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

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

Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways

An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hepatic fatty acid oxidation. The fructose-enriched diet induced sex-specific effects on hepatic lipid metabolism in young rats. These results imply that male and female rats employ different strategies to cope with dietary fructose-related energy overload and to avoid lipid accumulation in the liver

Urban project for construction, reconstruction, extension and adaptation of facilities in the complex of the General Hospital of the Užice Health Center

Урбанистички пројекат са Идејним решењем изградње, доградње, реконструкције и адаптације Опште болнице Здравственог центра Ужице израђен је за потребе прилагођавања савременим интернационалним стандардима у здравству, дефинисања конуникација и функционалности према захтевима медицинске технологије, решавања саобраћајних приступа свих неопходних потреба, и очувања културно историјског наслеђа као сведочанства развоја здравства у Србији. У комплексу се налази утврђено непокретно културно добро од изузетног значаја – Партизанска болница. Планирана је изградња, реконструкцијa, доградњa и адаптацијa објеката укупне БРГП преко 100.000 m2,за преко 1.000 болничких постеља. Изради Урбанистичког пројекта и Идејног решења претходила су опширна истраживања и студије.The urban design project with the conceptual design for construction, reconstruction, extension and adaptation of facilities in the complex of the General Hospital of the Uzice Health Center was created for the needs of meeting the modern international standards in healthcare, defining communications and functionality according to the requirements of medical technology, solving traffic access for all necessary needs, and preserving the cultural and historical heritage as evidence of the development of healthcare in Serbia. The immovable cultural good of exceptional importance - the Partisan Hospital – is located within the complex. The gross unfolded building floor area is over 100,000 m2, with over 1,000 hospital beds. The development of the Urban Project and Conceptual Solution was preceded by extensive research and numerous studies.Уредник: Јасна Марићевић Прва награда у категорији "Урбанистички пројекти и реализације"Прва награда у категорији "Урбанистички пројекти и реализације"Уредник: Јасна Марићеви

Glucocorticoid-mediated effects of mif deficiency and fructose - enriched diet on energy metabolism in the mouse liver

Introduction: The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in the regulation of energy metabolism and glucocorticoid action in the liver. Genetic deletion of Mif may contribute to the development of systemic insulin resistance, especially in the setting of fructose overload that can be associated with perturbed hepatic metabolism. The aim: The aim of the present study was to elucidate the impact of combined effects of Mif deficiency and dietary sugar on energy metabolism and insulin sensitivity in the liver of male mice. Methods: Wild type (WT) and Mif deficient (MIF-/-) C57Bl/6J mice were used to analyze the effects of 9-week 20% fructose-enriched diet on energy intake, and indicators of insulin sensitivity and glucocorticoid receptor (GR) signaling. Deregulation of Akt signaling pathway was used as a hallmark of hepatic insulin resistance. Changes in energy metabolism were estimated by AMP-activated protein kinase (AMPK) and SIRT1 protein levels. Results: All fructose-fed animals had increased energy intake, while elevated APMK and SIRT1 protein levels compared to the WT ones. Although enhanced glucocorticoid prereceptor metabolism was observed in all fructose-fed mice, GR protein level was increased only in MIF-/- animals. Mif deficient animals exibited impaired systemic insulin sensitivity. However, the impaired hepatic insulin signaling, revealed by decreased pAkt/total Akt ratio, was observed only in fructose-fed MIF-/- animals. Conclusion: The results showed that Mif deficiency under the conditions of dietary fructose overload leads to systemic insulin resistance, and impaired hepatic insulin signaling and energy metabolism, possibly through enhanced glucocorticoid signaling.Đorđević A, editor. IUBMB Advanced School Nutrition, Metabolism and Aging; 2018; Petnica, Serbia. Belgrade: nstitute for Biological Research “Siniša Stanković”; 2018. p. 17

Dietary supplementation with liophilised strawberry improves insulin sensitivity and redox status in mouse model of diet induced obesity

Healthy dietary habits with abundant fruit consumption may reduce prevalence and positively affect development and progression of various chronic diseases including obesity and insulin-resistance related diseases. Strawberry (Fragaria × ananassa Duch.) represent a valuable source of vitamins, minerals, fatty acids, dietary fiber, and various bioactive polyphenolic compounds such as anthocyanins and flavonoids which are known for their antioxidant and anti-inflammatory activities. In this study we evaluated the effect of newly introduced strawberry cultivar „Aprika” supplemented in the form of lyophilized powder, on obesity-related metabolic alterations in high-fat-diet fed mice. We hypothesized that chronic (8 weeks) supplementation of lyophilized strawberries in the amount comparable to two servings per day in humans, would ameliorate insulin resistance associated with obesity in C57BL/6 mice. Furthermore, we hypothesized that strawberry meal consumed at 7PM i.e. before active feeding period of mice (which corresponds to early breakfast in humans) would induce more pronounced beneficial effects compared to meal consumed at 7AM i.e. at the end of the active feeding period (which corresponds to late dinner in humans). High fat diet induced hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity; and disturbed hepatic insulin signaling. Lyophilized strawberries, only when consumed before feeding period, reduced body weight gain and improved insulin sensitivity induced by high-fat diet (evidenced by lower area under the curve after an intraperitoneal GTT, reduced serum insulin levels and an insulin resistance index (IR-HOMA). Strawberry meals consumed after active feeding period had no such effect. However, strawberries, regardless of the time of consumption, restored protein level of Insulin receptor substrate 1 (IRS1) in the liver and increased hepatic antioxidant enzymes level. In conclusion, strawberries improve insulin sensitivity and raise hepatic antioxidant capacity in mouse model of diet induced obesity. Nevertheless, more beneficial effects were achieved when strawberries were consumed before active feeding period, as an early breakfas

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

Purpose High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. Methods In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NF kappa B, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Results High-fructose diet led to glucose intolerance, activation of NF kappa B and JNK pathways and increased intrahepatic IL-1 beta, TNF alpha and inhibitory phosphorylation of insulin receptor substrate 1 on Ser(307). It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. Conclusion High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids

Impact of insulin and glucocorticoid signalling on hepatic glucose homeostasis in the rat exposed to high-fructose diet and chronic stress.

Overconsumption of fructose-enriched beverages and everyday stress are involved in the pathogenesis of metabolic disorders through modulation of hepatic glucose metabolism. The aim of the study was to investigate whether interaction of high-fructose diet and chronic stress alter insulin and glucocorticoid signalling thus affecting hepatic glucose homeostasis. High-fructose diet led to hyperinsulinemia, increased glucose transporter 2 level, elevated protein kinase B (Akt) phosphorylation, increased glucokinase mRNA and phospho-to-total glycogen synthase kinase 3 ratio and decreased expression of gluconeogenic genes. Fructose diet also led to stimulated glucocorticoid prereceptor metabolism, but downstream signalling remained unchanged due to increased glucocorticoid clearance. Stress did not affect hepatic insulin and glucocorticoid signalling nor glucose metabolism, while the interaction of the factors was observed only for glucokinase expression. The results suggest that, under conditions of fructose-induced hyperinsulinemia, suppression of gluconeogenesis and glycogen synthase activation contribute to the maintenance of glucose homeostasis. The increased glucocorticoid inactivation may represent an adaptive mechanism to prevent hyperglycaemia

100 godina transformacije koncepta javnog interesa u prostornom razvoju Srbije: razumevanje društvenog konteksta

U organizaciji istraživačkih jedinica Laboratorija za kulturu planiranja i dizajn prostornih politika i Laboratorija za kolaborativne urbane prakse, koje rade pod okriljem Centra za istraživačku delatnost Arhitektonskog fakulteta Univerziteta u Beogradu, pokrenut je istraživački projekat pod nazivom 100 godina transformacije koncepta javnog interesa u prostornom razvoju Srbije. Projekat se sprovodi kroz saradnju sa partnerskim organizacijama Ministarstvo prostora i Nova planska praksa i uključuje veći broj istraživača. Osnovni cilj projekta je sagledavanje razvoja koncepta javnog interesa u prostornom razvoju Srbije u poslednjih sto godina. Težišno se posmatra razvoj ideje javnog interesa i način formulacije politika prostornog razvoja i instrumenata implementacije kroz tri vremenska razdoblja: od perioda Kraljevine Jugoslavije kao jedne od prvih evropskih država sa ustanovljenim legislativnim i regulativnom okvirom javnog interesa, preko socijalističkog perioda i njegovih modaliteta u vidu državnog socijalizma, socijalističkog samoupravljanja i centralizovane demokratije, do savremenog perioda post-socijalističke ekonomske, političke i institucionalne transformacije. Ako se pođe od teze da javni interes oblikuje vladajuća ideologija i skup dominantnih vrednosti i normi, moguće je pratiti uticaj njihovih transformacija na promene u planskom sistemu, planskoj praksi i shodno tome prostornim ishodima. Očekuje se da se u procesu traganja za osnovama koncepta javnog interesa u domenu prostornog razvoja i njihovoj promeni kroz vreme može doći do važnih uvida od značaja za unapređenje savremene planske prakse u Srbiji. U ovom radu će biti prikazani preliminarni rezultati prve faze istraživanja.Organized by research units of the Laboratory for the Planning Culture of Spatial Policy Design and the Laboratory for Collaborative Urban Practices, which work under the auspices of the Research Center at the Faculty of Architecture, University of Belgrade, a research project entitled 100 years of transformation of public interest concept in the spatial development of Serbia was launched. The project is implemented through cooperation with partner organizations Ministry of Space collective and New Planning Practice and includes a large number of researchers. The main goal of the project is to consider the development of the concept of public interest in the spatial development of Serbia in the last hundred years. The development of the idea of public interest and the way of formulating spatial development policies and implementation instruments through three time periods are focused on: from the period of the Kingdom of Yugoslavia as one of the fi rst European states with established legislative and regulatory framework of public interest, through the socialist period and its modalities in the form of state socialism, self-government socialism and centralized democracy, to the modern period of post-socialist economic, political and institutional transformation. If we start from the thesis that the public interest is shaped by the ruling ideology and a set of dominant values and norms, it is possible to monitor the impact of their transformations on changes in the planning system, planning practice and, consequently, spatial outcomes. It is expected that in the process of searching for the basics of the concept of public interest in the fi eld of spatial development and their change over time, important insights for the improvement of modern planning practice in Serbia can be gained. This project goes a step further than focusing on contemporary planning issues in Serbia and emphasizes the truly transitional nature of the Serbian planning system and planning practices. This paper will present the preliminary results of the research fi rst phase

Involvement of glucocorticoid prereceptor metabolism and signaling in rat visceral adipose tissue lipid metabolism after chronic stress combined with high-fructose diet

Both fructose overconsumption and increased glucocorticoids secondary to chronic stress may contribute to overall dyslipidemia. In this study we specifically assessed the effects and interactions of dietary fructose and chronic stress on lipid metabolism in the visceral adipose tissue (VAT) of male Wistar rats. We analyzed the effects of 9-week 20% high fructose diet and 4-week chronic unpredictable stress, separately and in combination, on VAT histology, glucocorticoid prereceptor metabolism, glucocorticoid receptor subcellular redistribution and expression of major metabolic genes. Blood triglycerides and fatty acid composition were also measured to assess hepatic Delta 9 desaturase activity. The results showed that fructose diet increased blood triglycerides and Delta 9 desaturase activity. On the other hand, stress led to corticosterone elevation, glucocorticoid receptor activation and decrease in adipocyte size, while phosphoenolpyruvate carboxykinase, adipose tissue triglyceride lipase, FAT/CD36 and sterol regulatory element binding protein-1c (SREBP-1c) were increased, pointing to VAT lipolysis and glyceroneogenesis. The combination of stress and fructose diet was associated with marked stimulation of fatty acid synthase and acetylCoA carboxylase mRNA level and with increased 11 beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase protein levels, suggesting a coordinated increase in hexose monophosphate shunt and de novo lipogenesis. It however did not influence the level of peroxisome proliferator-activated receptor-gamma, SREBP-1c and carbohydrate responsive element-binding protein. In conclusion, our results showed that only combination of dietary fructose and stress increase glucocorticoid prereceptor metabolism and stimulates lipogenic enzyme expression suggesting that interaction between stress and fructose may be instrumental in promoting VAT expansion and dysfunction