Association between Metabolically Healthy Status and Risk of Gastrointestinal Cancer.

PURPOSE: Although obesity is associated with numerous diseases, the risks of disease may depend on metabolically healthy status. Nevertheless, it is unclear to whether metabolically healthy status affects risk of gastrointestinal (GI) cancer in general Chinese population. MATERIALS AND METHODS: A total of 114,995 participants who met the criteria were included from the Kailuan Study. The study participants were divided into four groups according to body mass index (BMI)/waist circumference (WC) and metabolic status. Incident of GI cancer (esophageal cancer, gastric cancer, liver cancer, biliary cancer, pancreatic cancer, and colorectal cancer) during 2006-2020 were confirmed by review of medical records. The Cox proportional hazard regression models were used to assess the association metabolically healthy status with the risk of GI cancer by calculating the hazard ratios (HR) and 95% confidence interval (CI). RESULTS: During a mean 13.76 years of follow-up, we documented 2,311 GI cancers. Multivariate Cox regression analysis showed that compared with the metabolically healthy normal-weight group, metabolically healthy obese (MHO) participants demonstrated an increased risk of developing GI cancer (HR, 1.54; 95% CI, 1.11 to 2.13) by BMI categories. However, such associations were not found for WC category. These associations were moderated by age, sex, and anatomical site of the tumor. Individuals with metabolic unhealthy normal-weight or metabolic unhealthy obesity phenotype also have an increased risk of GI cancer. CONCLUSION: MHO phenotype was associated with increased risk of GI cancer. Moreover, individuals who complicated by metabolic unhealthy status have an increased risk of developing GI cancer. Hence, clinicians should consider the risk of incident GI cancer in people with abnormal metabolically healthy status and counsel them about metabolic fitness and weight control.

Natural course of metabolically healthy phenotype and risk of developing Cardiometabolic diseases: a three years follow-up study.

BACKGROUND: Whether the metabolically healthy obese (MHO) phenotype is a single, stable or a transitional, fluctuating state is currently unknown. The Mexican-Mestizo population has a genetic predisposition for the development of type 2 diabetes (T2D) and other cardiometabolic complications. Little is known about the natural history of metabolic health in this population. The aim of this study was to analyze the transitions over time among individuals with different degrees of metabolic health and body mass index, and evaluate the incidence of cardiometabolic outcomes according to phenotype. METHODS: The study population consisted of a metabolic syndrome cohort with at least 3 years of follow up. Participants were apparently-healthy urban Mexican adults ≥20 years with a body mass index (BMI) ≥20 kg/m2. Metabolically healthy phenotype was defined using the criteria of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) metabolic syndrome criteria and the subjects were stratified into 4 groups according to their BMI and metabolic health. For cardiometabolic outcomes we estimated the incidence of cardiometabolic outcomes and standardized them per 1, 000 person-years of follow-up. Finally, to evaluate the risk for transition and development of cardiometabolic outcomes, we fitted Cox Proportional Hazard regression models. RESULTS: Amongst the 5541 subjects, 54.2% were classified as metabolically healthy and 45.8% as unhealthy. The MHO prevalence was 39.3%. Up to a third of the population changed from their initial category to another and the higher transition rate was observed in MHO (42.9%). We also found several novel factors associated to transition to metabolically unhealthy phenotype; socioeconomic status, number of pregnancies, a high carbohydrate intake, history of obesity and consumption of sweetened beverages. Similarly, visceral adipose tissue (VAT) was a main predictor of transition; loss of VAT ≥5% was associated with reversion from metabolically unhealthy to metabolically healthy phenotype (hazard ratio (HR) 1.545, 95%CI 1.266-1.886). Finally, we observed higher incidence rates and risk of incident T2D and hypertension in the metabolically unhealthy obesity (MUHO) and metabolically unhealthy lean (MUHL) phenotypes compared to MHO. CONCLUSIONS: Metabolic health is a dynamic and continuous process, at high risk of transition to metabolically unhealthy phenotypes over time. It is imperative to establish effective processes in primary care to prevent such transitions.

Association between metabolically healthy obesity/overweight and cardiovascular disease risk: A representative cohort study in Taiwan.

OBJECTIVES: To investigate the relationship between metabolically healthy obesity and cardiovascular disease risk in Taiwanese individuals. METHODS: Taiwanese individuals were recruited from a nationwide, representative community-based prospective cohort study and classified according to body mass index as follows: normal weight (18.5-23.9 kilogram (kg)/meter(m)2) and obesity/overweight (≥24 kg/m2). Participants without diabetes, hypertension, and hyperlipidemia and who did not meet the metabolic syndrome without waist circumference criteria were considered metabolically healthy. The study end points were cardiovascular disease morbidity and mortality. Multivariable adjusted hazard ratios and 95% confidence intervals were obtained from a Cox regression analysis. RESULTS: Among 5 358 subjects (mean [standard deviation] age, 44.5 [15.3] years; women, 48.2%), 1 479 were metabolically healthy with normal weight and 491 were metabolically healthy with obesity. The prevalence of metabolically healthy obesity/overweight was 8.6% in the Taiwanese general population, which included individuals who were >20 years old, not pregnant, and did not have CVD (n = 5,719). In the median follow-up period of 13.7 years, 439 cardiovascular disease events occurred overall and 24 in the metabolically healthy obesity group. Compared with the reference group, the metabolically healthy obesity group had a significantly higher cardiovascular disease risk (adjusted hazard ratio: 1.74, 95% confidence interval: 1.02, 2.99). CONCLUSIONS: Individuals with metabolically healthy obesity have a higher risk of cardiovascular disease and require aggressive body weight control for cardiovascular disease control.

Effect of body shape on the development of cardiovascular disease in individuals with metabolically healthy obesity.

Studies about the effects of metabolically healthy obesity on cardiovascular disease (CVD) have yielded conflicting results. These heterogeneous results could be due to the limited usefulness of BMI in measuring general adiposity, as body mass index (BMI) does not accurately reflect body composition. This study aimed to evaluate the effect of body shape on CVD outcomes across different obesity phenotypes, and to provide an explanation for the heterogeneous effects of metabolically healthy obese (MHO) phenotype on CVD.We analyzed data from the Korean Genome and Epidemiology Study, a population-based cohort study conducted between 2001 and 2012. We divided the participants into 4 groups: metabolically healthy non-obese (MHNO), MHO, metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). To assess body shape, we calculated the z-score of the log-transformed a body shape index (LBSIZ). We computed Pearson correlation coefficients to examine the association of LBSIZ with muscle mass index, percentage of total fat mass (%Total FM), and percentage of abdominal fat mass (%Abdominal FM). We also used Cox proportional hazards regression to evaluate the effect of LBSIZ on CVD events according to the obesity phenotypes.A total of 9460 participants were assessed in this study. The incidence of CVD was 8.53 cases per 1000 person-year. LBSIZ showed strong positive correlation with %Total FM and %Abdominal FM, but negative correlation with muscle mass index. In Cox regression, MHO individuals did not show increased risk of CVD compared with MHNO individuals (hazard ratio [HR], 1.29; 95% confidence interval [CI], 0.96-1.73). However, MHO individuals in the 3rd (HR, 2.40; 95% CI, 1.28-4.51) and 4th (HR, 3.67; 95% CI, 1.99-6.74) quarters of LBSIZ showed significantly higher risk of CVD compared with MHNO individuals in the 1st quarter of LBSIZ. Moreover, LBSIZ showed a linear relationship with CVD among MHO individuals.While the MHO individuals showed similar CVD risk to the MHNO individuals, CVD risk increases with LBSIZ among the MHO individuals. LBSIZ appears to be a useful measure for CVD risk assessment in clinical practice and epidemiologic studies, especially for MHO patients.

Impact of Transition in Metabolic Health and Obesity on the Incident Chronic Kidney Disease: A Nationwide Cohort Study.

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.

A Novel Subset of CD95+ Pro-Inflammatory Macrophages Overcome miR155 Deficiency and May Serve as a Switch From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity.

Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.

Healthy Obese Subjects Differ in Chronotype, Sleep Habits, and Adipose Tissue Fatty Acid Composition from Their Non-Healthy Counterparts.

Obesity is not the same in all individuals and two different phenotypes have been described: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). The aim of this study was to identify factors that explain metabolic health status in a rigorously matched Spanish population. Subcutaneous and visceral fat, adipocyte size and fatty acid composition, cardiometabolic markers in serum, and lifestyle habits were assessed. Higher physical activity in the mornings (Odds Ratio (95% Confidence Interval) (OR (95% CI) = 1.54 (1.09-2.18), p = 0.01)), earlier bedtimes (8:30-10:30 pm) (OR = 2.11 (1.02-4.36), p = 0.04), a complete breakfast (OR = 1.59 (1.07-2.36), p = 0.02), and a greater number of meals per day (4.10 ± 0.05 vs. 3.93 ± 0.05, p < 0.01), were associated with the MHO phenotype. Concentrations of 20:5 n-3 eicosapentaenoic acid (0.26 ± 0.46 vs. 0.10% ± 0.11%, p = 0.04) and 18:3 n-6 gamma-linolenic acid (0.37 ± 0.24 vs. 0.23% ± 0.22%, p = 0.04) in subcutaneous adipocytes were higher and omental adipocyte size (187 094 ± 224 059 µm3 vs. 490 953 ± 229 049 µm3, p = 0.02) was lower in MHO subjects than in those with MUO. Visceral fat area differed between MHO and MUO subjects (135 ± 60 cm2 vs. 178 ± 85 cm2, p = 0.04, respectively). The study highlights specific lifestyle habits that could form part of obesity therapies, not only involving healthier eating habits but also earlier sleeping and exercise patterns.

Metabolically healthy versus unhealthy obesity and risk of fibrosis progression in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Little is known about the impact of metabolically healthy obesity on fibrosis progression in non-alcoholic fatty liver disease (NAFLD). We investigated the association of body mass index (BMI) category, body fat percentage and waist circumference with worsening of noninvasive fibrosis markers in metabolically healthy and unhealthy individuals with NAFLD. METHODS: A cohort study was performed on 59 957 Korean adults with NAFLD (13 285 metabolically healthy and 46 672 metabolically unhealthy individuals) who were followed for a median of 7.7 years. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homoeostasis model assessment of insulin resistance <2.5. Progression from low to intermediate or high probability of advanced fibrosis was assessed using the NAFLD fibrosis score (NFS). RESULTS: During 339 253.1 person-years of follow-up, 9857 subjects with low NFS at baseline progressed to intermediate or high NFS. Among metabolically healthy individuals, the multivariable-adjusted HRs (95% CI) for NFS worsening comparing BMIs 23-24.9, 25-29.9 and ≥30 with a BMI of 18.5-22.9 kg/m2 were 1.19 (1.00-1.42), 1.79 (1.52-2.10) and 3.52 (2.64-4.69), respectively, whereas the corresponding HRs (95% CI) in metabolically unhealthy individuals were 1.37 (1.24-1.52), 2.18 (1.99-2.39) and 4.26 (3.83-4.75). A similar trend was observed in the analyses using body fat and waist circumference. CONCLUSION: In the large-scale cohort of young and middle-aged individuals with NAFLD, BMI was positively associated with worsening of noninvasive fibrosis marker regardless of metabolic health status. Excess adiposity per se, even without accompanying metabolic health status, may contribute to fibrosis progression in NAFLD.

25 Hydroxyvitamin D Levels are Negatively and Independently Associated with Fat Mass in a Cohort of Healthy Overweight and Obese Subjects.

BACKGROUND: Obesity is associated with lower serum vitamin D (25(OH)D) levels through several mechanisms. The aim of the study was to examine the possibility of a negative association between fat mass and 25(OH)D levels in a cohort of otherwise healthy overweight and obese subjects, independently of age, sex, blood pressure levels and anthropometric and metabolic parameters. MATERIALS AND METHODS: 147 overweight and obese subjects (106 women and 41 men), aged between 18 and 69 years, were enrolled into the study. All of them did not show any clinically evident metabolic or chronic diseases (i.e. hypertension, diabetes mellitus, renal failure, etc.) and did not use any kind of drug. Serum fasting levels of 25(OH)D, insulin, glucose, uric acid and lipids (triglycerides, total, HDL and LDL cholesterol) were measured. The season in which the blood samples were collected was autumn. Insulin resistance was assessed by using the Homeostasis Model Assessment (HOMA-IR). Body composition parameters (Fat Mass [FM], Fat Free Mass [FFM], body cell mass [BCM], Total Body Water [TBW]) were measured by electrical Bioimpedance Analysis (BIA). Lastly, demographic, anthropometric and clinical parameters (age, Body Mass Index [BMI], Waist Circumference [WC], Systolic (SBP) and Diastolic (DBP) blood pressure) were also assessed. RESULTS: 25(OH)D levels were significantly and negatively correlated with BMI (P <0.001), WC (P <0.01), DBP (P <0.05), insulin (P <0.001), HOMA-IR (P <0.01), triglycerides (P <0.01), and fat mass (P <0.001). A multivariate regression analysis was performed by considering 25(OH)D levels as the dependent variable and sex, waist circumference, fat mass, DBP, triglycerides, and insulin (or HOMAIR) as the independent ones, and 25(OH)D levels maintained a significant and independent relationship only with fat mass (negative) (P <0.01). CONCLUSION: This study clearly shows that 25(OH)D circulating levels are progressively lower with the increase of fat mass, independently of sex, body fat distribution, blood pressure and insulin and metabolic parameters. These data strongly show that adipose tissue accumulation per se is absolutely the main factor responsible factor for lower 25(OH)D levels in obese subjects, possibly through sequestration of fat soluble 25(OH)D in fat mass.

Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach.

INTRODUCTION: As a small proportion of obese individuals do not develop metabolic complications and non-alcoholic fatty liver disease (NAFLD), this study aimed to provide a comprehensive clinical, metabolic and genetic description of obese subjects with healthy livers. METHODS: A total of 183 subjects were stratified, according to BMI, presence of metabolic syndrome, biochemical liver tests and hepatic steatosis on ultrasound, into: (i) lean controls (n = 69); (ii) obese healthy (n = 50); and (iii)obese NAFLD (n = 62) groups. Detailed clinical, genetic and metabolic evaluations were then performed. RESULTS: Obese healthy subjects did not differ in glucose parameters from lean controls, and had a lower rate of minor TM6SF2 gene variants compared with obese NAFLD (2/49 vs. 11/60, respectively; P = 0.035) and lean controls (13/64; P = 0.035), but significantly higher leptin concentrations than lean controls (P < 0.001); they also higher adiponectin concentrations (P < 0.001), and lower TNF-α and IL-6 concentrations (P = 0.01 and P < 0.001, respectively), than obese NAFLD subjects. Also, metabolomic studies identified ether- and ester-containing phospholipids [PC ae C44:6, PC ae C42:5, PC aa C40:4; P < 0.001, corrected by the false discovery rate (FDR) method] and found that the amino-acids lysine, glycine and isoleucine (FDR < 0.001) differed between the two obese groups, but not between lean controls and obese healthy subjects. CONCLUSION: Obese people with healthy livers are characterized by intact glucose homoeostasis, lower pro-inflammatory cytokine levels, and higher adiponectin and leptin concentrations compared with obese people with NAFLD. In addition, the major allele of TM6SF2, a set of phosphatidylcholines and several amino acids are associated with healthy livers in obesity.

Metabolically healthy obesity and subclinical atherosclerosis in persons with spinal cord injury.

OBJECTIVE: Despite preserved metabolic function, metabolically healthy obesity may increase the risk of subclinical atherosclerosis. Given the high prevalence of cardiometabolic diseases in individuals with spinal cord injury, the aim of this study was to investigate the association of insulin resistance, systemic low-grade inflammation, and markers of subclinical atherosclerosis with metabolically healthy obesity in individuals with spinal cord injury. METHODS: Insulin resistance index (HOMA-IR), high-sensitivity C-reactive protein, carotid artery intima-media thickness and carotid-femoral pulse wave velocity were measured in individuals with spinal cord injury classified with metabolically healthy obesity (n = 12), metabolically unhealthy obesity (n = 8), or metabolically healthy normal-weight (n = 18). Metabolically healthy obesity was defined as spinal cord injury-specific cut-off of body mass index ≥ 22 kg/m2 with < 3 metabolic abnormalities. RESULTS: There were no differences in HOMA-IR or high-sensitivity C-reactive protein in metabolically healthy obesity compared with metabolically healthy normal-weight (p > 0.05). Pulse wave velocity was higher in metabolically healthy obesity than in metabolically healthy normal-weight (p ≤ 0.05), but lower than in metabolically unhealthy obesity (p ≤ 0.05). Metabolically healthy obesity had similar carotid artery intima-media thickness vs metabolically healthy normal-weight (p > 0.05), but lower carotid artery intima-media thickness compared with metabolically unhealthy obesity (p ≤ 0.05). CONCLUSION: Despite a somewhat preserved metabolic and inflammatory status, individuals with spinal cord injury with metabolically healthy obesity present with an intermediate subclinical atherosclerotic phenotype, as evidenced by increased aortic stiffness but not carotid thickness.

The molecular mechanisms of obesity paradox.

Clinical observations suggest a complex relationship between human obesity and cardiovascular disease. Whilst abdominal (visceral) adiposity leads to deleterious metabolic disturbances, subcutaneous fat accumulation has a benign effect on cardiometabolic risk. Notably, an accumulating body of evidence paradoxically links increased body mass index with a better prognosis in patients with established cardiovascular disease, a finding that has been termed the 'obesity paradox'. Whilst this is now acknowledged to be an epidemiological finding, a metabolically healthy obese group associated with low cardiovascular risk has also been identified. The current concept of adipose tissue (AT) biology suggests that AT expansion is feasible without accompanying adipocyte dysfunction. A metabolically healthy obese phenotype can be promoted by exercise, but is also linked with intrinsic AT molecular characteristics such as efficient fat storage and lipid droplet formation, high adipogenesis capacity, low extracellular matrix fibrosis, angiogenesis potential, adipocyte browning and low macrophages infiltration/activation. Such features are associated with a secretomic profile of human AT which is protective for the cardiovascular system. In the present review, we summarize the existing knowledge on the molecular mechanisms underlying the 'obesity paradox' and whether fatness can be healthy too.

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans.

Recruitment of brown adipose tissue (BAT) has emerged as a potential tool to combat obesity and associated metabolic complications. Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.

Peripheral invariant natural killer T cell deficiency in metabolically unhealthy but normal weight versus metabolically healthy but obese individuals.

Objective To investigate the proportion of circulating invariant natural killer T (iNKT) cells in four body health types. Methods In this cross-sectional study, participants were classified into four body health types according to the body mass index and metabolic status: metabolically healthy and normal weight (MHNW), metabolically unhealthy but normal weight (MUNW), metabolically healthy but obese (MHO), or metabolically unhealthy and obese (MUO). Demographic and clinical characteristics were measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) and visceral adiposity index (VAI) were calculated. The proportion of circulating iNKT cells was also evaluated by flow cytometry. Results The study enrolled 41 MHNW, 37 MUNW, 30 MHO, and 43 MUO participants. Compared with the MHNW group, the MUNW, MHO, and MUO groups had significantly lower iNKT cell proportions. The iNKT cell proportion was significantly higher in the MHO group than the MUNW and MUO groups. The iNKT cell proportion was inversely correlated with high-sensitivity C-reactive protein, HOMA-IR, and VAI values. Conclusion The proportion of iNKT cells was lower in people (lean or obese) with excessive visceral fat accumulation, suggesting that iNKT cell deficiency may be involved in the pathophysiology of obesity-related metabolic disorders.

Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity.

AIMS: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. RESULTS: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. INNOVATION: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. CONCLUSION: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity.