Cross-talk of insulin, leptin and glucocorticoid signaling in the rat hypothalamus and skeletal muscle during metabolic disturbances induced by dietary fructose and stress

Abstract

Modern way of living includes unpredictable stressful daily events and consumption of caloric fructose-rich food. Increased incidence of insulin resistance and metabolic syndrome raise the necessity to investigate how these two factors present in our everyday lives influence metabolic health. The aim of this doctoral dissertation is to test the hypothesis that fructose diet combined with chronic unpredictable stress induces more pronounced metabolic derangements in the skeletal muscle and hypothalamus of male Wistar rats than each of the factors applied separately. With that in mind, we analyzed hypothalamic insulin and leptin signaling and their effects on appetite regulation, skeletal muscle insulin signaling, and lipid metabolism, muscle glucocorticoid signaling and inflammation after challenging conditions of excessive fructose consumption (9 weeks) and/or exposure to chronic unpredictable stress (4 weeks). Results showed that fructose diet combined with chronic stress altered expression of hypothalamic neuropeptides causing increased appetite and energy intake, increased activity of AMPK energy sensor and impaired insulin signaling. In the skeletal muscle, combination of fructose and stress caused muscle lipid overload and disturbed lipid metabolism by increasing lipolysis and β-oxidation. Decreased muscle glucocorticoid signaling enabled rise of uncontrolled lipid-induced inflammation creating a setting for muscle insulin signaling impairment detected after combination of the treatments. Results of this doctoral dissertation have clearly showed that combination of fructose diet and chronic stress exposure had more detrimental effects on the hypothalamus and skeletal muscle of male rats than each of the treatments applied separately.

Moderan način života se sastoji od svakodnevnih nepredvidivih stresnih događaja i konzumiranja kalorične hrane bogate fruktozom. Povećana učestalost insulinske rezistencije i metaboličkog sindroma nameće potrebu da se istraži kako ova dva faktora prisutna u našem svakodnevnom životu utiču na metaboličko zdravlje. Cilj ove doktorske disertacije je da se ispita hipoteza da ishrana bogata fruktozom u kombinaciji sa hroničnim nepredvidivim stresom izaziva izraženije metaboličke poremećaje u skeletnim mišićima i hipotalamusu mužjaka pacova nego svaki od primenjenih tretmana ponaosob. Imajući to na umu, analizirali smo signalizaciju insulina i leptina u hipotalamusu i njihove efekte na regulaciju apetita, signalizaciju insulina u skeletnim mišićima, metabolizam lipida, signalizaciju glukokortikoida i inflamaciju nakon prekomernog unosa fruktoze (9 nedelja) i/ili izloženosti hroničnom nepredvidivom stresu (4 nedelje). Rezultati su pokazali da ishrana bogata fruktozom u kombinaciji sa hroničnim stresom menja ekspresiju neuropeptida hipotalamusa, izazivajući povećan apetit i unos energije, povećanu aktivnost energetskog senzora AMPK i narušava insulinsku signalizaciju. U skeletnim mišićima, kombinacija fruktoze i stresa izazvala je povećanje unosa lipida i nivoa lipolize i β-oksidacije. Inhibirana glukokortikoidna signalizacija omogućava povećanje nekontrolisane inflamacije izazvane lipidima, doprinoseći poremećaju mišićne insulinske signalizacije nakon kombinacije tretmana. Rezultati ove doktorske disertacije jasno su pokazali da je kombinacija ishrane bogate fruktozom i hronične izloženosti stresu izazvala štenije efekte na hipotalamus i skeletne mišiće mužjaka pacova nego svaki od tretmana primenjen pojedinačno.