The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect.

In diet-induced obesity, metformin (MF) has weight-lowering effect and improves glucose homeostasis and insulin sensitivity. However, there is no information on the efficiency of MF and the mechanisms of its action in melanocortin-type obesity. We studied the effect of the 10-day treatment with MF at the doses of 200, 400 and 600 mg/kg/day on the food intake and the metabolic and hormonal parameters in female C57Bl/6J (genotype Ay/a) agouti-mice with melanocortin-type obesity, and the influence of MF on the hypothalamic signaling in obese animals at the most effective metabolic dose (600 mg/kg/day). MF treatment led to a decrease in food intake, the body and fat weights, the plasma levels of glucose, insulin and leptin, all increased in agouti-mice, to an improvement of the lipid profile and glucose sensitivity, and to a reduced fatty liver degeneration. In the hypothalamus of obese agouti-mice, the leptin and insulin content was reduced and the expression of the genes encoding leptin receptor (LepR), MC3- and MC4-melanocortin receptors and pro-opiomelanocortin (POMC), the precursor of anorexigenic melanocortin peptides, was increased. The activities of AMP-activated kinase (AMPK) and the transcriptional factor STAT3 were increased, while Akt-kinase activity did not change from control C57Bl/6J (a/a) mice. In the hypothalamus of MF-treated agouti-mice (10 days, 600 mg/kg/day), the leptin and insulin content was restored, Akt-kinase activity was increased, and the activities of AMPK and STAT3 were reduced and did not differ from control mice. In the hypothalamus of MF-treated agouti-mice, the Pomc gene expression was six times higher than in control, while the gene expression for orexigenic neuropeptide Y was decreased by 39%. Thus, we first showed that MF treatment leads to an improvement of metabolic parameters and a decrease of hyperleptinemia and hyperinsulinaemia in genetically-induced melanocortin obesity, and the specific changes in the hypothalamic signaling makes a significant contribution to this effect of MF.

Vitamin D supplementation guidelines.

Research carried out during the past two-decades extended the understanding of actions of vitamin D, from regulating calcium and phosphate absorption and bone metabolism to many pleiotropic actions in organs and tissues in the body. Most observational and ecological studies report association of higher serum 25-hydroxyvitamin D [25(OH)D] concentrations with improved outcomes for several chronic, communicable and non-communicable diseases. Consequently, numerous agencies and scientific organizations have developed recommendations for vitamin D supplementation and guidance on optimal serum 25(OH)D concentrations. The bone-centric guidelines recommend a target 25(OH)D concentration of 20ng/mL (50nmol/L), and age-dependent daily vitamin D doses of 400-800IU. The guidelines focused on pleiotropic effects of vitamin D recommend a target 25(OH)D concentration of 30ng/mL (75nmol/L), and age-, body weight-, disease-status, and ethnicity dependent vitamin D doses ranging between 400 and 2000IU/day. The wise and balanced choice of the recommendations to follow depends on one's individual health outcome concerns, age, body weight, latitude of residence, dietary and cultural habits, making the regional or nationwide guidelines more applicable in clinical practice. While natural sources of vitamin D can raise 25(OH)D concentrations, relative to dietary preferences and latitude of residence, in the context of general population, these sources are regarded ineffective to maintain the year-round 25(OH)D concentrations in the range of 30-50ng/mL (75-125nmol/L). Vitamin D self-administration related adverse effects, such as hypercalcemia and hypercalciuria are rare, and usually result from taking extremely high doses of vitamin D for a prolonged time.

α-Tocopherol at Nanomolar Concentration Protects Cortical Neurons against Oxidative Stress.

The aim of the present work is to study the mechanism of the α-tocopherol (α-T) protective action at nanomolar and micromolar concentrations against H2O2-induced brain cortical neuron death. The mechanism of α-T action on neurons at its nanomolar concentrations characteristic for brain extracellular space has not been practically studied yet. Preincubation with nanomolar and micromolar α-T for 18 h was found to increase the viability of cortical neurons exposed to H2O2; α-T effect was concentration-dependent in the nanomolar range. However, preincubation with nanomolar α-T for 30 min was not effective. Nanomolar and micromolar α-T decreased the reactive oxygen species accumulation induced in cortical neurons by the prooxidant. Using immunoblotting it was shown that preincubation with α-T at nanomolar and micromolar concentrations for 18 h prevented Akt inactivation and decreased PKCδ activation induced in cortical neurons by H2O2. α-T prevented the ERK1/2 sustained activation during 24 h caused by H2O2. α-T at nanomolar and micromolar concentrations prevented a great increase of the proapoptotic to antiapoptotic proteins (Bax/Bcl-2) ratio, elicited by neuron exposure to H2O2. The similar neuron protection mechanism by nanomolar and micromolar α-T suggests that a "more is better" approach to patients' supplementation with vitamin E or α-T is not reasonable.