Metabolički sindrom izazvan ishranom bogatom fruktozom : uloga signalnih puteva regulisanih glukokortikoidnim hormonima u visceralnom masnom tkivu i hipotalamusu pacova
Fructose-diet induced metabolic syndrome : the role of glucocorticoid signalling in the visceral adipose tissue and hipothalamus of rats
Doctoral thesis (Published version)
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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. We hypothesized that glucocorticoid signalling is involved in the effects of different long-term fructose diets on the development of visceral adiposity through alterations in hypothalamic leptin sensitivity and adipogenic transcription factors in the visceral adipose tissue of male Wistar rats. We analyzed the effects of 9-week drinking of 10% and 60% fructose solutions on visceral adiposity, dyslipidemia, insulin and leptin sensitivity, adipose tissue histology and both plasma and tissue corticosterone levels. Leptin sensitivity was analyzed by measuring plasma leptin concentrations, hypothalamic leptin receptor (Ob-Rb) protein level and suppressor of cytokine signaling (SOCS3) and neuropeptide (NPY) mRNA level. Glucocorticoid signalling was assessed in both hypothalamus and visceral adipose tissue at the level of prereceptor metabolism and at the level of glucocorticoid receptor (GR) expression and compartmental redistribution. The level of expression of GR target genes PEPCK and HSL was also determined. In addition, we analyzed the levels of PPARγ, SREBP-1 and lipin-1 as a key transcriptional factors involved in adipogenesis and lipogenesis. To examine adipose tissue inflammatory state we analyzed protein level and intracellular redistribution of nuclear factor kappa B (NFB), as well as mRNA levels of TNF-α, IL-6 and MIF. The results revealed different impact of applied fructose diets on visceral adiposity, leptin and glucocorticoid signalling. Only the rats kept on 60% fructose diet accumulated visceral fat and developed adiposity, which was paralleled with reduced hypothalamic Ob-Rb level and elevated SOCS3 and NPY levels. Interestingly, 10% fructose consumption led to enhanced glucocorticoid signalling and lipolysis in the adipose tissue, while consumption of 60% liquid fructose led to diminished glucocorticoid signalling, activation of adipogenic transcription factors and adipogenesis. In addition, fructose diet attenuated NFκB activation and did not alter proinflammatory cytokines in the adipose tissue, regardless of fructose concentration. In conclusion, these results propose that long-term fructose diet leads to hypothalamic leptin resistance and development of visceral adiposity, but only at higher fructose concentrations. The results also suggest that adiposity-related effects of fructose consumption may involve the interplay between leptin and glucocorticoid signalling at the level of central effector pathways that control energy balance.
Keywords:Fructose; Hypothalamus; Visceral adipose tissue; Leptin; Glucocorticoids; Adipogenesis; Lipolysis; Inflammation
Source:University of Belgrade, Faculty of Biology, 2014, 1-164
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