A two-week exercise intervention improves cold symptoms and sleep condition in cold-sensitive women.

BACKGROUND: We examined whether an aerobic exercise intervention in young women with cold sensitivity symptoms improves sleep quality and decreases cold complaints. Furthermore, we examined the association with increased foot skin temperature (Tsk) before falling asleep and decrease in sensitivity to cold in the brain. METHODS: We recruited 16 female adult volunteers who had cold sensitivity and were not engaged in daily exercise training, and they were divided into an exercise group (EXE) and a control group (CON). EXE was given a 2-week exercise intervention that consisted mainly of walking and jogging. Before and after the intervention, temperature sensation and body temperature parameters were measured just before bedtime; electroencephalogram measurements were taken during sleep; and subjective sleep surveys, including Oguri-Shirakawa-Azumi (OSA) sleep inventory (middle-aged and aged version) and visual analogue scale (VAS), were conducted immediately after waking up. All experiments were performed in the winter season. RESULTS: In EXE, overall and foot warmth and comfort increased (p < 0.05) after the 2-week exercise intervention. The exercise intervention also decreased (p < 0.05) the scores for cold feeling in the fingertips, feet, and toes. In the OSA sleep inventory, factor IV (refreshing) and factor V (sleep length) were increased (p < 0.05) by the exercise intervention. Subjective sleep quality evaluated by VAS increased (p < 0.05) with exercise intervention. The exercise intervention in EXE shortened middle awake time after sleep onset (p < 0.05) and prolonged deep sleep length (p < 0.05). The exercise intervention increased (p < 0.05) alpha-wave power before sleep. In CON, all variables remained unchanged throughout the 2-week control period. CONCLUSION: Short-term aerobic exercise alleviated peripheral extremity cold sensitivity symptoms and improved subjective sleep quality. Our findings suggest that these improvements were not due to increased Tsk at rest before bedtime but to decreased sensitivity to cold in the brain that was expressed as increased alpha activity.

Fenofibrate for diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) remains a major cause of sight loss worldwide, despite new therapies and improvements in the metabolic control of people living with diabetes. Therefore, DR creates a physical and psychological burden for people, and an economic burden for society. Preventing the development and progression of DR, or avoiding the occurrence of its sight-threatening complications is essential, and must be pursued to save sight. Fenofibrate may be a useful strategy to achieve this goal, by reversing diabetes' effects and reducing inflammation in the retina, as well as improving dyslipidaemia and hypertriglyceridaemia.  OBJECTIVES: To investigate the benefits and harms of fenofibrate for preventing the development and progression of diabetic retinopathy in people with type 1 (T1D) or type 2 diabetes (T2D), compared with placebo or observation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and three trials registers (February 2022). SELECTION CRITERIA: We included randomised controlled trials (RCTs) that included people with T1D or T2D, when these compared fenofibrate with placebo or with observation, and assessed the effect of fenofibrate on the development or progression of DR (or both). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for data extraction and analysis. Our primary outcome was progression of DR, a composite outcome of 1) incidence of overt retinopathy for participants who did not have DR at baseline, or 2) advancing two or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale for participants who had any DR at baseline (or both), based on the evaluation of stereoscopic or non-stereoscopic fundus photographs, during the follow-up period. Overt retinopathy was defined as the presence of any DR observed on stereoscopic or non-stereoscopic colour fundus photographs. Secondary outcomes included the incidence of overt retinopathy, reduction in visual acuity of participants with a reduction in visual acuity of 10 ETDRS letters or more, proliferative diabetic retinopathy, and diabetic macular oedema; mean vision-related quality of life, and serious adverse events of fenofibrate. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included two studies and their eye sub-studies (15,313 participants) in people with T2D. The studies were conducted in the US, Canada, Australia, Finland, and New Zealand; follow-up period was four to five years. One was funded by the government, the other by industry. Compared to placebo or observation, fenofibrate likely results in little to no difference in progression of DR (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.60 to 1.25; 1 study, 1012 participants; moderate-certainty evidence) in a population with and without overt retinopathy at baseline. Those without overt retinopathy at baseline showed little or no progression (RR 1.00, 95% CI 0.68 to 1.47; 1 study, 804 participants); those with overt retinopathy at baseline found that their DR progressed slowly (RR 0.21, 95% CI 0.06 to 0.71; 1 study, 208 people; test for interaction P = 0.02). Compared to placebo or observation, fenofibrate likely resulted in little to no difference in either the incidence of overt retinopathy (RR 0.91; 95% CI 0.76 to 1.09; 2 studies, 1631 participants; moderate-certainty evidence); or the incidence of diabetic macular oedema (RR 0.39; 95% CI 0.12 to 1.24; 1 study, 1012 participants; moderate-certainty evidence). The use of fenofibrate increased severe adverse effects (RR 1.55; 95% CI 1.05 to 2.27; 2 studies, 15,313 participants; high-certainty evidence). The studies did not report on incidence of a reduction in visual acuity of 10 ETDRS letters or more, incidence of proliferative diabetic retinopathy, or mean vision-related quality of life. AUTHORS' CONCLUSIONS: Current, moderate-certainty evidence suggests that in a mixed group of people with and without overt retinopathy, who live with T2D, fenofibrate likely results in little to no difference in progression of diabetic retinopathy. However, in people with overt retinopathy who live with T2D, fenofibrate likely reduces the progression. Serious adverse events were rare, but the risk of their occurrence was increased by the use of fenofibrate. There is no evidence on the effect of fenofibrate in people with T1D. More studies, with larger sample sizes, and participants with T1D are needed. They should measure outcomes that are important to people with diabetes, e.g. change in vision, reduction in visual acuity of 10 ETDRS letters or more, developing proliferative diabetic retinopathy; and evaluating the requirement of other treatments, e.g. injections of anti-vascular endothelial growth factor therapies, steroids.

Evaluation of probability distribution models for stutter ratios in the typing system of GlobalFiler and 3500xL Genetic Analyzer.

As DNA typing systems have become increasingly sensitive in recent years, probability distribution models for back, forward, double-back, and minus 2-nt stutter ratios have been desired to be considered in DNA evidence interpretation using specific software programs. However, experimental investigations have been insufficient, especially for forward, double-back, and minus 2-nt stutters. In this study, we experimentally reevaluated the probability distribution models for each stutter ratio in the typing systems of GlobalFiler™ PCR Amplification Kit and 3500xL Genetic Analyzer from Thermo Fisher Scientific. In addition, to enhance the reliability of longest uninterrupted stretch (LUS) values and corrected allele numbers used in previously developed models for stutter ratios using sequence information (i.e., LUS model and multi-seq model), we propose the weighted average of LUS values and corrected allele numbers based on the number of observations in sequence-based population data. Back stutter ratios demonstrated a positive correlation with allele numbers (allele model) in eight loci, LUS values (LUS model) in eight loci, and corrected allele numbers (multi-seq model) in five loci. The forward stutter ratios (FSRs) of D22S1045 followed the LUS model. FSRs other than D22S1045 and double-back stutter ratios followed the LUS model by considering multiple loci together. Minus 2-nt stutter ratios observed in SE33 and D1S1656 did not increase with the increase in the allele numbers. The adopted models for each stutter ratio can be implemented in software programs for DNA evidence interpretation and enable a reliable interpretation of crime stain profiles in forensic caseworks.

Endogenous testosterone reduces hepatic lipid accumulation in protein-restricted male rats.

OBJECTIVES: Protein deficiency is known to cause ectopic fat accumulation in the liver. The aim of this study was to analyse the mechanism of suppression of hepatic fat accumulation by testosterone and to clarify the mechanism behind the gender difference in fatty liver formation due to protein deficiency. METHODS: Hepatic fat accumulation due to protein deficiency was evaluated in male and female rats before and after sexual maturation. Then, the effects of testosterone on liver lipid, muscle protein metabolism and energy expenditure in adipose tissue were investigated in castrated or testosterone-injected male rats fed control or protein-restricted diet. RESULTS: Hepatic triglyceride accumulation diminished with sex maturation in male but not in female protein-restricted rats. Protein restriction resulted in a significant increase in hepatic triglyceride content in castrated rats but not in sham-operated rats demonstrating that endogenous testosterone reduces hepatic lipid accumulation in male rats. Protein restriction reduced plasma IGF-I and muscle protein synthesis measured using the SUnSET method. Castration increased the plasma corticosterone level and muscle autophagic activity. Muscle weight was reduced and energy expenditure in adipose tissue was increased only when both factors were combined. CONCLUSIONS: Muscle protein synthesis downregulation owing to protein restriction and activation of autophagy following castration reduced muscle mass thereby releasing surplus energy and promoting steatosis in protein-restricted castrated rats despite increased energy expenditure in adipose tissue. We hypothesize that endogenous testosterone reduces hepatic lipid accumulation in protein-deficient male rats and provide novel findings on the gender-specific differences in hepatic steatosis.

[A case of anti-SRY-Related HMG-Box Gene 1 (SOX1) antibody-positive chorea].

A 77-year-old man with a history of lung cancer at the age of 71 developed involuntary right leg movement for a month. Neurological examination revealed a right-sided hemi-chorea. Autoimmune disease was suspected owing to the presence of oligoclonal bands and the elevated IgG-index in the cerebrospinal fluid. We detected anti-SRY-Related HMG-Box Gene 1 (SOX1) antibodies, known to be serological markers of Lambert-Eaton syndrome with small cell lung cancer, but not tumors. The results of tests for antiphospholipid, anti-LGI1, and anti-CASPR2 antibodies associated with non-paraneoplastic autoimmune chorea were all negative. This is the first suggestive case of autoimmune chorea in which anti-SOX1 antibodies were detected.

Primary Position Upbeat Nystagmus with Low Serum Vitamin B12.

A 38-year-old man presented with primary position upbeat nystagmus accompanied by peripheral neuropathy. The serum vitamin B12 level was low along with high plasma homocysteine level, indicating vitamin B12 deficiency. Cyanocobalamin supplementation showed partial clinical and electrophysiological improvement. Although brain magnetic resonance imaging did not show any abnormal intensity lesions, the electrophysiological findings suggested that a pontomedullary medial lesion was responsible for the upbeat nystagmus. To our knowledge, this is the first case of upbeat nystagmus with low serum vitamin B12. Physicians need to recognize the possibility of vitamin B12 deficiency as a cause of upbeat nystagmus.

[Reversible Cerebral Vasoconstriction Syndrome (RCVS) Induced by a Chinese Herbal Medicine; Tokishigyakukagoshuyushokyoto].

A 52-year-old woman taking a Chinese herbal medicine for 10 months was admitted to our hospital for recurrent severe headaches, nausea and vomiting. Brain magnetic resonance imaging revealed convexity subarachnoid hemorrhage in the left occipital and parietal lobes. Brain magnetic resonance angiography (MRA) showed multifocal segmental stenosis of cerebral arteries. Clinical symptoms resolved after treatments with nicardipine and verapamil. Follow-up MRA at 31 days after the onset showed complete disappearance of multifocal stenosis of cerebral arteries, confirming the diagnosis of reversible cerebral vasoconstriction syndrome (RCVS). It was suggested that licorice and evodia fruit, which were components of a Chinese herbal medicine named tokishigyakukagoshuyushokyoto were the precipitating factors of vasoconstriction. It is important for physicians to recognize that herbal supplements could be one of the causes of RCVS. (Received January 22, 2019; Accepted April 3, 2019; Published July 1, 2019).

Effectiveness of a healthcare retreat for male employees with cardiovascular risk factors.

Lifestyle modification is the primary treatment strategy for obesity, hypertension, dyslipidemia, and hyperglycemia. Recently, the Japanese government designed a healthcare retreat program for persons with cardiovascular risk factors. However, the structure and effectiveness of this program has not been fully discussed. Employees of a company group with obesity and one or more other cardiovascular risk factors were enrolled in the study. The participants in the three-day retreat program were compared with those receiving a brochure-based advice for their subsequent changes in the annual health check-up data using the propensity score matching method. Among the 415 eligible employees, 220 underwent the intensive program and 195 received a brochure-based advice. In the propensity score-matched subjects, reduction in body weight (2.7 kg vs. 0.99 kg, p < 0.01), waist circumference (3.5 cm vs. 1.5 cm, p < 0.01), and non-HDL cholesterol (8.8 mg/dl vs. 1.3 mg/dl, p = 0.05) were significantly greater in the intensive care group one year later. The superiority of the intensive program, however, was gradually attenuted for subsequent two years later. This healthcare retreat with counseling and training program would improve body weight and waist circumference for one to two subsequent years.

A case of ectopic ACTH syndrome due to DDAVP-sensitive but V1b receptor-negative bronchial typical carcinoid with lymphatic metastasis and plasma ProGRP elevation.

Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing's syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.

[A sigh increases motivation for difficult and monotonous tasks: The effect of one-time voluntary brief exhalation on relief and achievement needs].

We tested possible intrapersonal effects of a sigh as a psychological "resetter/rebooter." Fifty-eight undergraduates were randomly assigned to a sigh or a normal exhalation (control) group. We asked participants on each task to model the experimenter demonstrating how to exhale air into a small plastic bag for breathing manipulation under the pretext that we were interested in the exhaled gas in stressful situations. Results revealed that the sigh group did not experience more relief (as shown by prolonged reaction time) after exposure to threat stimuli, but showed more persistence on a highly-difficult puzzle task (p = .03, d = .62) and more willingness to continue working on a monotonous task (p < .10, d = .48), than the normal exhalation group. A sigh may have an adaptive function to motivate further work; although it may not induce relief--suggesting that a "sigh of refresh" is a voluntary but a "sigh of relief" is an involuntary response.

Identification and functional analysis of choline transporter in tongue cancer: A novel molecular target for tongue cancer therapy.

We examined the functional characteristics of choline uptake in human tongue carcinoma using the cell line HSC-3. Furthermore, we explored the possible correlation between the inhibition of choline uptake and apoptotic cell death. Both choline transporter-like protein 1 (CTL1) and CTL2 mRNAs and proteins were expressed, and were located in plasma membrane and mitochondria, respectively. Choline uptake was saturable and mediated by a single transport system, which is pH-dependent. Several cationic drugs inhibited cell viability and [(3)H]choline uptake. Choline uptake inhibitors and choline deficiency inhibited cell viability and increased caspase-3/7 activity. We conclude that extracellular choline is mainly transported via a CTL1 that relies on a directed H(+) gradient as a driving force. The functional inhibition of CTL1 by cationic drugs could promote apoptotic cell death. Furthermore, CTL2 may be the major site for the control of choline oxidation in mitochondria and hence for the supply of endogenous betaine and S-adenosyl methionine, which serves as a major methyl donor. Identification of this CTL1- and CTL2-mediated choline transport system provides a potential new target for tongue cancer therapy.

Enhanced oleate uptake and lipotoxicity associated with laurate.

Free fatty acids have been reported to induce cell death (lipotoxicity), but the effects depend on the carbon chain length and number of double bonds. Medium-chain saturated fatty acids (MC-SFAs), such as laurate, have less lipotoxicity than long-chain saturated fatty acids (LC-SFAs), such as palmitate. Monounsaturated fatty acids, such as oleate, have also been reported not only to exert cytotoxic effects, but also to reduce the lipotoxicity of LC-SFA. However the interaction between MC-SFA and oleate with respect to cell death is unclear. In this report, we found that lipotoxicity was enhanced by a combination of laurate and oleate relative to either fatty acid alone. The possible mechanisms involved were examined by measuring the production of reactive oxygen species, mitochondrial depolarization, caspase-3 activity, and lipid droplet formation. Although the stress signals and cell death pathways were distinct among different cell types, we found a common phenomenon of enhanced lipid droplet formation in all cells tested. Using fluorescent- or radioisotope-labeled fatty acids, we found that oleate, but not laurate, increased the uptake of fluorescent-labeled fatty acids, and the combinatory effect was more efficient than with oleate alone. We also found that laurate increased oleate uptake, but the effect of oleate on laurate uptake varied among cell types. These results suggest that laurate enhances the influx rate of oleate, the increased intracellular concentration of which not only enhances lipid storage, but also induces cell death by lipotoxic stress responses, which vary according to cell type.

Differences in vulnerability to traumatic stress among patients with psychiatric disorders: One-year follow-up study after the Great East Japan Earthquake.

AIMS: The aim of this study was to evaluate differences in vulnerability to traumatic stress and the 1-year course of post-traumatic stress symptoms among patients with pre-existing psychiatric disorders after the Great East Japan Earthquake. METHODS: The Impact of Event Scale-Revised (IES-R) was used to assess post-traumatic stress symptoms in 612 patients with schizophrenic (ICD-10 F2; n = 163), mood (F3; n = 299), or neurotic disorders (F4; n = 150) at 1-4 months and again at 13-16 months after the disaster (retention rate: 68%). RESULTS: The mean IES-R total score for all diagnostic groups was 18.6 at index and 13.4 at follow up. The mean IES-R total score for patients with neurotic disorders (22.5) was significantly higher than that of patients with mood disorders (18.1) and schizophrenic disorders (15.9). At follow up, these scores decreased for all groups and inter-group differences were not observed. CONCLUSIONS: Vulnerability to traumatic stress after a disaster was most severe in patients with neurotic disorders, followed by mood disorders, and, lastly, schizophrenic disorders. This difference among the three diagnostic groups was not found 1 year after the disaster.

Combination of Root Surface Modification with BMP-2 and Collagen Hydrogel Scaffold Implantation for Periodontal Healing in Beagle Dogs.

UNLABELLED: Objective : Biomodification of the root surface plays a major role in periodontal wound healing. Root surface modification with bone morphogenetic protein (BMP) stimulates bone and cementum-like tissue formation; however, severe ankylosis is simultaneously observed. Bio-safe collagen hydrogel scaffolds may therefore be useful for supplying periodontal ligament cells and preventing ankylosis. We examined the effects of BMP modification in conjunction with collagen hydrogel scaffold implantation on periodontal wound healing in dogs. MATERIAL AND METHODS: The collagen hydrogel scaffold was composed of type I collagen sponge and collagen hydrogel. One-wall infrabony defects (5 mm in depth, 3 mm in width) were surgically created in six beagle dogs. In the BMP/Col group, BMP-2 was applied to the root surface (loading dose; 1 µg/µl), and the defects were filled with collagen hydrogel scaffold. In the BMP or Col group, BMP-2 coating or scaffold implantation was performed. Histometric parameters were evaluated at 4 weeks after surgery. RESULTS: Single use of BMP stimulated formation of alveolar bone and ankylosis. In contrast, the BMP/Col group frequently enhanced reconstruction of periodontal attachment including cementum-like tissue, periodontal ligament and alveolar bone. The amount of new periodontal ligament in the BMP/Col group was significantly greater when compared to all other groups. In addition, ankylosis was rarely observed in the BMP/Col group. CONCLUSION: The combination method using root surface modification with BMP and collagen hydrogel scaffold implantation facilitated the reestablishment of periodontal attachment. BMP-related ankylosis was suppressed by implantation of collagen hydrogel.

Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation.

BACKGROUND: Visceral fat accumulation is a major etiological factor in the progression of type 2 diabetes mellitus and atherosclerosis. We described previously visceral fat accumulation and multiple cardiovascular risk factors in a considerable number of Japanese non-obese subjects (BMI <25 kg/m(2)). Here, we investigated differences in systemic arteriosclerosis, serum adiponectin concentration, and eating behavior in type 2 diabetic patients with and without visceral fat accumulation. METHODS: The study subjects were 75 Japanese type 2 diabetes mellitus (age: 64.8 ± 11.5 years, mean ± SD). Visceral fat accumulation represented an estimated visceral fat area of 100 cm(2) using the bioelectrical impedance analysis method. Subjects were divided into two groups; with (n = 53) and without (n = 22) visceral fat accumulation. Systemic arteriosclerosis was scored for four arteries by ultrasonography. Eating behavior was assessed based on The Guideline for Obesity questionnaire issued by the Japan Society for the Study of Obesity. RESULTS: The visceral fat accumulation (+) group showed significantly higher systemic vascular scores and significantly lower serum adiponectin levels than the visceral fat accumulation (-) group. With respect to the eating behavior questionnaire items, (+) patients showed higher values for the total score and many of the major sub-scores than (-) patients. CONCLUSIONS: Type 2 diabetic patients with visceral fat accumulation showed 1) progression of systemic arteriosclerosis, 2) low serum adiponectin levels, and 3) differences in eating behavior, compared to those without visceral fat accumulation. Taken together, the findings highlight the importance of evaluating visceral fat area in type 2 diabetic patients. Furthermore, those with visceral fat accumulation might need to undergo more intensive screening for systemic arteriosclerosis and consider modifying their eating behaviors.

Comparison of fracture sites and post lengths in longitudinal root fractures.

INTRODUCTION: Comparing the epidemiology of fractures originating in the cervical and apical regions may help to understand the causes and risk of a vertical root fracture. We aimed to determine the frequency of vertical root fractures in different fracture sites and how the fracture site relates to fracture direction and post length. METHODS: Teeth diagnosed with a vertical root fracture were retrospectively surveyed for age and sex of the patient, type of tooth, a fracture region in the longitudinal axial direction, site of the fracture, and presence of a post. The fracture region in the longitudinal axial direction was classified as an incomplete fracture, complete fracture, and uncertain. Incomplete fractures were further classified into a fracture originating in the cervical region, a fracture originating in the midregion, and a fracture originating in the apical region. Posts were evaluated by loss of post and length of post. RESULTS: Fractures originating in the cervical and apical region occurred around the same frequency, whereas fractures originating in the midregion were extremely scarce. Of the fractures originating in the cervical region, 36.2% were in a mesial and/or distal site and 57.4% in a buccal and/or lingual site. Of the fractures originating in the apical region, 90.8% were in the buccal and/or lingual site. The number of cases of fractures originating in the apical region decreased with increased post length. CONCLUSIONS: Sites of fracture and post length differed greatly between fractures originating in the cervical region and the apical region, suggesting that risk factors for fractures originating in the cervical and apical regions are different.

Positive feedback regulation between adiponectin and T-cadherin impacts adiponectin levels in tissue and plasma of male mice.

Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.

Adipose hypothermia in obesity and its association with period homolog 1, insulin sensitivity, and inflammation in fat.

Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.