Decreased adiponectin/leptin ratio relates to insulin resistance in adults with obesity.

Adipose tissue dysfunction is a key mechanism that leads to adiposity-based chronic disease. This study aimed to investigate the reliability of the adiponectin/leptin ratio (AdipoQ/Lep) as an adipose tissue and metabolic function biomarker in adults with obesity, without diabetes. Data were collected from a clinical trial conducted in 28 adults with obesity (mean body mass index: 35.4 ± 3.7 kg/m2) (NCT02169778). With the use of a forward stepwise multiple linear regression model to explore the relationship between AdipoQ/Lep and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), it was observed that 48.6% of HOMA-IR variance was explained by triacylglycerols, AdipoQ/Lep, and waist-to-hip ratio (P < 0.001), AdipoQ/Lep being the strongest independent predictor (Beta = -0.449, P < 0.001). A lower AdipoQ/Lep was correlated with higher body mass index (Rs = -0.490, P < 0.001), body fat mass (Rs = -0.486, P < 0.001), waist-to-height ratio (Rs = -0.290, P = 0.037), and plasma resistin (Rs = -0.365, P = 0.009). These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance and emphasize that AdipoQ/Lep may be a promising early marker of insulin resistance development in adults with obesity.NEW & NOTEWORTHY Adiponectin/leptin ratio, triacylglycerols, and waist-to-hip ratio explained almost half of HOMA-IR variance in the context of obesity. This study provides evidence to support adipose tissue dysfunction as a central feature of the pathophysiology of obesity and insulin resistance. Early identification of individuals at higher risk of developing metabolic complications through adipose tissue dysfunction assessment and the staging of obesity and its transient phenotypes can contribute to improve therapeutic decision-making.

Physical exercise positively modulates nonalcoholic steatohepatitis-related hepatic endoplasmic reticulum stress.

Obesity is a predictive factor for the development of nonalcoholic steatohepatitis (NASH). Although some of the mechanisms associated with NASH development are still elusive, its pathogenesis relies on a complex broad spectrum of (interconnected) metabolic-based disorders. We analyzed the effects of voluntary physical activity (VPA) and endurance training (ET), as preventive and therapeutic nonpharmacological strategies, respectively, against hepatic endoplasmic reticulum (ER) stress, ER-related proapoptotic signaling, and oxidative stress in an animal model of high-fat diet (HFD)-induced NASH. Adult male Sprague-Dawley rats were divided into standard control liquid diet (SCLD) or HFD groups, with sedentary, VPA, and ET subgroups in both (sedentary animals with access to SCLD [SS], voluntarily physically active animals with access to SCLD [SV], and endurance-trained animals with access to SCLD [ST] in the former and sedentary animals with access to liquid HFD [HS], voluntarily physically active animals with access to liquid HFD [HV], and endurance-trained animals with access to liquid HFD [HT] in the latter, respectively). Hepatic ER stress and ER-related proapoptotic signaling were evaluated by Western blot and reverse transcriptase-polymerase chain reaction; redox status was evaluated through quantification of lipid peroxidation, protein carbonyls groups, and glutathione levels as well as antioxidant enzymes activity. In SCLD-treated animals, VPA significantly decreased eukaryotic initiation factor-2 alpha (eIF2α). In HFD-treated animals, VPA significantly decreased eIF2α and phospho-inositol requiring enzyme-1 alpha (IRE1α) but ET significantly decreased eIF2α and significantly increased both spliced X-box binding protein 1 (sXBP1) and unspliced X-box binding protein 1; a significant increase of phosphorylated-eIF2α (p-eIF2α) to eIF2α ratio occurred in ET versus VPA. HS compared to SS disclosed a significant increase of total and reduced glutathione, HV compared to SV a significant increase of oxidized glutathione, HT compared to ST a significant increase of p-eIF2α to eIF2α ratio and sXBP1. Physical exercise counteracts NASH-related ER stress and its associated deleterious consequences through a positive and dynamical modulation of the hepatic IRE1α-X-box binding protein 1 pathway.

Effects of xenoestrogens in human M1 and M2 macrophage migration, cytokine release, and estrogen-related signaling pathways.

Bisphenol A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and di(n-butyl)phthalate (DBP) are environmental estrogens that have been associated with a wide range of adverse health outcomes for which inflammation has also been hypothesized as a potentially involved mechanism and where macrophages play a central role. This study was carried out to evaluate if xenoestrogen (XE) treatment of classically (M1) or alternatively (M2) activated macrophages could affect their behavior. For this purpose, human peripheral blood monocyte-derived macrophages either unstimulated or activated with lipopolysaccharide (100 ng/mL, M1) or with interleukin (IL) 4 (15 ng/mL, M2) were treated with 17ß-estradiol (E2 ), BPA, DEHP and DBP alone or in combination with selective ERα or ERß antagonists. Migratory capability, cytokine release, and estrogen-associated signaling pathways were evaluated to assess macrophage function. All tested XEs had a tendency to stimulate M2 migration, an effect that followed the same direction than E2 . Moreover, all XEs significantly induced IL10 in M1 and decreased IL6 and globally decreased IL10, IL6, TNFα, and IL1ß release by M2 macrophages. However, DEHP and DBP significantly increased IL1ß release in M1 and M2 macrophages, respectively. Some of the effects described above were shown to be mediated by either ERα or ERß and were simultaneous to modulation of NF-κB, AP1, JNK, or ERK signaling pathways. We provide new evidence of the effect of XE on macrophage behavior and their mechanisms with relevance to the understanding of the action of environmental chemicals on the immune system and inflammation-associated diseases. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1496-1509, 2016.

Effects of environmental organochlorine pesticides on human breast cancer: putative involvement on invasive cell ability.

Human exposure to persistent organic pollutants (POPs) is a certainty, even to long banned pesticides like o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT), and its metabolites p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), and p,p'-dichlorodiphenyldichloroethane (p,p'-DDD). POPs are known to be particularly toxic and have been associated with endocrine-disrupting effects in several mammals, including humans even at very low doses. As environmental estrogens, they could play a critical role in carcinogenesis, such as in breast cancer. With the purpose of evaluating their effect on breast cancer biology, o,p'-DDT, p,p'-DDE, and p,p'-DDD (50-1000 nM) were tested on two human breast adenocarcinoma cell lines: MCF-7 expressing estrogen receptor (ER) α and MDA-MB-231 negative for ERα, regarding cell proliferation and viability in addition to their invasive potential. Cell proliferation and viability were not equally affected by these compounds. In MCF-7 cells, the compounds were able to decrease cell proliferation and viability. On the other hand, no evident response was observed in treated MDA-MB-231 cells. Concerning the invasive potential, the less invasive cell line, MCF-7, had its invasion potential significantly induced, while the more invasive cell line MDA-MB-231, had its invasion potential dramatically reduced in the presence of the tested compounds. Altogether, the results showed that these compounds were able to modulate several cancer-related processes, namely in breast cancer cell lines, and underline the relevance of POP exposure to the risk of cancer development and progression, unraveling distinct pathways of action of these compounds on tumor cell biology.

Persistent organic pollutant levels in human visceral and subcutaneous adipose tissue in obese individuals--depot differences and dysmetabolism implications.

BACKGROUND: The role of persistent organic pollutants (POPs) with endocrine disrupting activity in the aetiology of obesity and other metabolic dysfunctions has been recently highlighted. Adipose tissue (AT) is a common site of POPs accumulation where they can induce adverse effects on human health. OBJECTIVES: To evaluate the presence of POPs in human visceral (vAT) and subcutaneous (scAT) adipose tissue in a sample of Portuguese obese patients that underwent bariatric surgery, and assess their putative association with metabolic disruption preoperatively, as well as with subsequent body mass index (BMI) reduction. METHODS: AT samples (n=189) from obese patients (BMI ≥ 35) were collected and the levels of 13 POPs were determined by gas chromatography with electron-capture detection (GC-ECD). Anthropometric and biochemical data were collected at the time of surgery. BMI variation was evaluated after 12 months and adipocyte size was measured in AT samples. RESULTS: Our data confirm that POPs are pervasive in this obese population (96.3% of detection on both tissues), their abundance increasing with age (RS=0.310, p<0.01) and duration of obesity (RS=0.170, p<0.05). We observed a difference in AT depot POPs storage capability, with higher levels of ΣPOPs in vAT (213.9 ± 204.2 compared to 155.1 ± 147.4 ng/g of fat, p<0.001), extremely relevant when evaluating their metabolic impact. Furthermore, there was a positive correlation between POP levels and the presence of metabolic syndrome components, namely dysglycaemia and hypertension, and more importantly with cardiovascular risk (RS=0.277, p<0.01), with relevance for vAT (RS=0.315, p<0.01). Finally, we observed an interesting relation of higher POP levels with lower weight loss in older patients. CONCLUSION: Our sample of obese subjects allowed us to highlight the importance of POPs stored in AT on the development of metabolic dysfunction in a context of obesity, shifting the focus to their metabolic effects and not only for their recognition as environmental obesogens.

Estrogen signaling in metabolic inflammation.

There is extensive evidence supporting the interference of inflammatory activation with metabolism. Obesity, mainly visceral obesity, is associated with a low-grade inflammatory state, triggered by metabolic surplus where specialized metabolic cells such as adipocytes activate cellular stress initiating and sustaining the inflammatory program. The increasing prevalence of obesity, resulting in increased cardiometabolic risk and precipitating illness such as cardiovascular disease, type 2 diabetes, fatty liver, cirrhosis, and certain types of cancer, constitutes a good example of this association. The metabolic actions of estrogens have been studied extensively and there is also accumulating evidence that estrogens influence immune processes. However, the connection between these two fields of estrogen actions has been underacknowledged since little attention has been drawn towards the possible action of estrogens on the modulation of metabolism through their anti-inflammatory properties. In the present paper, we summarize knowledge on the modification inflammatory processes by estrogens with impact on metabolism and highlight major research questions on the field. Understanding the regulation of metabolic inflammation by estrogens may provide the basis for the development of therapeutic strategies to the management of metabolic dysfunctions.

Methotrexate enhances 3T3-L1 adipocytes hypertrophy.

Methotrexate (MTX) is broadly used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA). The prevalence of metabolic syndrome (MeS) in patients with this condition is relatively high. Given the importance of adipose tissue in the development of obesity metabolic complications, this study aimed to investigate the effect of methotrexate on preadipocyte proliferation, adipogenesis, and glucose uptake by adipocytes. 3T3-L1 preadipocytes proliferation was evaluated by sulforhodamine B staining and (3)H-thymidine incorporation, after 24 or 48 h of treatment with MTX (0.1 and 10 µM). Preadipocytes were induced to differentiate with an appropriate adipogenic cocktail in the presence or absence of MTX. Adipogenesis was determined by measuring lipid accumulation after staining with oil red O. (3)H-Deoxyglucose ((3)H-DG) uptake was determined by liquid scintillation counting. MTX treatment reduced culture protein content in a concentration-dependent manner and (3)H-thymidine incorporation (P < 0.05). MTX (0.1 µM) treatment increased lipid accumulation and basal (3)H-DG uptake by adipocytes (P < 0.05). In 0.1 µM MTX-treated adipocytes, insulin stimulation did not result in an increase of (3)H-DG uptake, contrarily to what was observed in control cells. These results demonstrate that methotrexate interferes with adipocyte proliferation and promotes the hypertrophic growth of adipocytes. These molecular effects may have implications on metabolic profile of RA patients treated with MTX.

Characterization of an obese population: a retrospective longitudinal study from real-world data in northern Portugal.

BACKGROUND: Obesity is a serious and largely preventable global health problem. Obesity-related electronic health records can be a useful resource to identify and address obesity. The analysis of real-world data from T82-coded (International Classification of Primary Care coding, for obesity) primary care individuals can be an excellent national source of data on obesity's prevalence, characteristics, and impact on the National Health Service. METHODS: Retrospective longitudinal study, based on a database of electronic medical records, from the Regional Health Administration of northern Portugal. The study objectives were to determine the prevalence of obesity and to characterize an adult obese population in northern Portugal from a bio-demographic point of view along with profiles of comorbidities and the use of health resources. This study used a database of 266,872 patients in December 2019 and screened for diagnostic code T82 from the International Classification of Primary Care. RESULTS: The prevalence of obesity was 10.2% and the highest prevalence of obesity was in the 65-74 age group (16.1%). The most prevalent morbidities in patients with obesity as coded through ICPC-2 were K86 (uncomplicated hypertension), T90 (non-insulin-dependent diabetes), and K87 (complicated hypertension). Descriptive information showed that T82 subjects used more consultations, medications, and diagnostic tests than non-T82 subjects. CONCLUSIONS: Routine recording of weight and height deserves special attention to allow obesity recognition at an early stage and move on to the appropriate intervention. Future work is necessary to automate the codification of obesity for subjects under 18 years of age, to raise awareness and anticipate the prevention of problems associated with obesity. Practical strategies need to be implemented, such as the creation of a specific program consultation with truly targeted approaches to obesity.

Measuring adherence to inhaled control medication in patients with asthma: Comparison among an asthma app, patient self-report and physician assessment.

BACKGROUND: Previous studies have demonstrated the feasibility of using an asthma app to support medication management and adherence but failed to compare with other measures currently used in clinical practice. However, in a clinical setting, any additional adherence measurement must be evaluated in the context of both the patient and physician perspectives so that it can also help improve the process of shared decision making. Thus, we aimed to compare different measures of adherence to asthma control inhalers in clinical practice, namely through an app, patient self-report and physician assessment. METHODS: This study is a secondary analysis of three prospective multicentre observational studies with patients (≥13 years old) with persistent asthma recruited from 61 primary and secondary care centres in Portugal. Patients were invited to use the InspirerMundi app and register their inhaled medication. Adherence was measured by the app as the number of doses taken divided by the number of doses scheduled each day and two time points were considered for analysis: 1-week and 1-month. At baseline, patients and physicians independently assessed adherence to asthma control inhalers during the previous week using a Visual Analogue Scale (VAS 0-100). RESULTS: A total of 193 patients (72% female; median [P25-P75] age 28 [19-41] years old) were included in the analysis. Adherence measured by the app was lower (1 week: 31 [0-71]%; 1 month: 18 [0-48]%) than patient self-report (80 [60-95]) and physician assessment (82 [51-94]) (p < 0.001). A negligible non-significant correlation was found between the app and subjective measurements (ρ 0.118-0.156, p > 0.05). There was a moderate correlation between patient self-report and physician assessment (ρ = 0.596, p < 0.001). CONCLUSIONS: Adherence measured by the app was lower than that reported by the patient or the physician. This was expected as objective measurements are commonly lower than subjective evaluations, which tend to overestimate adherence. Nevertheless, the low adherence measured by the app may also be influenced by the use of the app itself and this needs to be considered in future studies.