Possible involvement of endoplasmic reticulum stress in obesity associated with leptin resistance

Leptin is a hormone, which plays a central role in inhibiting food intake and body weight gain. Leptin is secreted from exocrine as well as endocrine cells. Circulating leptin activates JAK-STAT tyrosine kinases through Ob-Rb leptin receptor in the hypothalamus and brain stem. In recent years, “leptin resistance” has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are not well understood. Recently, we hypothesized possibility that endoplasmic reticulum (ER) stress is involved in leptin resistance. In the present manuscript, we would like to mention possible mechanisms of ER stress-induced leptin resistance and possible implication in obesity. In addition, pathophysiological role of leptin’s action in regulating endocrine as well as exocrine functions at the state of ER stress are discussed

Endoplasmic reticulum stress in the pathogenesis of diabetes

The accumulation of unfolded protein in the endoplasmic reticulum (ER) causes ER stress. Cells activate unfolded protein responses (UPR) to cope with such a stressful situation. Increasing evidence suggests that ER stress is involved in the pathogenesis of diabetes, especially insulin resistance and the impairment of insulin secretion. In addition, several UPR components have been suggested to play a key role in diabetes. In the present review, we summarize and discuss recent knowledge of ER stress regarding the pathogenesis of diabetes

Myeloid Differentiation Factor 88 (MyD88)-Deficiency Increases Risk of Diabetes in Mice

BACKGROUND: Multiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR) 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88) is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD)-induced obesity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP), which were linked to the onset of severe diabetes. On the other hand, TNF-alpha would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-alpha level was attenuated in MyD88-deficient mice fed with HFD. CONCLUSIONS/SIGNIFICANCE: The present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome

Fluvoxamine Attenuated Endoplasmic Reticulum Stress-Induced Leptin Resistance

Increasing evidence indicates that endoplasmic reticulum stress (ER stress) is involved in the development of metabolic syndrome. However, pharmacological treatments targeting ER stress are not well understood. In the present study, we found that fluvoxamine, a selective serotonin reuptake inhibitor used for depression, can attenuate ER stress-induced “leptin resistance,” i.e., insensitivity to the anti-obesity hormone leptin. Treatment with tunicamycin, an ER stress-inducing reagent, caused cell death which was significantly inhibited by fluvoxamine. Leptin activates JAK2–STAT3 signaling. ER stress caused an impairment of leptin-induced STAT3 phosphorylation which was reversed by fluvoxamine. Fluvoxamine would be a novel leptin-sensitizing drug, which targets ER stress

Incorporation of the Endoplasmic Reticulum Stress-Induced Spliced Form of XBP1 mRNA in the Exosomes

It is known that endoplasmic reticulum (ER) and nucleus communicate with each other to cope with ER stress. However, the mechanisms through which extracellular transmission of ER stress occurs remain unexplored. When the ER stress-induced unfolded protein response (UPR) is activated, the X-box binding protein 1 (XBP1) mRNA is spliced by inositol-requiring enzyme-1α (IRE1α) to produce the spliced form of XBP1 (sXBP1). In the present study, we found that sXBP1 mRNA in the cell may be incorporated into the exosomes and was released extracellularly. We found that the ratio of the mRNA levels of sXBP1 to unspliced XBP1 (uXBP1) in the exosome was higher than that of cells in MIN6 mouse pancreatic β cells. A similar effect was observed when XBP1 splicing was induced by overexpressing IRE1α in HEK293T cells. These results suggest that the incorporation of sXBP1 into the exosomes is a novel mechanism of UPR transmitted to extracellularly, which would be triggered when cells are exposed to stress

Validity and utility of the Japanese version of the brief unhelpful thoughts and beliefs about stuttering scale: UTBAS-6-J

Do adults who stutter have abnormally high social anxiety? Is it related to maladaptive cognition? As these are persistent, unresolved questions in stuttering research, it behooves clinicians to at least assess and attempt to identify social anxiety in patients who stutter and its basis before decisions are made about stuttering treatment. The Unhelpful Thoughts and Beliefs About Stuttering (UTBAS) scale is a self-administered questionnaire that measures the degree of non-adaptive cognition in people who stutter (PWS) due to social anxiety. The 66-item UTBAS is time-consuming to complete, prompting the development of a shorter 6-item version, the UTBAS-6, which is in English. Here, we aimed to assess some psychometric properties of the Japanese version of the UTBAS-6, the UTBAS-6-J, which has not been done to date. In 56 adult patients (mean 32.6 ± 11.1 years) who stutter, we quantified the reliability, the internal consistency, and the concurrent validity of the UTBAS-6-J. Along with the UTBAS-6-J, patients also were administered the Overall Assessment of the Speaker’s Experience of Stuttering – Japanese version (OASES-A-J), the Modified Erickson Communication Attitude Scale – Japanese version (S-24-J), and the Liebowitz Social Anxiety Scale – Japanese version (LSAS-J). Cronbach’s alpha for UTBAS-6-J total scores was 0.974, indicating excellent internal consistency. UTBAS-6-J scores were significantly correlated with scores on the OASES-A-J, the S-24-J, and the LSAS-J (all p < 0.005). Concurrent validity of the UTBAS-6-J with these three questionnaires was confirmed. The UTBAS-6-J has good internal consistency and concurrent validity, which will aid clinical decision-making about stuttering treatments

Effect of endothelin-1 (1-31) on the renal resistance vessels

Human chymase produces not only angiotensin II but also endothelin(ET)-1(1-31). We previously reported that ET-1(1-31) had several biological activities in vascular smooth muscle cells. In this study, we investigated the vasoconstrictor effect of ET-1(1-31) on the renal resistance vessels using in vitro micro perfused rabbit afferent and efferent arterioles.ET-1(1-31) decreased the lumen diameter of the afferent and efferent arterioles dose-dependently.ET-1(1-31)-induced afferent arteriolar vasoconstriction was not affected by phosphoramidon, an ET converting enzyme inhibitor. ET-1(1-31)-induced renal arteriolar vasoconstriction was inhibited by BQ123, an ETA receptor inhibitor, but not by BQ788, an ETB receptor inhibitor. These results suggest that ET-1(1-31)-induced renal arteriolar vasoconstriction may be mediated by ETA-like receptors

Observation of Antarctic ice sheet change by Synthetic Aperture Radar

第3回極域科学シンポジウム/第32回極域地学シンポジウム 11月29日（木） 統計数理研究所 ３階セミナー

Associations between daily lifestyle characteristics and latent depressive symptoms in elementary school children: A cross-sectional survey

This study aimed to identify associations between daily lifestyle characteristics and latent depressive symptoms in young children by analyzing self-reported questionnaire data. In 2011, in Nagasaki Japan, a cross-sectional survey of 1961 children aged between 10 and 12 years was conducted. Children answered questionnaires that collected demographic information, along with daily lifestyle characteristics, and were administered the Birleson Depression Self-Rating Scale for Children (DSRSC-J). The mean age of the participants was 10.98 years (±0.83 standard deviation [SD]) with a mean DSRSC-J raw score of 11.61 (±6.34 SD). In total, 24.7% of participants reported depressive symptoms. A multiple logistic regression analysis revealed that depressive symptoms were associated with female gender (odds ratio [OR]:1.86; 95% CI: 1.48?2.33), experiencing growth (OR: 1.25; 1.07-1.44), a bedtime later than 11 pm (OR: 1.25; 1.01-1.66), skipping breakfast (OR: 1.55; 1.15-2.10), and not having a set dinner time (OR: 1.65; 1.32?2.07). Conversely, absence of depressive symptoms was associated with involvement in school-related athletic clubs (OR: 0.60, 95% Cl: 0.48?0.76) and at home studying for at least one hour per day (OR: 0.67, 95% Cl: 0.54?0.84). Depressive symptoms in young children were associated with social contact and their parent’s lifestyles. Non-experts in the field of mental health who interact with young children should carefully note the presence of factors associated with depressive symptoms as this would help children with latent depressive symptoms receive prompt and timely care

Adenosine receptors in the isolated rabbit afferent and efferent arterioles

Adenosine has been noted as one of the endogenous modulators of renal hemodynamics. Renal hemodynamic was mainly regulated by two resistance vessels, the afferent arteriole and efferent arteriole. However, there is still no consensus as to the intrarenal vascular action site of adenosine. In this study, we examined the direct effect of adenosine on the isolated microperfused rabbit afferent and efferent arterioles. Adenosine decreased the lumen diameter of microperfused afferent arterioles dose-dependently (Control : 14.35±0.97μm, adenosine 10-7M : 12.73±1.40μm, 10-6M : 8.18±1.21μm, 10-5M : 4.33±1.16μm, n=6). Adenosine increased the lumen diameter of adenosine A1 antagonist, 8-(normantan-3-yl)-1,3-dipropylxanthin (KW-3902), pretreated-microperfused afferent arterioles preconstricted by norepinephrine. Pretreatment with adenosine A2 antagonist, (E)-1,3,-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthin (KF-7837), enhanced adenosine induced-afferent arteriolar vasoconstrictor effect. Adenosine did not change the lumen diameter of microperfused efferent arterioles, but adenosine increased the lumen diameter of norepinephrine preconstricted-microperfused efferent arterioles. The present data suggest that the afferent arterioles possesses both adenosine A1 and A2 receptors and the efferent arterioles possesses predominantly adenosine A2 receptors at least in the rabbit kidney