Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type 2 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes. Type 2 diabetes was induced by streptozotocin/high-fat diet (STZ/HFD) in mice. In HepG2 cells, irisin ameliorated the GlcN-induced increases in glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression, and glycogen synthase (GS) phosphorylation; it prevented GlcN-induced decreases in glycogen content and the phosphoinositide 3-kinase (PI3K) p110α subunit level, and the phosphorylation of Akt/protein kinase B, forkhead box transcription factor O1 (FOXO1) and glycogen synthase kinase-3 (GSK3). These effects of irisin were abolished by the inhibition of PI3K or Akt. The effects of irisin were confirmed in mouse primary hepatocytes with GlcN-induced insulin resistance and in human HepG2 cells with palmitate-induced insulin resistance. In diabetic mice, persistent subcutaneous perfusion of irisin improved the insulin sensitivity, reduced fasting blood glucose, increased GSK3 and Akt phosphorylation, glycogen content and irisin level, and suppressed GS phosphorylation and PEPCK and G6Pase expression in the liver. Irisin improves glucose homoeostasis by reducing gluconeogenesis via PI3K/Akt/FOXO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via PI3K/Akt/GSK3-mediated GS activation. Irisin may be regarded as a novel therapeutic strategy for insulin resistance and type 2 diabetes.

Salusin-β in the RVLM increases sympathetic outflow, blood pressure and heart rate via NAD(P)H oxidase-derived superoxide anions in renovascular hypertensive rats.

BackgroundAdipose afferent reflex (AAR) is a sympatho-excitatory reflex induced by chemical stimulation of white adipose tissue (WAT). Ionotropic glutamate receptors including NMDA receptors (NMDAR) and non-NMDA receptors (non-NMDAR) in paraventricular nucleus (PVN) mediate the AAR. Enhanced AAR contributes to sympathetic activation and hypertension in obesity rats. This study was designed to investigate the role and mechanism of superoxide anions in PVN in modulating the AAR.Methodology/Principal FindingsRenal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in anesthetized rats. AAR was evaluated by the RSNA and MAP responses to injections of capsaicin into four sites of right inguinal WAT (8.0 nmol in 8.0 µl for each site). Microinjection of polyethylene glycol-superoxide dismutase (PEG-SOD), the superoxide anion scavenger tempol or the NAD(P)H oxidase inhibitor apocynin into the PVN decreased the baseline RSNA and MAP, and attenuated the AAR. Unilateral WAT injection of capsaicin increased superoxide anions in bilateral PVN, which was prevented by the WAT denervation. WAT injection of capsaicin increased superoxide anion level and NAD(P)H oxidase activity in the PVN, which was abolished by the PVN pretreatment with the combined NMDAR antagonist AP5 and non-NMDAR antagonist CNQX. Microinjection of the NMDAR agonist NMDA or the non-NMDAR agonist AMPA increased superoxide anion level and NAD(P)H oxidase activity in the PVN.ConclusionsNAD(P)H oxidase-derived superoxide anions in the PVN contributes to the tonic modulation of AAR. Activation of ionotropic glutamate receptors in the PVN is involved in the AAR-induced production of superoxide anions in the PVN.

Background: Mild cognitive impairment (MCI) is considered to be a transitional state between normal aging and Alzheimer's dementia (AD). Recent studies have indicated that executive function (EF) declines during MCI. However, only a limited number of studies have investigated the neural basis of EF deficits in MCI. Herein, we investigate the changes of regional brain spontaneous activity and functional connectivity (FC) of the executive control network (ECN) between high EF and low EF groups.Methods: According to EF composite score (ADNI-EF) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we divided MCI into two groups, including the MCI-highEF group and MCI-lowEF group. Resting-state functional MRI was utilized to investigate the fractional amplitude of low-frequency fluctuation (fALFF) and ECN functional connectivity across 23 healthy controls (HC), 11 MCI-highEF, and 14 MCI-lowEF participants. Moreover, a partial correlation analysis was carried out to examine the relationship between altered fALFF or connectivity of the ECN and the ADNI-EF.Results: Compared to HC, the MCI-highEF participants demonstrated increased fALFF in the left superior temporal gyrus (STG), as well as decreased fALFF in the right precentral gyrus, right postcentral gyrus, and left middle frontal gyrus (MFG). The MCI-lowEF participants demonstrated increased fALFF in the cerebellar vermis and decreased fALFF in the left MFG. Additionally, compared to HC, the MCI-highEF participants indicated no significant difference in connectivity of the ECN. Furthermore, the MCI-lowEF participants showed increased ECN FC in the left cuneus and left MFG, as well as decreased ECN functional connectivity in the right parahippocampal gyrus (PHG). Notably, the altered fALFF in the left MFG was positively correlated to ADNI-EF, while the altered fALFF in cerebellar vermis is negatively correlated with ADNI-EF across the two MCI groups and the HC group. Altered ECN functional connectivity in the right PHG is negatively correlated to ADNI-EF, while altered ECN functional connectivity in the left cuneus is negatively correlated to ADNI-EF across the three groups.Conclusions: Our current study demonstrates the presence of different patterns of regional brain spontaneous activity and ECN FC in the MCI-highEF group and MCI-lowEF group. Furthermore, the ECN FC of the MCI-highEF group was not disrupted, which may contribute to retained EF in MCI.