Silvana A. Bordin

Institute of Biomedical Sciences – University of São Paulo

Laboratório de Biologia Molecular

Among all the metabolic biological rhythms, gestation is notably a period in which physiological insulin resistance is temporarily defined by coordinated molecular adaptations involving the endocrine pancreas and the insulin-responsive tissues. During the third gestational period, there is an increase in the beta cells mass and in the secretory action of insulin. These two factors, together, are able to maintain maternal blood sugar levels at a normal rate. After birth, the endocrine pancreas goes through a rapid involution, which helps prevent maternal hypoglycemia. Such functional remodeling mechanisms help to maintain the mothers energetic homeostasis and must take place in a very limited and specific time frame. In the last 12 years, our research group has outlined the molecular events coordinating the functional remodeling of maternal pancreatic islets in the perinatal period. We have described many mechanisms responsible for insulin secretion (Bordin et al., 2004; Anhê et al., 2006, 2007; Lellis-Santos et al., 2012) and beta cells modulation (Nicoletti-Carvalho et al., 2010; Bromati et al., 2011). Concomitantly, we showed that skeletal muscle (Anhê et al., 2007), liver (Rodrigues et al., 2014) and hypothalamus show coordinated responses to pancreatic adaptations. We have also demonstrated that discreet functional alterations at the end of gestation, induced by an excess of glucocorticoids, are associated with detrimental effects such as lower in insulin secretion, the development of late glucose intolerance (Gomes et al., 2014) and loss of hepatic responses to circadian oscillations in hormones and nutrient levels. Homeostasis of hepatic metabolism is arguably the most dependent on temporal oscillations in nutrients and hormone levels, associated or not with gestation. Aiming at unraveling the molecular mechanism that mediate circadian regulation of the energetic metabolism, we began a series of studies that use rupture models in physiological circadian rhythms (pinealctomy, light-dark cycle alterations, day feeding in mice). Our studies show that melatonin regulates hepatic gluconeogenesis in an endoplasmic-reticulum-stress-dependent way (Nogueira et al., 2011). Moreover, we showed that lack of melatonin during gestation alters glycemic homeostasis while in adult life (Ferreira et al., 2013). These phenomena seem to rely, in great part, on glucocorticoid levels and its way of action during the day. The molecular events involved in epigenetic regulation of the energetic metabolism by glucocorticoids is the focus of our present researches.

TEAM

PHD

• Carolina Vieira Campos
• Filiphe de Paula Nunes Mesquita
• Frhancielly Shirley Souza Sodré
• Gizela Maria Agostini Zonta
• Vanessa Barbosa Veronesi

SCIENTIFIC INITIATION

• Tiffany Boiani Watanabe

main discoveries

• Description of non-canonic pathways that regulate beta cell mass and function in physiological conditions (ERK3, STAT3, Rasd1, MKP1, UPR);
• Detailing of glucocorticoid physiological effects on pancreatic islets remodeling during gestation and lactation;
• Identification of late deleterious effects in mothers, started by the excess of glucocorticoids in gestation, and its correlation to differential expression in microRNAs;
• Study of the binomial melatonin-glucocorticoids on the regulation of hepatic metabolism.

main articles

• Melatonin improves insulin sensitivity independently of weight loss in old obese rats
• Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats
• Effects of melatonin on DNA damage induced by cyclophosphamide in rats
• Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats
• Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice
• Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation