Abstract
Metabolic syndrome can lead to several challenging complications including degeneration of the pancreas and hypogonadism. Recently, we have shown that Bisamide Derivative of Dicarboxylic Acid (BDDA) can contribute to pancreatic restoration in mice with metabolic disorders via its positive effects on lipid and glucose metabolism, and by increasing the numbers of pancreatic stem cells. In the present study, we hypothesized that BDDA might also be effective in restoring hypogonadism caused by metabolic syndrome. Experiments were performed on male C57BL/6 mice with hypogonadism, where metabolic disorders have been introduced by a combination of streptozotocin treatment and high fat diet. Using a combination of histological and biochemical methods along with a flow cytometric analysis of stem and progenitor cell markers, we evaluated the biological effects of BDDA on testicular tissue, germ cells, spermatogonial stem cells in vitro and in vivo, as well as on fertility. We demonstrate that in mice with metabolic disorders, BDDA has positive effects on spermatogenesis and restores fertility. We also show that BDDA exerts its therapeutic effects by reducing inflammation and by modulating spermatogonial stem cells. Thus, our results suggest that BDDA could represent a promising lead compound for the development of novel therapeutics able to stimulate regeneration of the testicular tissue and to restore fertility in hypogonadism resulting from complications of metabolic syndrome.
Highlights
MATERIALS AND METHODSThe International Association of Diabetes defines metabolic syndrome (MS) as a combination of abdominal obesity, insulin resistance, hyperglycemia, dyslipidemia, arterial hypertension, violation of the hemostatic system, and chronic subclinical inflammation (Standl, 2005; International Diabetes Federation, 2016)
We have previously shown that streptozotocin and a high fat diet causes an increase in the concentrations of glucose, insulin, triglycerides (TG) and very-low-density lipoproteins (VLDL) in the serum of male C57BL/6 mice, as well as increases the body mass index (BMI) (Pakhomova et al, 2020)
We have further demonstrated that bisamide derivative of dicarboxylic acid (BDDA) improves the physiological function of the pancreas in animals with Metabolic disorders (MD)
Summary
MATERIALS AND METHODSThe International Association of Diabetes defines metabolic syndrome (MS) as a combination of abdominal obesity, insulin resistance, hyperglycemia, dyslipidemia, arterial hypertension, violation of the hemostatic system, and chronic subclinical inflammation (Standl, 2005; International Diabetes Federation, 2016). There is a considerable and steady increase in the prevalence of MS among adolescents and young people (Rask-Madsen and Kahn, 2012). In men with MS, a low level of testosterone often correlates with disturbances of carbohydrate and fat metabolism (Dhindsa, 2004; Kapoor et al, 2007; Wespes, 2013; Lamm et al, 2016; Dimopoulou et al, 2018). Metabolic disorders (MD) in MS can lead to the development of hypogonadism with a prevalence reaching 50– 75% (Lamm et al, 2016). Current treatment of hypogonadism can only reduce the symptoms of androgen deficiency but is not able to cure it (Lunenfeld et al, 2015)
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