Contribution of early postnatal overfeeding to metabolic disorders in animal model of polycystic ovary syndrome

Abstract

Sindrom policističnih jajnika (PCOS) je reproduktivni poremećaj u čijoj osnovi je hiperandrogenemija, ali ga prate i metaboličke komplikacije. PCOS se može javiti u prepubertetskom uzrastu, a povećanje telesne mase tokom ovog uzrasta predisponira za kasniji razvoj sindroma. Kalorijski suficit u perinatalnom periodu, koji se kod glodara postiže manipulacijom veličine legla, utiče na neuroendokrino programiranje, dovodeći do gojenja i ranijeg nastupanja puberteta. Cilj ove disertacije je bio da se na animalnom modelu PCOS ispita doprinos povećanog kalorijskog unosa u ranom postnatalnom periodu razvoju metaboličkih poremećaja udruženih sa sindromom. Model PCOS je kreiran tretmanom ženki pacova 5α-dihidrotestosteronom (DHT), a prepubertetska gojaznost postignuta kalorijskim suficitom kroz smanjenje veličine legla. Analizirani su parametri sistemske insulinske osetljivosti i lipidni status, kao i markeri insulinske signalizacije i energetskog metabolizma na nivou visceralnog (VAT) i subkutanog (SAT) masnog tkiva i skeletnih mišića. DHT tretman u kombinaciji sa povećanim kalorijskim unosom je uslovio sistemsku hiperinsulinemiju i smanjenje insulinske osetljivosti. Uprkos hipertrofiji adipocita, insulinska osetljivost na nivou VAT je očuvana, verovatno usled aktivacije AMPK. Izostanak proliferacije SAT i istovremeno aktivirani lipolitički i lipogeni putevi ukazuju na njegovu disfunkcionalnost. Skeletni mišići u uslovima smanjene osetljivosti na insulin koriste masne kiseline kao energetski supstrat, a aktivacija AMPK doprinosi funkcionalnosti tkiva kroz povećanje stope β-oksidacije. Dobijeni rezultati sugerišu da povećanje telesne mase pre puberteta predisponira razvoj insulinske rezistencije u PCOS, dok je za njeno puno ispoljavanje ključna interakcija sa hiperandrogenemijom.

Polycystic ovary syndrome (PCOS) is a reproductive disorder based on hyperandrogenemia but also associated with metabolic complications. PCOS can occur in girls before puberty, and the increase in body weight at this age predisposes them to later development of the syndrome. Increased caloric intake in the perinatal period, easily mimicked in rodents by manipulating litter size, affects neuroendocrine programming and leads to hyperphagia and weight gain, as well as earlier onset of puberty. The aim of this doctoral dissertation was to examine the contribution of increased caloric intake in early postnatal period to the development of metabolic disorders associated with the syndrome using an animal model of PCOS. An animal model of PCOS induced by 5α-dihydrotestosterone was additionally challenged with caloric excess by litter size reduction to induce prepubertal obesity. Parameters of systemic insulin sensitivity and lipid status were analyzed, as were markers of insulin signaling and energy metabolism at the level of visceral (VAT) and subcutaneous (SAT) adipose tissue and skeletal muscle. The combination of treatments resulted in systemic hyperinsulinemia and decreased insulin sensitivity. Despite adipocyte hypertrophy, insulin sensitivity is maintained at the VAT level, likely due to activation of AMPK. The absence of SAT proliferation and the concomitantly activated lipolytic and lipogenic metabolic pathways suggest its dysfunction. Skeletal muscles in conditions of reduced sensitivity to insulin use fatty acids as an energy substrate, and activation of AMPK contributes to the functionality of this tissue by increasing the rate of β-oxidation. Our results suggest that weight gain before puberty predisposes to the development of insulin resistance in PCOS, while interaction with hyperandrogenemia is critical for its full manifestation.