Hair cortisol levels are associated with overweight and obesity in the ELSA-Brasil cohort.

Introduction: Hair cortisol level has recently been identified as a promising marker for detecting long-term cortisol levels and a marker of hypothalamic-pituitary-adrenal cortex (HPA) axis activity. However, research on the association between obesity and an altered cortisol metabolism remains controversial. Objective: This study aimed to investigate the relationship between hair cortisol levels and overweight and obesity in participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods: This was a cross-sectional study involving 2,499 participants from the second follow-up (visit 3, 2017-2019) attending research centers in Rio de Janeiro and Rio Grande do Sul states. Hair samples were collected, and cortisol levels were analyzed using enzyme-linked immunosorbent assay (ELISA) kits. Cortisol levels were classified as low (< 40 pg/mg), medium (40-128 pg/mg), or high (> 128 pg/mg). The participants were classified as eutrophic, overweight, or obese according to their weight (kg) and height (m2). Odds ratios (ORs) with 95% confidence intervals (95%CI) were estimated. Results: Of the 2499 individuals, 30% had eutrophic weight, 40% were overweight, and 30% were obese. Notably, cortisol levels gradually increased with increasing body weight. Among participants with high hair cortisol levels, 41.2% were classified as overweight and 34.2% as obese. Multinomial logistic regression analysis indicated that participants with high cortisol levels were 43% (OR =1.43; 95%CI: 1.02-2.03) more likely to be overweight and 72% (OR =1.72; 95%CI:1.20-2.47) more likely to be obese than participants with low hair cortisol levels. After adjustment for all covariates, high cortisol levels remained associated with obesity (OR = 1.54; 95%CI:1.02-2.31) and overweight (OR =1.33; 95%CI:0.91-1.94). Conclusion: In the ELSA-Brazil cohort, hair stress were positively associated with overweight and obesity. These results underscore the importance of considering stress and cortisol as potential factors in obesity prevention and intervention efforts, and highlight a novel aspect of the complex relationship between stress and obesity in the Brazilian population.

Cholesterol Exacerbates the Pathophysiology of Non-Alcoholic Steatohepatitis by Upregulating Hypoxia-Inducible Factor 1 and Modulating Microcirculatory Dysfunction.

Cholesterol is a pivotal lipotoxic molecule that contributes to the progression of Non-Alcoholic Steatohepatitis NASH). Additionally, microcirculatory changes are critical components of Non-Alcoholic Fatty Liver Disease (NAFLD) pathogenesis. This study aimed to investigate the role of cholesterol as an insult that modulates microcirculatory damage in NAFLD and the underlying mechanisms. The experimental model was established in male C57BL/6 mice fed a high-fat high-carbohydrate (HFHC) diet for 39 weeks. Between weeks 31-39, 2% cholesterol was added to the HFHC diet in a subgroup of mice. Leukocyte recruitment and hepatic stellate cells (HSC) activation in microcirculation were assessed using intravital microscopy. The hepatic microvascular blood flow (HMBF) was measured using laser speckle flowmetry. High cholesterol levels exacerbated hepatomegaly, hepatic steatosis, inflammation, fibrosis, and leukocyte recruitment compared to the HFHC group. In addition, cholesterol decreased the HMBF-cholesterol-induced activation of HSC and increased HIF1A expression in the liver. Furthermore, cholesterol promoted a pro-inflammatory cytokine profile with a Th1-type immune response (IFN-γ/IL-4). These findings suggest cholesterol exacerbates NAFLD progression through microcirculatory dysfunction and HIF1A upregulation through hypoxia and inflammation. This study highlights the importance of cholesterol-induced lipotoxicity, which causes microcirculatory dysfunction associated with NAFLD pathology, thus reinforcing the potential of lipotoxicity and microcirculation as therapeutic targets for NAFLD.

Cirrhotic Liver Sustains In Situ Regeneration of Acellular Liver Scaffolds after Transplantation into G-CSF-Treated Animals.

Acellular liver scaffolds (ALS) produced by decellularization have been successfully explored for distinct regenerative purposes. To date, it is unknown whether transplanted ALSs are affected by cirrhotic livers, either becoming cirrhotic themselves or instead remaining as a robust template for healthy cell growth after transplantation into cirrhotic rats. Moreover, little is known about the clinical course of recipient cirrhotic livers after ALS transplantation. To address these questions, we transplanted ALSs into cirrhotic rats previously treated with the granulocyte colony-stimulating factor. Here, we report successful cellular engraftment within the transplanted ALSs at 7, 15, and 30 days after transplantation. Recellularization was orchestrated by liver tissue cell activation, resident hepatocytes and bile duct proliferation, and an immune response mediated by the granulocyte components. Furthermore, we showed that transplanted ALSs ensured a pro-regenerative and anti-inflammatory microenvironment, attracted vessels from the host cirrhotic tissue, and promoted progenitor cell recruitment. ALS transplantation induced cirrhotic liver regeneration and extracellular matrix remodeling. Moreover, the transplanted ALS sustained blood circulation and attenuated alterations in the ultrasonographic and biochemical parameters in cirrhotic rats. Taken together, our results confirm that transplanted ALSs are not affected by cirrhotic livers and remain a robust template for healthy cell growth and stimulated cirrhotic liver regeneration.

Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress.

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product-receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat-high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.

Pyridoxamine and Caloric Restriction Improve Metabolic and Microcirculatory Abnormalities in Rats with Non-Alcoholic Fatty Liver Disease.

INTRODUCTION: This study aims to examine the effect of a diet intervention and pyridoxamine (PM) supplementation on hepatic microcirculatory and metabolic dysfunction in nonalcoholic fatty liver disease (NAFLD). METHODS: NAFLD in Wistar rats was induced with a high-fat diet for 20 weeks (NAFLD 20 weeks), and control animals were fed with a standard diet. The NAFLD diet intervention group received the control diet between weeks 12 and 20 (NAFLD 12 weeks), while the NAFLD 12 weeks + PM group also received PM. Fasting blood glucose (FBG) levels, body weight (BW), visceral adipose tissue (VAT), and hepatic microvascular blood flow (HMBF) were evaluated at the end of the protocol. RESULTS: The NAFLD group exhibited a significant increase in BW and VAT, which was prevented by the diet intervention, irrespective of PM treatment. The FBG was elevated in the NAFLD group, and caloric restriction improved this parameter, although additional improvement was achieved by PM. The NAFLD group displayed a 31% decrease in HMBF, which was partially prevented by caloric restriction and completely prevented when PM was added. HMBF was negatively correlated to BW, FBG, and VAT content. CONCLUSION: PM supplementation in association with lifestyle modifications could be an effective intervention for metabolic and hepatic vascular complications.

Pyridoxamine improves metabolic and microcirculatory complications associated with nonalcoholic fatty liver disease.

OBJECTIVE: We investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease. METHODS: Nonalcoholic fatty liver disease was established by a high-fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A-positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT-PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy. RESULTS: The increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high-fat diet-induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF-α) mRNA transcripts in the liver. CONCLUSION: Pyridoxamine modulates oxidative stress, advanced glycation end products, TNF-α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease-associated microcirculatory and metabolic complications.

Influence of Physical Exercise on Advanced Glycation End Products Levels in Patients Living With the Human Immunodeficiency Virus.

Introduction: Combined antiretroviral therapy (cART) used to treat acquired immunodeficiency virus (HIV) induces a number of adverse effects, such as insulin resistance and dyslipidemia, which ultimately increases the cardiovascular risk. Advanced glycation end products (AGEs) have been implicated in the etiology of cardiovascular diseases, diabetes and other chronic diseases. It is known that physical exercise improves the lipid profile, insulin resistance and reduces the risk of cardiovascular diseases. However, the impact of physical exercise on AGE levels in HIV-infected patients has not been so far investigated. Therefore, this study compared AGEs levels in people with and without HIV and verified the effect of physical training on serum AGE levels. Methods: Participants were initially assigned into three groups: healthy control (CTL, n = 35), physically inactive HIV-infected (In-HIV, n = 33) and physically active HIV-infected (Ac-HIV, n = 19). The In-HIV group underwent physical training for 3 months, consisting of 60-min sessions of multimodal supervised exercise (aerobic, resistance and flexibility) with moderate intensity (50-80% heart rate reserve), performed 3 times/week. AGEs were measured in serum by fluorescence spectrometry. Results: At baseline, serum AGEs fluorescence level was significantly higher in inactive HIV-patients when compared to controls or active HIV-patients (In-HIV: 0.93 ± 0.08 vs. controls: 0.68 ± 0.13 and Ac-HIV: 0.59 ± 0.04 A.U.; P < 0.001). Triglycerides were also higher in In-HIV than CTL (182.8 ± 102 vs. 132.8 ± 52.3 mg/dL; P < 0.05). Waist circumference was lower in Ac-HIV, compared to In-HIV and controls (83.9 ± 10.4 vs. 92.9 ± 13.5 and 98.3 ± 12.4, respectively; P < 0.05). Body mass, fasting blood glucose, LDL, HDL, and total cholesterol were similar between groups. After training, AGE levels decreased (Baseline: 0.93 ± 0.08 vs. 3 months follow-up: 0.59 ± 0.04 AU; P < 0.001), no further difference being detected vs. CTL or Ac-HIV. Conclusion: HIV-infected patients under cART exhibited elevated AGEs levels compared to healthy individuals and physically active patients. Short-term aerobic training of moderate intensity counteracted this condition.

Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease.

BACKGROUND: This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). METHODS: In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. RESULTS: Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. CONCLUSION: The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.