Food restriction improves glucose and lipid metabolism through Sirt1 expression: a study using a new rat model with obesity and severe hypertension

AimsTo determine the effects of food restriction (FR) on the expression of Sirt1 and its down-stream factors related to lipid and glucose metabolism in obese and hypertensive rats (SHRSP/IDmcr-fa), as a model of human metabolic syndrome.Main methodsMale, 10-week-old SHRSP/IDmcr-fa rats were treated with 85% FR for 2 weeks. Metabolic parameters, serum adipocytokines and distribution of serum adiponectin multimers were investigated. Sirt1 expression was determined in epididymal adipose tissue, liver and skeletal muscle. We also determined the expression of PPARα, γ and other adipocyte-related genes in epididymal adipose tissue, and glucose transporters (GLUT2 and GLUT4) in the liver and skeletal muscle.Key findingsFR improved the general conditions as well as blood chemistry of SHRSP/IDmcr-fa rats. In the epididymal adipose tissue of the FR rats, Sirt1 expression was enhanced, as was adiponectin, whereas leptin was downregulation, findings that were paralleled by the serum protein levels. Furthermore, the serum ratio of high to total adiponectin was increased in the FR group. The mRNA expression of Sirt1 was upregulated in the adipose tissue in the FR group. Sirt1 mRNA expression was downregulated, while PPARα and GLUT2 expression was enhanced in the liver. No differences were found in terms of Sirt1, PPAR or GLUT4 expression in skeletal muscle.SignificanceThese results indicate that FR corrects adipokine dysfunction by activating PPARγ via Sirt1 in adipose tissue. Furthermore, glucose and lipid metabolism are activated by upregulation of GLUT2 via the activation of PPARα in the liver.     

Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation

Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA-195 (miR-195). We found that miR-195 was prominently down-regulated in the proliferative phase of primary-cultured mouse HSCs. Supporting this fact, IFN-β induced miR-195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX-2. IFN-β down-regulated cyclin E1 and up-regulated p21 mRNA levels in LX-2 cells. Luciferase reporter assay revealed the direct interaction of miR-195 with the cyclin E1 3'UTR. Overexpression of miR-195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX-2 cells. Moreover miR-195 inhibition restored cyclin E1 levels that were down-regulated by IFN-β. In conclusion, IFN-β inhibited the proliferation of LX-2 cells by delaying cell cycle progression in G1 to S phase, partially through the down-regulation of cyclin E1 and up-regulation of p21. IFN-induced miR-195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver.     

Polyphenols in alcoholic beverages activating constitutive androstane receptor CAR

The constitutive androstane receptor CAR is a xenosensing nuclear receptor that can be activated by natural polyphenols such as flavonoids and catechins. We examined alcoholic beverage phytochemicals for their ability to activate CAR. HepG2 cells were transfected with CAR expression vector and its reporter gene, and then treated with trans-resveratrol, ellagic acid, β-caryophyllene, myrcene, and xanthohumol. A luciferase assay revealed that ellagic acid and trans-resveratrol activated both human and mouse CAR. Since CAR regulates many genes involved in energy metabolism, the possibility exists that these polyphenols would reduce the risk of certain alcohol-induced metabolic disorders with the help of CAR.     

The Brain’s Response to the Human Voice Depends on the Incidence of Autistic Traits in the General Population

Optimal brain sensitivity to the fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker’s intonation, and consequently, the speaker’s attitude. However, whether sensitivity in the brain’s response to a human voice F0 contour change varies with an interaction between an individual’s traits (i.e., autistic traits) and a human voice element (i.e., presence or absence of communicative action such as calling) has not been investigated. In the present study, we investigated the neural processes involved in the perception of F0 contour changes in the Japanese monosyllables “ne” and “nu.” “Ne” is an interjection that means “hi” or “hey” in English; pronunciation of “ne” with a high falling F0 contour is used when the speaker wants to attract a listener’s attention (i.e., social intonation). Meanwhile, the Japanese concrete noun “nu” has no communicative meaning. We applied an adaptive spatial filtering method to the neuromagnetic time course recorded by whole-head magnetoencephalography (MEG) and estimated the spatiotemporal frequency dynamics of event-related cerebral oscillatory changes in beta band during the oddball paradigm. During the perception of the F0 contour change when “ne” was presented, there was event-related de-synchronization (ERD) in the right temporal lobe. In contrast, during the perception of the F0 contour change when “nu” was presented, ERD occurred in the left temporal lobe and in the bilateral occipital lobes. ERD that occurred during the social stimulus “ne” in the right hemisphere was significantly correlated with a greater number of autistic traits measured according to the Autism Spectrum Quotient (AQ), suggesting that the differences in human voice processing are associated with higher autistic traits, even in non-clinical subjects.     

Ontogeny of ENaC expression in the gills and the kidneys of the Japanese black salamander (Hynobius nigrescens Stejneger)

A full-length cDNA cloning and tissue distribution of epithelial sodium channel (ENaC) protein were studied during ontogeny by immunohistochemistry in the external gills, and the kidney, pronephros and mesonephros, of the Japanese black salamander, Hynobius nigrescens (Family Hynobiidae; a primitive caudate species). The amino acid sequence of Hynobius ENaCα is 64 and 63% identical to Bufo ENaCα and Rat ENaCα, respectively. In aquatic larva salamander at the digit differentiation stage, Hynobius ENaCα mRNA was expressed in the external gills and pronephros. In the adult, the mRNA was expressed in the skin and the mesonephros. In the larvae, juvenile, and adult specimens, Hynobius ENaCα immunoreactivity was observed at the apical cell membrane of the external gills, late parts of the distal tubules, and mesonephric duct in the kidney. Colocalization of the apical Hynobius ENaCα and the basolateral Na(+) ,K(+) -ATPase was observed in the tubular cells of pronephros and mesonephros. These results suggest that Hynobius ENaCα plays an important role in the regulation of sodium transport in the external gills and pronephros of aquatic larvae, and in the skin and mesonephros of terrestrial adult. This is the first study to indicate ENaC expression during ontogeny in amphibians. Since no orthologs or paralogs for ENaC have been found, so far, in databases of the genomes of teleosts, it is assumed that ENaC might have played a role in terrestriality during the evolution of early tetrapods, the origin of lissamphibians.     

NK1.1(+) cells regulate neutrophil migration in mice with Acinetobacter baumannii pneumonia

Acinetobacter baumannii is a major cause of both community-associated and nosocomial infections worldwide. These infections are difficult to treat because the bacterium rapidly develops resistance to multiple antibiotics. However, little is known about the nature of the innate cellular response to A. baumannii infection. In the present study, we identified the cells infiltrating the lungs of mice with Acinetobacter pneumonia and analyzed their response to infection. Normal mice eradicated the A. baumannii infection within 3 days of inoculation. Neutrophils were rapidly recruited to the lungs, followed by macrophages and NK1.1(+) cells. Neutrophil-depleted mice showed acute and severe symptoms, and all of the mice died within 3 days of inoculation. The majority of macrophage-depleted mice responded in a similar manner to the control mice. These results indicate that neutrophils are essential for the elimination of A. baumannii. Half of NK1.1(+) cell-depleted mice died within 1 day of inoculation and the number of infiltrating neutrophils was lower than that in control mice up until 3 days post-inoculation. Moreover, the expression levels of keratinocyte chemoattractant protein (KC) decreased in NK1.1(+) cell-depleted mice. These results indicate that NK1.1(+) cells recruit neutrophils during the early phase of Acinetobacter infection by increasing KC expression.     

Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.     

LP28, a lily pollen-specific LEA-like protein, is located in the callosic cell wall during male gametogenesis

. LP28, a pollen-specific LEA-like protein identified in Lilium longiflorum purportedly related to the desiccation tolerance of pollen, was localized during male gametogenesis using immuno-electron microscopy. At premeiotic interphase, LP28 label is absent from the microsporocyte. LP28 label was first detected in the cell wall of the microsporocyte at meiotic prophase I. LP28 gradually increased as the cell wall thickened. In the dyad, after the first meiotic division, LP28 label also appeared in the septum. In the tetrad, after the second meiotic division, LP28 was detected throughout the cell wall, including the septa. Immunolabeling of callose during meiosis indicated that the appearance and localization of LP28 was very similar to that of callose. After the microspores were released from the tetrad by digesting the callosic cell wall, LP28 was not found in the microspores. In bicellular pollen, just after microspore mitosis, LP28 appeared in the generative cell wall, which also consisted of callose. After pollen germination, LP28 also accumulated in the callosic layer of the elongated pollen tube wall and the callose plug. Thus, LP28 colocalized with the callosic cell wall during male gametogenesis. The possible role of LP28 with respect to wall formation during meiosis and pollen development is discussed.