Fructose-diet induced metabolic syndrome : the role of glucocorticoid signalling in the visceral adipose tissue and hipothalamus of rats

Upotreba zašećerenih napitaka bogatih fruktozom predstavlja jedan od glavnih uzročnika povećanja prevalence gojaznosti i pridruženih metaboličkih poremećaja. Pokazano je da je fruktoza uključena u razvoj i progresiju metaboličkog sindroma putem poremećaja regulacije metaboličkih puteva u hipotalamusu i masnom tkivu, kao glavnim organima zaduženim za kontrolu unosa hrane i energetskog metabolizma. Takođe, poznato je da je ishrana bogata fruktozom povezana sa stanjem leptinske rezistencije u hipotalamusu. Postoje i dokazi da pojačana regeneracija glukokortikoida, posredovana enzimom 11β hidroksisteroid dehidrogenazom tipa 1 (11βHSD1), može doprineti razvoju adipoznosti i metaboličkih poremećaja. Glukokortikoidni hormoni su uključeni u regulaciju homeostaze triglicerida u masnom tkivu i mogu da modulišu i proces lipolize i proces lipogeneze putem povećanja ekspresije lipolitičkih enzima, kao što je lipaza osetljiva na dejstvo hormona (eng. hormone-sensitive lipase, HSL) ili posredstvom drugih regulatora metabolizma lipida, kao što su fosfoenolpiruvat karboksikinaza (eng. phosphoenolpyruvate carboxykinase, PEPCK) i lipin-1. Proces adipogeneze u masnom tkivu odvija se uz učešće brojnih transkripcionih regulatora koji stimulišu ekspresiju gena lipogeneze među kojima se nalazi i gen koji kodira γ izoformu receptora koji aktivira proliferaciju peroksizoma (eng. peroxisome proliferator-activated receptor γ, PPARγ) i protein koji se vezuje za element regulisan sterolom (eng. sterol regulatory element-binding protein-1, SREBP-1). Poremećaj funkcije masnog tkiva u metaboličkom sindromu može biti i rezultat hronične inflamacije koja se karakteriše akumulacijom makrofaga u masnom tkivu i povećanom sekrecijom proinflamatornih citokina...The rise in consumption of refined sugars high in fructose appears to be an important factor for the development of obesity and metabolic syndrome. Fructose has been shown to be involved in genesis and progression of the syndrome through deregulation of metabolic pathways in the hypothalamus and adipose tissue as major organs for control of food intake and energy metabolism. Fructose consumption has been previously associated with the state of leptin resistance in the hypothalamus. Furthermore, there is evidence that enhanced glucocorticoids regeneration, mediated by the enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), may contribute to adiposity and metabolic disease. Glucocorticoids are involved in the regulation of triglyceride homeostasis in the adipose tissue and can modulate both lipolysis and lipogenesis through increased synthesis of lipolytic enzymes, such as hormone-sensitive lipase (HSL), or through other regulators of lipid metabolism, like phosphoenolpyruvate carboxykinase (PEPCK) and lipin-1. During expansion, adipose tissue responds by increasing adipogenesis through a complex regulatory network of transcription factors including peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element-binding protein-1 (SREBP-1), both involved in stimulation of lipogenic gene expression. Adipose tissue dysfunction in metabolic syndrome may result from chronic inflammation characterized by accumulation of adipose tissue macrophages and higher secretion of proinflammatory cytokines..

The role of glucocorticoid hormones in diet-induced metabolic diseases

Summary. Excessive fructose intake promotes the development of metabolic syndrome through the deregulation of metabolic pathways in the hypothalamus, liver and adipose tissue, which play crucial roles in metabolic homeostasis by responding to the body’s nutritional and energy requirements. Variable amounts and modes of fructose intake have been shown to result in different patterns of expression of metabolic disturbances, which generally include adiposity, insulin and leptin resistance, dyslipidemia and hypertension. We explored the possible mediatory role of glucocorticoid signaling on the effects of two different dietary fructose loads on hypothalamic leptin sensitivity and hepatic and adipose tissue lipid metabolism, which are responsible for the development of signs of metabolic syndrome. Experimental rats were provided with 10% and 60% fructose solutions ad libitum over a period of nine weeks. Our results revealed that the applied fructose had different impacts on leptin and glucocorticoid signaling and different consequences on visceral adiposity and hepatic lipid metabolism. Only rats maintained on the high-burden 60% fructose diet accumulated visceral fat through the activation of adipogenic transcription factors and adipogenesis. This was paralleled by diminished glucocorticoid signaling in the adipose tissue and the establishment of the state of hypothalamic leptin resistance. The high-burden dietary fructose triggered hepatic de novo lipogenesis and a concomitant inhibition of β oxidation. Consumption of 10% fructose enhanced glucocorticoid signaling and lipolysis in the adipose tissue, creating a circulatory influx of free fatty acids and providing substrates for enhanced β oxidation and triglyceride synthesis in the liver. In summary, our results show that a long-term high dietary fructose load leads to hypothalamic leptin resistance, the development of visceral adiposity and increased hepatic de novo lipogenesis. Glucocorticoids regulate adipocyte storage functionality and thus may indirectly contribute to the observed changes in hepatic lipid metabolism, aggravating the metabolic disturbance

Isoflavone content and antioxidant activity of soybean inoculated with plant-growth promoting rhizobacteria

Plant-growth promoting rhizobacteria (PGPR) elicit activation of the phenylpropanoid pathway in plants, which leads to phenolics production and enhanced antioxidant capacity. The purpose of this work was to assess the antioxidant activity of soybean plants, Glycine max L., inoculated with PGPR (isolates of Azotobacter chroococcum, Streptomyces sp. and mixture of these) during plant development, as well as the yield of inoculated soybean plants. PGPR applied in the experiment stimulated flavonoids and isoflavone synthesis, which enhanced the non-enzymatic antioxidant ability of the soybean plants. Moreover, PGPRs stimulated the accumulation of daidzein and genistin in soybean seedlings (5-fold and 2-fold compared to the control values, respectively). The mixture of PGPRs had a positive impact on the antioxidant activity (10-20 % higher activity) and yield components of soybean, which proposed this inoculum as possibly a potent bio-fertilizer in soybean production

High dietary fructose load aggravates lipid metabolism in the liver of Wistar rats through imbalance between lipogenesis and fatty acid oxidation

Fructose ingestion is often associated with hepatic steatosis and hypertriglyceridemia. The homeostasis of hepatic lipids is mainly determined by the interplay of lipogenesis and fatty acid β‑oxidation. In this study, we hypothesized that high fructose intake disturbs hepatic lipid metabolism through an imbalance between these processes. Therefore, we analyzed the effects of a 9-weeklong consumption of a 60% fructose solution on physiological parameters, glycemia, and blood lipid profiles in male Wistar rats. The expression of key regulators of fatty acid oxidation (FAO) and lipogenesis in the liver were assessed by western blot and quantitative polymerase chain reaction. The results showed that fructose-fed rats were normoglycemic and hypertriglyceridemic with visceral adiposity, but without hepatic lipid deposition. A high-fructose diet is associated with increased nuclear levels of the lipogenic regulator sterol regulatory element binding protein 1c (SREBP-1c), which was followed by increased acetyl‑CoA carboxylase and fatty acid synthase mRNAs. The nuclear level of the FAO transcriptional regulators peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1) and lipin‑1 were unaltered, while carnitine palmitoyltransferase 1 (CPT1) mRNA was significantly decreased. Overall, our findings showed that liquid fructose overconsumption is associated with perturbation of hepatic lipid metabolism through predominance of lipogenesis over β-oxidation, resulting in spillover of triglycerides and visceral adiposity.Turkish Journal of Biology (2016), 40(6): 1235-124

Disturbances of systemic and hippocampal insulin sensitivity in macrophage migration inhibitory factor (MIF) knockout male mice lead to behavioral changes associated with decreased PSA-NCAM levels

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine well known for its role in inflammation enhancement. However, a growing body of evidence is emerging on its role in energy metabolism in insulin sensitive tissues such as hippocampus, a brain region implicated in cognition, learning and memory. We hypothesized that genetic deletion of MIF may result in the specific behavioral changes, which may be linked tо impairments in brain or systemic insulin sensitivity by possible changes of the hippocampal synaptic plasticity. To assess memory, exploratory behavior and anxiety, three behavioral tests were applied on Mif gene-deficient (MIF −/− ) and “wild type” C57BL/6J mice (WT). The parameters of systemic and hippocampal insulin sensitivity were also determined. The impact of MIF deficiency on hippocampal plasticity was evaluated by analyzing the level of synaptosomal polysialylated-neural cell adhesion molecule (PSA-NCAM) plasticity marker and mRNA levels of different neurotrophic factors. The results showed that MIF −/− mice exhibit emphasized anxiety-like behaviors, as well as impaired recognition memory, which may be hippocampus-dependent. This behavioral phenotype was associated with impaired systemic insulin sensitivity and attenuated hippocampal insulin sensitivity, characterized by increased inhibitory Ser 307 phosphorylation of insulin receptor substrate 1 (IRS1). Finally, MIF −/− mice displayed a decreased hippocampal PSA-NCAM level and unchanged Bdnf, NT-3, NT-4 and Igf-1 mRNA levels. The results suggest that the lack of MIF leads to disturbances of systemic and hippocampal insulin sensitivity, which are possibly responsible for memory deficits and anxiety, most likely through decreased PSA-NCAM-mediated neuroplasticity rather than through neurotrophic factors.Hormones and Behavior (2017), 96: 95-10

Mif deficiency promotes adiposity in fructose-fed mice.

The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in wild type and MIF-/- C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogenic transcriptional regulators peroxisome proliferator activated receptor gamma (PPARG) and sterol regulatory element-binding protein 1c (SREBP1c) was also assessed. Results showed disturbed insulin sensitivity in all MIF-/- mice, regardless of the diet. Mice on fructose diet had increased energy intake, but increased visceral adiposity and enlarged adipocytes were observed only in fructose-fed MIF-/- mice. Increased VAT corticosterone level and 11 beta-hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase and GR protein levels were observed in the same animals, together with induced expression of examined lipogenic genes and accumulation of PPARG and SREBP1c. In conclusion, the results showed that dietary fructose was associated with increased visceral adiposity through activation of GR-regulated lipogenic genes, but only in the absence of MIF, which set the state of hyperinsulinemia and insulin resistance.Disclaimer: this is not the definitive version of record of this article. This manuscript has been accepted for publication in Journal of Endocrinology, but the version presented here has not yet been copy-edited, formatted or proofed. The definitive version is now freely available at [https://doi.org/10.1530/JOE-18-0333] 2019

The efficacy outcomes in non-small cell lung cancer patients treated with PD axis inhibitor agents - a population-based study of the Vojvodina region

Background: By 2021, the FDA approved the use of the drugs pembrolizumab and atezolizumab in the first-line treatment of patients with high positivity of programmed death ligand-1 (PD-L1) in locally advanced and metastatic non-small-cell-lung cancer (NSCLC). This approval was the result of statistically significant evidence from international, multicentric clinical studies that all reported increasing progression-free survival (PFS) and overall survival (OS) in these patients.Methods: In our study, we reported the demographic and clinical characteristics of 79 patients diagnosed with NSCLC with expression of PD-L1 ≥50% from January 2019 to December 2022 at the Institute for Pulmonary Diseases of Vojvodina, who received pembrolizumab therapy as the first-line treatment. Patients were divided according to the histological type of lung cancer as adenocarcinoma (ADC) or squamous cell carcinoma (SCC) of the lung. In 52 of the 79 patients, PFS and in 32 of them overall survival (censored OS) was shown according to the histological type of tumor, the tumor proportion score (TPS) of PDL-1 expression, and the metastatic status within the Tumor Nodes Metastasis (TNM) disease classification. Independent factors of death outcome were shown by multivariable proportional hazard regression analysis.Results: The study included 79 patients diagnosed with NSCLC with an expression of PD-L1 ≥50%, 50 (63.3%) patients with ADC, and 29 (36.7%) patients with SCC, whose 55 (69.6%) PDL-1 expression was obtained from broncho biopsy (BB). The majority of patients, 49 (62%), had a TPS PD-L1 score of 51%–79%. Median, PFS for adenocarcinoma was 22 months and censored OS was 27 months, while for squamous cell carcinoma, median PFS was 12 months, and censored OS was 21 months. M1b disease stage, which was the most common in patients, had a PFS of 16 months and a censored OS of 18 months.Conclusion: Pembrolizumab monotherapy in patients with NSCLC in the fourth stage of the disease and with the positivity of the immune checkpoint protein TPS PD-L1 above 50% represents a safe therapy that allows a satisfactory period without disease progression and overall survival with acceptable treatment complications