Expression of clock gene Dbp in omental and mesenteric adipose tissue in patients with type 2 diabetes.

INTRODUCTION: We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene Dbp and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor (Ppar)-γ and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity. RESEARCH DESIGN AND METHODS: The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2). RESULTS: Acetylation of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue. CONCLUSIONS: The changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.

Induction of Dbp by a histone deacetylase inhibitor is involved in amelioration of insulin sensitivity via adipocyte differentiation in ob/ob mice.

We previously reported that a histone deacetylase inhibitor (HDACi) increases D-site binding protein (Dbp) mRNA expression in adipose tissue and subsequently improved insulin sensitivity of obese (ob/ob) mice. However, the potential mechanism of this phenomenon was unclear. Thus, the aim of this study was to clarify the molecular mechanism involved in enhanced Dbp mRNA expression and improvement of insulin sensitivity in mice. Ob/ob mice were treated with HDACi every second day for 3 weeks. At the end of treatment, an insulin tolerance test was performed and epididymal adipose tissue obtained for fractionation into adipocytes and preadipocytes. HDACi improved insulin sensitivity in ob/ob mice and significantly increased Dbp mRNA in epididymal adipose tissue. Further, epididymal adipocytes of ob/ob mice showed a tendency towards a larger size distribution, while HDACi increased the proportion of smaller sized cells in fractionated preadipocytes. Dbp knocked-down 3T3-L1 cells down-regulated peroxisome proliferator-activated receptor-γ (PPAR-γ1) protein expression during adipogenesis, which suppressed adipocyte differentiation. These data indicate that DBP promotes adipocyte differentiation via direct up-regulation of PPAR-γ1 production in preadipocytes. In fractionated preadipocytes of ob/ob mice, DBP binding to the promoter region of the Ppar-γ gene and splicing variant of Ppar-γ (Ppar-γ1sv) mRNA expression were suppressed. HDACi significantly increased DBP binding to the Ppar-γ gene and Ppar-γ1sv transcription. Altogether, this indicates a modification in genetic regulation downstream from the circadian clock that can ameliorate an environmental function of adipose tissue, leading to improved insulin sensitivity in ob/ob mice.

Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine.

Brown adipocyte activation or beige adipocyte emergence in white adipose tissue (WAT) increases energy expenditure, leading to a reduction in body fat mass and improved glucose metabolism. We found that activin E functions as a hepatokine that enhances thermogenesis in response to cold exposure through beige adipocyte emergence in inguinal WAT (ingWAT). Hepatic activin E overexpression activated thermogenesis through Ucp1 upregulation in ingWAT and other adipose tissues including interscapular brown adipose tissue and mesenteric WAT. Hepatic activin E-transgenic mice exhibited improved insulin sensitivity. Inhibin ßE gene silencing inhibited cold-induced Ucp1 induction in ingWAT. Furthermore, in vitro experiments suggested that activin E directly stimulated expression of Ucp1 and Fgf21, which was mediated by transforming growth factor-ß or activin type I receptors. We uncovered a function of activin E to stimulate energy expenditure through brown and beige adipocyte activation, suggesting a possible preventive or therapeutic target for obesity.

Pulmonary administration of curcumin inhibits B16F10 melanoma lung metastasis and invasion in mice.

PURPOSE: Curcumin is expected to have beneficial effects including an anti-cancer effect. However, its lower bioavailability is a critical concern and limits the utility of curcumin in clinical practice. In this study, we investigated whether transpulmonary delivery of curcumin is pharmacologically effective along with improving its bioavailability in mice with lung metastasis. METHODS: C57BL/6J mice were injected with B16F10 melanoma cells via their tail vein and given curcumin by pulmonary administration every other day. The lung tissue of the vehicle-treated mice on day 17 was covered by nodules of metastatic melanoma. RESULTS: Pulmonary curcumin administration significantly and dose-dependently protected the lung metastasis of melanoma. The phosphorylation of JNK (c-Jun NH2 terminal kinase) and HLJ1 expression levels in the lung metastatic nodules of the melanoma were significantly increased by pulmonary curcumin administration. The anti-metastatic effect of curcumin was blunted in mice injected with HLJ1 knocked-down B16F10 melanoma. Systemic bioavailability after pulmonary administration was 61-times higher than after oral administration. Additionally, the curcumin concentration in the lung tissue was sustained to a high level until 24 h after pulmonary administration. CONCLUSIONS: This study showed the usefulness of curcumin to suppress lung metastasis of melanoma by pulmonary administration, a method that may overcome the low-bioavailability of curcumin.

Prevention against renal damage in rats with subtotal nephrectomy by sacubitril/valsartan (LCZ696), a dual-acting angiotensin receptor-neprilysin inhibitor.

Although patients with chronic kidney disease (CKD) are at increased risk for end-stage renal disease and cardiovascular events, adequate drug therapies for preventing the deterioration of these conditions are still not established. This study was undertaken to evaluate a preventive effect of an angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (LCZ696), which is converted to sacubitril and valsartan in the body, against the progression of renal disease in rats with subtotal nephrectomy, an animal model of human CKD. Mean survival time after subtotal nephrectomy was about 100 days in Wistar rats with vehicle. LCZ696-(30 mg/kg) and valsartan-(15 mg/kg) prolonged the survival of these animals, and the effect of LCZ696 on survival was significantly greater than that of valsartan. Renoprotective effects of LCZ696 judged by serum creatinine and urinary protein excretions were larger than those of valsartan. Cardioprotective effects judged by cardiac left ventricular mass, fractional shortening, and fibrosis of LCZ696 and valsartan were not detected under the present condition. Thus, the renoprotective effect of LCZ696 was stronger than that of valsartan in rats with subtotal nephrectomy. This study provides the idea that, compared to valsartan, LCZ696 is more effective for the treatment of human CKD.

Effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.

Perceived moral traits of others differentiate the neural activation that underlies inequity-aversion.

We have a social preference to reduce inequity in the outcomes between oneself and others. Such a preference varies according to others. We performed functional magnetic resonance imaging during an economic game to investigate how the perceived moral traits of others modulate the neural activities that underlie inequity-aversion. The participants unilaterally allocated money to three partners (good, neutral, and bad). During presentation of the good and neutral partners, the anterior region of the rostral medial frontal cortex (arMFC) showed increased functional connectivity with the caudate head and the anterior insula, respectively. Following this, participants allocated more money to the good partner, and less to the bad partner, compared with the neutral partner. The caudate head and anterior insula showed greater activation during fair allocation to the good and unfair allocation to the neutral partners, respectively. However, these regions were silent during allocations to the bad partner. Therefore, the arMFC-caudate/insula circuit encompasses distinct neural processes that underlie inequity-aversion in monetary allocations that the different moral traits of others can modulate.

Neural basis of decision making guided by emotional outcomes.

Emotional events resulting from a choice influence an individual's subsequent decision making. Although the relationship between emotion and decision making has been widely discussed, previous studies have mainly investigated decision outcomes that can easily be mapped to reward and punishment, including monetary gain/loss, gustatory stimuli, and pain. These studies regard emotion as a modulator of decision making that can be made rationally in the absence of emotions. In our daily lives, however, we often encounter various emotional events that affect decisions by themselves, and mapping the events to a reward or punishment is often not straightforward. In this study, we investigated the neural substrates of how such emotional decision outcomes affect subsequent decision making. By using functional magnetic resonance imaging (fMRI), we measured brain activities of humans during a stochastic decision-making task in which various emotional pictures were presented as decision outcomes. We found that pleasant pictures differentially activated the midbrain, fusiform gyrus, and parahippocampal gyrus, whereas unpleasant pictures differentially activated the ventral striatum, compared with neutral pictures. We assumed that the emotional decision outcomes affect the subsequent decision by updating the value of the options, a process modeled by reinforcement learning models, and that the brain regions representing the prediction error that drives the reinforcement learning are involved in guiding subsequent decisions. We found that some regions of the striatum and the insula were separately correlated with the prediction error for either pleasant pictures or unpleasant pictures, whereas the precuneus was correlated with prediction errors for both pleasant and unpleasant pictures.

Information-sharing ethical dilemmas and decision-making for public health nurses in Japan.

BACKGROUND: Information sharing is one of the most important means of public health nurses collaborating with other healthcare professionals and community members. There are complicated ethical issues in the process. RESEARCH OBJECTIVES: To describe the ethical dilemmas associated with client information sharing that Japanese public health nurses experience in daily practice and to clarify their decision-making process to resolve these dilemmas. RESEARCH DESIGN: Data were collected using a three-phase consensus method consisting of semi-structured interviews, self-administered questionnaires and a group interview. PARTICIPANTS AND RESEARCH CONTEXT: We surveyed administrative public health nurses in Shizuoka Prefecture, Japan. The semi-structured interviews were carried out with 12 administrative public health nurses, and the self-administered questionnaires were sent to all 899 administrative public health nurses. The group interview was carried out with eight administrative public health nurses. ETHICAL CONSIDERATIONS: Ethical approval was granted by the ethics committee of the School of Health Sciences, Nagoya University, Japan (8-158, 9-130). FINDINGS: Information-sharing ethical dilemmas occurred most often when clients' decisions did not coincide with the nurses' own professional assessments, particularly when they faced clinical issues that were inherently ambiguous. In their decision-making processes, nurses prioritised 'protection of health and life'. DISCUSSION: These findings suggest that, above all, they sought to address urgent risks to clients' lives while upholding the principle of client autonomy as much as possible. In such cases, the nurses made decisions regarding whether to share information about the client depending on the individual situation. CONCLUSION: Public health nurses should protect the client's health while taking into consideration their relationship with the client.

Hand before foot? Cortical somatotopy suggests manual dexterity is primitive and evolved independently of bipedalism.

People have long speculated whether the evolution of bipedalism in early hominins triggered tool use (by freeing their hands) or whether the necessity of making and using tools encouraged the shift to upright gait. Either way, it is commonly thought that one led to the other. In this study, we sought to shed new light on the origins of manual dexterity and bipedalism by mapping the neural representations in the brain of the fingers and toes of living people and monkeys. Contrary to the 'hand-in-glove' notion outlined above, our results suggest that adaptations underlying tool use evolved independently of those required for human bipedality. In both humans and monkeys, we found that each finger was represented separately in the primary sensorimotor cortex just as they are physically separated in the hand. This reflects the ability to use each digit independently, as required for the complex manipulation involved in tool use. The neural mapping of the subjects' toes differed, however. In the monkeys, the somatotopic representation of the toes was fused, showing that the digits function predominantly as a unit in general grasping. Humans, by contrast, had an independent neurological representation of the big toe (hallux), suggesting association with bipedal locomotion. These observations suggest that the brain circuits for the hand had advanced beyond simple grasping, whereas our primate ancestors were still general arboreal quadrupeds. This early adaptation laid the foundation for the evolution of manual dexterity, which was preserved and enhanced in hominins. In hominins, a separate adaptation, involving the neural separation of the big toe, apparently occurred with bipedality. This accords with the known fossil evidence, including the recently reported hominin fossils which have been dated to 4.4 million years ago.

Developing intuition: neural correlates of cognitive-skill learning in caudate nucleus.

The superior capability of cognitive experts largely depends on automatic, quick information processing, which is often referred to as intuition. Intuition develops following extensive long-term training. There are many cognitive models on intuition development, but its neural basis is not known. Here we trained novices for 15 weeks to learn a simple board game and measured their brain activities in early and end phases of the training while they quickly generated the best next-move to a given board pattern. We found that the activation in the head of caudate nucleus developed over the course of training, in parallel to the development of the capability to quickly generate the best next-move, and the magnitude of the caudate activity was correlated with the subject's performance. In contrast, cortical activations, which already appeared in the early phase of training, did not further change. Thus, neural activation in the caudate head, but not those in cortical areas, tracked the development of capability to quickly generate the best next-move, indicating that circuitries including the caudate head may automate cognitive computations.

Prefrontal and medial temporal contributions to episodic memory-based reasoning.

Episodic memory retrieval and reasoning are fundamental psychological components of our daily lives. Although previous studies have investigated the brain regions associated with these processes separately, the neural mechanisms of reasoning based on episodic memory retrieval are largely unknown. Here, we investigated the neural correlates underlying episodic memory-based reasoning using functional magnetic resonance imaging (fMRI). During fMRI scanning, subjects performed three tasks: reasoning, episodic memory retrieval, and episodic memory-based reasoning. We identified dissociable activations related to reasoning, episodic memory retrieval, and linking processes between the two. Regions related to reasoning were identified in the left ventral prefrontal cortices (PFC), and those related to episodic memory retrieval were found in the right medial temporal lobe (MTL) regions. In addition, activations predominant in the linking process between the two were found in the left dorsal and right ventral PFC. These findings suggest that episodic memory-based reasoning is composed of at least three processes, i.e., reasoning, episodic memory retrieval, and linking processes between the two, and that activation of both the PFC and MTL is crucial in episodic memory-based reasoning. These findings are the first to demonstrate that PFC and MTL regions contribute differentially to each process in episodic memory-based reasoning.

Differential contributions of the anterior temporal and medial temporal lobe to the retrieval of memory for person identity information.

Although previous studies have suggested the importance of the bilateral anterior temporal (ATL) and medial temporal lobes (MTL) in the retrieval of person identity information, there is little evidence concerning how these regions differentially contribute to the process. Here we investigated this question using functional magnetic resonance imaging (fMRI). Before scanning, subjects learned associations among faces (F), names (N), and job titles (as a form of person-related semantics, S). During retrieval with fMRI, subjects were presented with previously learned and new S stimuli, and judged whether the stimuli were old or new. Successful retrieval (H) trials were divided into three conditions: retrieval of S and associated F and N (HSFN); retrieval of S and associated F (HSF); and retrieval of S only (HS). The left ATL was significantly activated in HSFN, compared to HSF or HS, whereas the right ATL and MTL were significantly activated in HSFN and HSF relative to HS. In addition, activity in bilateral ATL was significantly correlated with reaction time for HSFN, whereas we found no significant correlation between activity in the right MTL and reaction time in any condition. The present findings suggest that the left ATL may mediate associations between names and person-related semantic information, whereas the right ATL mediates the association between faces and person-related semantic information in memory for person identity information. In addition, activation of the right MTL region implies that this area may contribute to a more general relational processing of associative components, including memory for person identity information.