Metabolizam lipida i signalni put glukokortikoida u visceralnom masnom tkivu i jetri Mif -/- miševa na režimu ishrane obogaćene fruktozom

Abstract

Faktor inhibicije migracije makrofaga (MIF) jedan je od glavnih pro-inflamatornih citokina sa ulogom u metaboličkoj inflamaciji. Metabolička inflamacija niskog intenziteta u visceralnom masnom tkivu i jetri povezana je sa gojaznošću i dislipidemijom - metaboličkim poremećajima koji su često izazvani ishranom obogaćenom fruktozom i predstavljaju faktore rizika za razvoj dijabetesa tipa 2. Cilj ove doktorske disertacije bio je da se utvrdi da li MIF ostvaruje svoj uticaj na lipidni metabolizam u masnom tkivu i jetri posredstvom glukokortikoidnih hormona (GH), važnih regulatora energetskog metabolizma. U tom cilju bili su ispitani najvažniji parametri lipidnog metabolizma i inflamacije, signalni put GH-a, kao i enzimi i transkripcioni regulatori uključeni u lipidni metabolizam, direktno ili indirektno regulisani glukokortikoidnim receptorom, kod miševa „divljeg tipa“ i miševa sa deletiranim genom za MIF (MIF-/-) u normalnim uslovima i pod uslovima energetskog opterećenja izazvanog fruktozom. Rezultati su pokazali da nedostatak gena Mif dovodi do hiperleptinemije, hiperglikemije, hiperinsulinemije i sistemske insulinske rezistencije nezavisno od režima ishrane. Iako nije bilo promena u nivou triglicerida i slobodnih masnih kiselina u krvi, ishrana bogata fruktozom dovela je do pojave visceralne gojaznosti, steatoze jetre, ali i aktivacije signalnog puta GH-a u masnom tkivu i jetri MIF-/- miševa. Inflamacija u masnom tkivu nije zabeležena, dok je u jetri svih MIF-/- miševa primećeno povećanje ekspresije pro-inflamatornih citokina, kao i nekrotične i regenerativne promene. Na osnovu dobijenih rezultata zaključeno je da ishrana obogaćena fruktozom izaziva poremećaj metabolizma glukoze i lipida kod MIF-/- miševa usled pojačane signalizacije GH-a u uslovima insulinske rezistencije.

Macrophage migration inhibitory factor (MIF) is one of the main pro-inflammatory cytokines with a role in metabolic inflammation. Low-grade inflammation in the visceral adipose tissue and liver is associated with obesity and dyslipidemia - metabolic disorders that are often caused by a fructose-enriched diet and are risk factors for the development of type 2 diabetes. The aim of this doctoral dissertation was to determine whether MIF exerts its influence on lipid metabolism in the adipose tissue and liver through glucocorticoid hormones (GC), important regulators of energy metabolism. To this end, the most important parameters of lipid metabolism and inflammation, the GC signaling pathway, as well as enzymes and transcriptional regulators involved in lipid metabolism, directly or indirectly regulated by the glucocorticoid receptor, were examined in wild type mice and mice with deleted Mif gene (MIF-/-) under normal conditions and under fructose-induced energy overconsumption. The results showed that Mif deficiency leads to hyperleptinemia, hyperglycemia, hyperinsulinemia, and systemic insulin resistance independently of diet. Although there were no changes in blood triglycerides and free fatty acids levels, a fructose-enriched diet led to visceral obesity, liver steatosis, and activation of the GC signaling pathway in adipose tissue and the liver of MIF-/- mice. Inflammation was not found in adipose tissue, while an increase in the expression of pro-inflammatory cytokines, as well as necrotic and regenerative changes, were observed in the liver of all MIF-/- mice. Based on the obtained results, it was concluded that fructose-enriched diet causes disturbances in glucose and lipid metabolism in MIF-/- mice due to enhanced GC signaling in conditions of insulin resistance.