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Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also show sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.

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BACKGROUND: Obesity-mediated oxidative stress results in mitochondrial dysfunction, which has been implicated in the pathogenesis of metabolic syndrome and T2DM. Recently, mitophagy, a cell-reparative process has emerged as a key facet in maintaining the mitochondrial health, which may contribute to contain the metabolic abnormalities in obese individuals. However, the status of mitophagy in metabolically healthy obese (MHO) and metabolically abnormal diabetic obese (MADO) subjects remains to be elucidated. Hence, the present study aims to unravel the alterations in mitochondrial oxidative stress (MOS) and mitophagy in these subjects. METHODS: 60 subjects including MHNO (metabolically healthy non-obese), MHO and MADO were enrolled as per the Asian criteria for obesity (n = 20 each). Biochemical parameters, MOS indices, transcriptional and translational expression of mitophagy markers (PINK1, PARKIN, MFN2, NIX, LC3-II, and LAMP-2), and transmission electron microscopic (TEM) studies were performed in peripheral blood mononuclear cells. RESULTS: The MHO subjects displayed a favorable metabolic profile, despite accompanied by an increased adiposity as compared to the MHNO group; while MADO group exhibited several metabolic abnormalities, inspite of similar body composition as MHO subjects. A progressive rise in the MOS was observed in MHO and MADO subjects as compared to the MHNO group, and it showed a positive and significant correlation with the body composition in these groups. Further, mitophagy remained unaltered in the MHO group, while it was significantly downregulated in the MADO group. In addition, TEM studies revealed a significant increase in the percentage of damaged mitochondria in MADO patients as compared to other groups, while MHO and MHNO groups did not show any significant alterations for the same. CONCLUSION: A favorable metabolic profile and moderate levels of MOS in the MHO group may play a crucial role in the sustenance of mitophagy, which may further limit the aggravation of MOS, inflammation, and emergence of metabolic aberrations in contrast to MADO subjects, who exhibited multiple metabolic abnormalities and attenuated mitophagy. Therefore, these MHO subjects are likely to be at a lower risk of developing metabolic syndrome and T2DM.

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AIM: Obesity is associated with the development of metabolic complications such as insulin resistance (IR). The mechanisms leading to IR remain unclear. This study aimed to investigate the relationship between adipose tissue fibrosis and IR in obese patients before and after bariatric surgery. METHODS: Thirty-five obese patients awaiting bariatric surgery (12 with type 2 diabetes) were included in the study. Non-diabetic patients were classified as either insulin-sensitive (n=11) or insulin-resistant (n=12), based on the Matsuda insulin sensitivity index (ISIMatsuda). Homoeostasis model assessment (HOMA-IR) was used for longitudinal evaluation of insulin resistance. Fibrosis was quantified by Masson's trichrome staining on microscopy, and mRNA levels of fibrosis-related genes were examined in subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies collected during and 6 months after bariatric surgery (SAT only). RESULTS: Despite their similar age, body mass index and fat mass, SAT fibrosis was significantly higher in diabetic vs insulin-sensitive patients (P<0.05), and associated with IR as assessed by both ISIMatsuda (r=-0.417, P=0.038) and HOMA-IR (r=0.464, P=0.007) at baseline, whereas VAT fibrosis was not. Six months after surgery and significant weight loss, fibrosis levels remained unchanged in SAT, although IR was significantly reduced in all groups (P<0.0001). No correlation was found between SAT fibrosis and IR after surgery. CONCLUSION: Overall, these results show a significant but, most likely, transient association between SAT fibrosis and IR in obese humans.

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OBJECTIVE: The aim of this study was to evaluate the characteristics of the young Korean obese but metabolically healthy subjects and to identify the factors associated with metabolic health status among them. METHODS: We reviewed the medical record of South-Korea Navy soldiers at 1st marine division with routine medical examination. Within this population, we selected obese subjects whose body mass index (BMI) were more than 25 kg/m². The clinical characteristics between obese subjects with metabolically healthy and unhealthy factors were retrospectively compared. RESULTS: Of the 1,522 subjects with medical record, 319 (20.9%) subjects were identified as obese. Among them, 60 subjects (18.8%) were classified as metabolically unhealthy, whereas 259 (81.2%) subjects were metabolically healthy. Multivariate analysis revealed that higher BMI (odds ratio, OR 1.26, 95% confidence interval, CI, 1.07-1.49), higher alanine transaminase (ALT) (OR 1.03, 95% CI 1.01-1.06), and drinking alcohol (OR 3.65, 95% CI 1.02-13.02) were associated with metabolically unhealthy status in obese subjects. Meanwhile, regular physical activity was associated with metabolically healthy status in obese subjects. (OR 0.33, 95% CI 0.17-0.62) CONCLUSION: This study found that higher BMI, higher ALT, and drinking alcohol were related to metabolically unhealthy status in young Korean obese subjects; meanwhile, regular physical activity was related to metabolically healthy status.

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OBJECTIVE: To determine whether dietary quality differs between metabolically-healthy-obese (MHO) and metabolically-abnormal-obesity (MAO) in a nationally representative sample. METHODS: National Health and Nutrition Examination Survey (NHANES) data (2007-2008; 2009-2010) were used to identify obese adolescents (≥95th body mass index (BMI) %tile) and adults (≥30kg/m(2)). MHO was defined as <2 abnormal cardiometabolic risk factors (elevated blood pressure, triglycerides, glucose, low high density lipoprotein cholesterol (HDL-C); or on medications). Healthy Eating Index 2005 (HEI-2005) scores were calculated from 24-hour recall data. General linear regression models determined whether HEI-2005 scores differed between MHO and MAO after controlling for age, race, gender, NHANES wave, BMI, physical activity and health status by age group (12-18; 19-44; 45-85years). RESULTS: Compared with MAO, MHO adolescents (n=133) had higher total HEI-2005 score, higher milk scores, and higher scores from calories from solid fats, alcohol beverages and added sugars. MHO women 19-44years (n=240) had higher total HEI-2005, higher whole fruit, higher whole grain and higher meat and bean scores compared with MAO. No significant differences were observed between MHO and MAO for HEI-2005 total scores in men 19-44years, or adults 45-85years. CONCLUSION: MHO adolescents and women 19-44years have better dietary compliance to the U.S. guidelines when compared with MAO, suggesting potential intervention targets to improve cardiometabolic risk within obesity.

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Up to 30% of obese people do not display the "typical" metabolic obesity-associated complications. For this group of patients, the term "metabolically healthy obese (MHO)" has been established during the past years and has been the focus of research activities. The development and severity of insulin resistance as well as (subclinical) inflammations seems to play a key role in distinguishing metabolically healthy from metabolically non-healthy individuals. However, an internationally consistent and accepted classification that might also include inflammatory markers as well as features of non-alcoholic fatty liver disease is missing to date, and available data - in terms of prevalence, definition and severity - are heterogeneous, both during childhood/adolescence and during adulthood. In addition, the impact of MHO on future morbidity and mortality compared to obese, metabolically non-healthy as well as normal weight, metabolically healthy individuals is absolutely not clear to date and even conflicting. This review summarizes salient literature related to that topic and provides insight into our current understanding of MHO, covering all age spans from childhood to adulthood.

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