best efficacy could be found among patients with weakness of the spleen and the stomach in the dilatational wave group. Conclusion Efficacy of treating obese patients with abnormity of lipids and serum leptin by electro-acupuncture combined with thunder-fire moxibustion in the dilatational wave group was significantly better than that of the continuous wave group, and efficacy for obese patients with weakness of the spleen and the stomach was superior to that of those with stomach-intestine excessive heat and spleen-kidney yang deficiency.

Metabolic syndrome in non-obese Taiwan Residents： new definition of metabolically obese, normal-weight individual

Background Not only the obese, but also the non-obese adults have the high prevalence of metabolic syndrome in the upper normal weight. The aim of this study was to assess the prevalence rates of metabolic syndrome and its individual components in non-obese adult Taiwan Residents （body mass index （BMI） ≤ 26.9 kg/m^2）. Methods A cross-sectional study was conducted from January 2006 to December 2007. One thousand six hundred and fifty-nine subjects （aged 47.5±12.4 years）, 60.8% of which were men, were enrolled. The prevalence and odds ratios of metabolic syndrome, defined by the American Heart Association/National Heart, Lung and Blood Institute （2005）, were analyzed in the BMI category according to 2.0 unit increments, in individuals seeking a health examination. Results The higher the BMI categories, the more prevalent the metabolic syndrome was in women and in men （P 〈0.001）. Compared with those women with a BMI ≤20.9 kg/m^2, the odds ratios for metabolic syndrome in women were 1.3 （95% CI： 0.5-3.2） with BMI 21.0-22.9 kg/m^2, 3.0 （1.3-7.1） with BMI 23.0-24.9 kg/m^2, and 8.6 （3.6-20.8） for women with BMI 25.0-26.9 kg/m^2, after controlling for age, smoking status, alcohol consumption, betel nut chewing, blood routine, biochemical data, hepatitis B virus surface antigen and anti-hepatitis C virus. The corresponding odds ratios in men were 1.6 （0.6-4.2）, 3.7 （1.6-8.8）, and 9.9 （4.2-23.2）. Conclusions Individuals in the upper normal weight and slightly overweight BMI range have relatively high prevalence and increased risk of having metabolic syndrome. Therefore, physicians should screen metabolic syndrome in not only obese but also non-obese individuals for the prevention of cardiovascular disease.

Prediction of Metabolic Disorders Using NMR-Based Metabolomics:The Shanghai Changfeng Study

A metabolically healthy status,whether obese or not,is a transient stage with the potential to develop into metabolic disor-ders during the course of life.We investigated the incidence of metabolic disorders in 1078 metabolically healthy Chinese adults from the Shanghai Changfeng Study and looked for metabolites that discriminated the participants who would develop metabolic disorders in the future.Participants were divided into metabolically healthy overweight/obesity(MHO)and meta-bolically healthy normal weight(MHNW)groups according to their body mass index(BMI)and metabolic status.Their serum metabolomic profile was measured using a ^(1)H nuclear magnetic resonance spectrometer(^(1)H-NMR).The prevalence of diabetes,hypertriglyceridemia,hypercholesterolemia and metabolic syndrome was similar between the MHNW and MHO participants at baseline.After a median of 4.2 years of follow-up,more MHO participants became metabolically unhealthy than MHNW participants.However,a subgroup of MHO participants who remained metabolically healthy(MHO→MHO)had a similar prevalence of metabolic disorders as the MHNW participants at the follow-up examination,despite a signifi-cant reduction in their serum concentrations of high-density lipoprotein(HDL)and an elevation in valine,leucine,alanine and tyrosine.Further correlation analysis indicated that serum intermediate-density lipoprotein(IDL)and very low-density lipoprotein cholesterol(VLDL-CH)might be involved in the transition from metabolically healthy to unhealthy status and could be valuable to identify the MHNW and MHO with increased metabolic risks.

Nonalcoholic fatty liver disease in lean subjects:is it all metabolic-associated fatty liver disease?

The epidemiology of nonalcoholic fatty liver disease goes hand-in-hand with the obesity pandemic.The pathogenesis of fatty liver has shifted from an hepatocentric view to an adipocentric view,in which the overloaded adipose tissue spills out lipids that spread to ectopic tissues and organs such as the liver,elicits inflammation,and changes its adipokines profile promoting insulin resistance and the metabolic syndrome.Up to 40%of nonalcoholic fatty liver disease(NAFLD)patients are not obese and up to 20%are actually lean.Furthermore roughly 10%of lean subjects have NAFLD.In fact,adiposopathy can occur in patients with normal weight,and it is associated with expansion of metabolically active visceral fat and a qualitatively different adipose tissue that becomes overwhelmed after challenged by a mildly positive energy balance.This defines the concept of personal fat threshold that when exceeded results in metabolic dysfunction.Overweight/obese persons have higher probability of exceeding that threshold,explaining why adiposopathy/metabolic syndrome/NAFLD is more frequent in the obese.In this article,the epidemiology,pathogenesis,and management of patients with lean NAFLD are reviewed with an emphasis on reconciling the concepts of NAFLD in its relationship with adiposity and of NAFLD in lean individuals.

Effects of acute or prolonged exposure to leptin on hepatic glucose oxidation

Objective To observe the short-term and long-term effects of leptin on hepatic glucose oxidation and glucokinase gene expression. Methods Rat hepatic cell line BRL was incubated with leptin of different doses (range from 10?ng/ml-200?ng/ml) for 1?h or 24?h. Glucose oxidation was determined by liquid scintillation counting. Glucokinase gene expression (corrected by β-actin) was determined by reverse transcription semi-quantitative polymerase chain reaction. Results Treatment with leptin 10?ng/ml for 1?h had no significant effects on glucose oxidation in hepatic cells. However, at the doses ranging from 50?ng/ml to 200?ng/ml, leptin significantly inhibited glucose oxidation. These effects disappeared when the hepatic cells were exposed to leptin for 24?h. Glucokinase mRNA expression was reduced significantly after both 1?h and 24?h exposure to leptin (100?ng/ml) as compared to that of the control group. Conclusion A low dose of leptin has no significant effect on glucose oxidation in hepatic cells. A relatively high dose of leptin has an acute inhibitory effect on the glucose oxidation in hepatic cells. This effect may likely involve the inhibition of glucokinase gene expression. The inhibitory effect on glucose oxidation is transient and disappears with prolonged exposure time.

Factors influencing glucose metabolism in young obese subjects with obstructive sleep apnea hypopnea syndrome

Objective To explore the factors influencing glucose metabolism in young obese subjects with obstructive sleep apnea hypopnea syndrome(OSAHS).Methods A total of 106 young obese subjects[18-44 years old,body mass index(BMI)≥30 kg/m^2]were enrolled and divided into two groups based on full-night polysomnography(PSG),OSAHS group[apnea hypopnea index(AHI)