AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding
Bojana Mićić, Ana Djordjević, Nataša Veličković, Sanja Kovačević, Teodora Martić, Djuro Μacut, Danijela Vojnović Milutinović
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients.