Abstract
Nowadays, endocrine disorders have become more frequent in both human and veterinary medicine. In horses, reduced physical activity combined with carbohydrate and sugar overload may result in the development of the so-called equine metabolic syndrome (EMS). EMS is characterized by insulin resistance, hyperinsulinemia, elevated blood triglyceride concentrations and usually obesity. Although the phenotypic features of EMS individuals are well known, the molecular mechanism underlying disease development remains elusive. Therefore, in the present study, we analyzed insulin-sensitive tissues, i.e., muscles, liver and adipose tissue in order to evaluate insulin resistance and apoptosis. Furthermore, we assessed mitochondrial dynamics and mitophagy in those tissues, because mitochondrial dysfunction is linked to the development of metabolic syndrome. We established the expression of genes related to insulin resistance, endoplasmic reticulum (ER) stress and mitochondria clearance by mitophagy using RT-PCR and Western blot. Cell ultrastructure was visualized using electron transmission microscopy. The results indicated that adipose tissue and liver of EMS horses were characterized by increased mitochondrial damage and mitophagy followed by triggering of apoptosis as mitophagy fails to restore cellular homeostasis. However, in muscles, apoptosis was reduced, suggesting the existence of a protective mechanism allowing that tissue to maintain homeostasis.
Highlights
Equine metabolic syndrome (EMS) is an increasingly common endocrine disease that is a constellation of clinical abnormalities associated primarily with insulin resistance
Increased fat content in liver and muscles is suspected to be a major factor leading to the development of systemic proinflammatory state, due to the elevated expression of tumor necrosis factor α (TNF-α) combined with suppressor of cytokine signaling 3 (SOCS3) and Toll-like receptor 4 (TLR4)
We have shown for the first time that adipose tissue and liver are affected by progressive p53-related apoptosis in EMS and that together with endoplasmic reticulum (ER) stress they induce autophagy to protect the cells against glucolipotoxicity
Summary
Equine metabolic syndrome (EMS) is an increasingly common endocrine disease that is a constellation of clinical abnormalities associated primarily with insulin resistance. It has been established that adipose tissue of both horses and humans affected with EMS secretes pro-inflammatory cytokines and adipokines to the peripheral blood, which might be a major factor contributing to insulin resistance development [2,3,4]. We demonstrated in our previous research [5] that in insulin-resistant EMS ponies, “cresty neck”-derived adipose tissue secreted abundantly pro-inflammatory cytokines, adipokines and hormones. This in turn leads to a low-grade systemic inflammation, which is crucial in the context of laminitis development. The progressive inflammation and oxidative stress of hepatocytes, adipocytes and myocytes, together with progressive apoptosis in the course of EMS may in turn be the factors that induce autophagy or/and mitophagy to rescue stressed cells
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