D-chiro-inositol glycan reduces food intake by regulating hypothalamic neuropeptide expression via AKT-FoxO1 pathway

The regulation of food intake is important for body energy homeostasis. Hypothalamic insulin signaling decreases food intake by upregulating the expression of anorexigenic neuropeptides and downregulating the expression of orexigenic neuropeptides. INS-2, a Mn2+ chelate of 4-O-(2-amino-2-deoxy-β-d-galactopyranosyl)-3-O-methyl-d-chiro-inositol, acts as an insulin mimetic and sensitizer. We found that intracerebroventricular injection of INS-2 decreased body weight and food intake in mice. In hypothalamic neuronal cell lines, INS-2 downregulated the expression of neuropeptide Y (NPY), an orexigenic neuropeptide, but upregulated the expression of proopiomelanocortin (POMC), an anorexigenic neuropeptide, via modulation of the AKT-forkhead box-containing protein-O1 (FoxO1) pathway. Pretreatment of these cells with INS-2 enhanced the action of insulin on downstream signaling, leading to a further decrease in NPY expression and increase in POMC expression. These data indicate that INS-2 reduces food intake by regulating the expression of the hypothalamic neuropeptide genes through the AKT-FoxO1 pathway downstream of insulin. © 2016 Elsevier Inc. All rights reserved.

Physiological Oxygen Level Is Critical for Modeling Neuronal Metabolism In Vitro

In vitro models are important tools for studying the mechanisms that govern neuronal responses to injury. Most neuronal culture methods employ nonphysiological conditions with regard to metabolic parameters. Standard neuronal cell culture is performed at ambient (21%) oxygen levels, whereas actual tissue oxygen levels in the mammalian brain range from 1% to 5%. In this study, we examined the consequences of oxygen level on the viability and metabolism of primary cultures of cortical neurons. Our results indicate that physiological oxygen level (5% O 2) has a beneficial effect on cortical neuronal survival and mitochondrial function in vitro. Moreover, oxygen level affects metabolic fluxes: glucose uptake and glycolysis was enhanced at physiological oxygen level, whereas glucose oxidation and fatty acid oxidation were reduced. Adenosine monophosphate-activated protein kinase (AMPK) was more activated in 5% O 2 and appears to play a role in these metabolic effects. Inhibiting AMPK activity with compound C decreased glucose uptake, intracellular ATP level, and viability in neurons cultured in 5% O 2. These data indicate that oxygen level is an important parameter to consider when modeling neuronal responses to stress in vitro. © 2011 Wiley Periodicals, Inc.