The Effect of Metformin and Carbohydrate-Controlled Diet on DNA Methylation and Gene Expression in the Endometrium of Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disease associated with infertility and metabolic disorders in reproductive-aged women. In this study, we evaluated the expression of eight genes related to endometrial function and their DNA methylation levels in the endometrium of PCOS patients and women without the disease (control group). In addition, eight of the PCOS patients underwent intervention with metformin (1500 mg/day) and a carbohydrate-controlled diet (type and quantity) for three months. Clinical and metabolic parameters were determined, and RT-qPCR and MeDIP-qPCR were used to evaluate gene expression and DNA methylation levels, respectively. Decreased expression levels of HOXA10, GAB1, and SLC2A4 genes and increased DNA methylation levels of the HOXA10 promoter were found in the endometrium of PCOS patients compared to controls. After metformin and nutritional intervention, some metabolic and clinical variables improved in PCOS patients. This intervention was associated with increased expression of HOXA10, ESR1, GAB1, and SLC2A4 genes and reduced DNA methylation levels of the HOXA10 promoter in the endometrium of PCOS women. Our preliminary findings suggest that metformin and a carbohydrate-controlled diet improve endometrial function in PCOS patients, partly by modulating DNA methylation of the HOXA10 gene promoter and the expression of genes implicated in endometrial receptivity and insulin signaling.

Antibiotics Alter the Expression of Genes Related to Behavioral Development in Honey Bees (Hymenoptera: Apidae).

Honey bees, as many species of social insects, display a division of labor among colony members based on behavioral specializations related to age. Adult worker honey bees perform a series of tasks in the hive when they are young (such as brood care or nursing) and at ca. 2-3 wk of age, shift to foraging for nectar and pollen outside the hive. The transition to foraging involves changes in metabolism and neuroendocrine activities. These changes are associated with a suite of developmental genes. It was recently demonstrated that antibiotics influence behavioral development by accelerating or delaying the onset of foraging depending on timing of antibiotic exposure. To understand the mechanisms of these changes, we conducted a study on the effects of antibiotics on expression of candidate genes known to regulate behavioral development. We demonstrate a delay in the typical changes in gene expression over the lifetime of the individuals that were exposed to antibiotics during immature stage and adulthood. Additionally, we show an acceleration in the typical changes in gene expression on individuals that were expose to antibiotics only during immature stage. These results show that timing of antibiotic exposure alter the typical regulation of behavioral development by metabolic and neuroendocrine processes.

Effects of in utero androgen excess and metformin treatment on hepatic functions.

This study aimed to evaluate the role of prenatal hyperandrogenization in liver functions and the extent of metformin as treatment. Pregnant rats were hyperandrogenized with subcutaneous testosterone (1mg/rat) between 16 and 19 of pregnancy. Prenatally hyperandrogenized (PH) female offspring displayed, at the adult life, two phenotypes; a PH irregular ovulatory phenotype (PHiov) and a PH anovulatory (PHanov) phenotype. From day 70 to the moment of sacrifice (90 days of age), 50% of the animals of each group received a daily oral dose of 50 mg/kg of metformin. We found that both PH phenotypes displayed a hepatic disruptions of insulin and glucose pathway and that metformin treatment reversed some of these alterations in a specific-phenotype manner. Our findings show, for the first time, that androgen excess in utero promotes hepatic dysfunctions and that metformin treatment is able to specifically reverse those hepatic alterations and sheds light on the possible mechanisms of metformin action.

Nonfunctional overreaching and hepatic adaptations of APPL1 and APPL2

Abstract AIMS Previously, we verified that overtrained mice upregulated the TRB3 levels, its association with Akt, and the hepatic concentrations of glycogen. It is known that APPL1 can limit the interaction between TRB3 and Akt, playing an important role in the glucose homeostasis. Thus, we verified the effects of three overtraining protocols on the hepatic levels of APPL1 and APPL2. METHODS Rodents were divided into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR). The hepatic contents of APPL1 and APPl2 were measured by the immunoblotting technique. RESULTS Significant elevation of APPL1 observed in the OTR/down and OTR/up groups, as well as the tendency of increase (p=0.071) observed in the OTR group. CONCLUSION These results indicate that this particular protein is likely to participate in the glucose homeostasis previously observed in response to these OT protocols.(AU)

Maternal vitamin D-restricted diet has consequences in the formation of pancreatic islet/insulin-signaling in the adult offspring of mice.

The maternal deficiency of vitamin D can act on organogenesis in mice offspring, being a risk factor for chronic diseases in adulthood. This study investigates the effects of maternal deficiency of vitamin D on structural islet remodeling and insulin-signaling pathway in the offspring. We studied male C57Bl/6 offspring at 3-month old (n = 10/group) from mother fed one of the two diets: control diet (C) or vitamin D-restricted diet (VitD-). After weaning, offspring only fed the control diet ad libitum. In the offspring, we studied insulin production, islet remodeling, and islet protein expression of the insulin-signaling pathway (Western blotting, isolated islet, n = 5/group). VitD- offspring showed greater glycemia (P = 0.012), smaller beta-cell mass (P = 0.014), and hypoinsulinemia (P = 0.024) than C offspring. Comparing VitD- offspring with C offspring, we observed lower protein levels in islet of insulin (P = 0.003), insulin receptor substrate-1 (P = 0.025), phosphatidylinositol-3-kinases (P = 0.045), 3-phosphoinositide-dependent protein kinase 1 (P = 0.017), protein kinase B (P = 0.028), with reduced expression of pancreas/duodenum homeobox-1 (PDX-1) (P = 0.016), glucose transporter-2 (P = 0.003), and glucokinase (P = 0.045). The maternal vitamin D-restricted diet modifies the development of the pancreas of the offspring, leading to islet remodeling and altered insulin-signaling pathway. The decrease of PDX-1 is probably significant to the changes in the beta-cell mass and insulin secretion in adulthood.