Publications by authors named "Tsuyoshi Goto"

195 Publications

Loss of CREB coactivator CRTC1 in SF1 cells leads to hyperphagia and obesity by high-fat diet but not normal chow diet.

Endocrinology 2021 Apr 13. Epub 2021 Apr 13.

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji city, Kyoto, Japan.

Cyclic adenosine monophosphate responsive element-binding protein-1 (CREB1)-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cyclic adenosine monophosphate. Whole-body knockdown of Crtc1 causes obesity, resulting in increased food intake and reduced energy expenditure. CRTC1 is highly expressed in the brain; therefore, it might play an important role in energy metabolism via the neuronal pathway. However, the precise mechanism by which CRTC1 regulates energy metabolism remains unknown. Here, we showed that mice lacking CRTC1, specifically in steroidogenic factor-1 expressing cells (SF1 cells), were sensitive to high-fat diet (HFD)-induced obesity, exhibiting hyperphagia and increased body weight gain. The loss of CRTC1 in SF1 cells impaired glucose metabolism. Unlike whole-body CRTC1 knockout mice, SF1 cell-specific CRTC1 deletion did not affect body weight gain or food intake in normal chow feeding. Thus, CRTC1 in SF1 cells is required for normal appetite regulation in HFD-fed mice. CRTC1 is primarily expressed in the brain. Within hypothalamus which plays an important role for appetite regulation, SF1 cells are only found in ventromedial hypothalamus. RNA sequencing analysis of micro-dissected ventromedial hypothalamus samples revealed that the loss of CRTC1 significantly changed the expression levels of certain genes. Our results revealed the important protective role of CRTC1 in SF1 cells against dietary metabolic imbalance.
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http://dx.doi.org/10.1210/endocr/bqab076DOI Listing
April 2021

Impact of Guidewire Route on Severe Dissection After Balloon Angioplasty for Femoropopliteal Chronic Total Occlusion Lesions: An Intravascular Ultrasound Analysis.

Eur J Vasc Endovasc Surg 2021 Feb 22. Epub 2021 Feb 22.

Department of Cardiology, Kurashiki Central Hospital, Okayama, Japan.

Objective: To determine the impact of the guidewire route on severe dissection after balloon angioplasty for femoropopliteal chronic total occlusion (CTO) lesions using a new intravascular ultrasound (IVUS) assessed classification scheme corresponding to a conventional angiographic classification scheme.

Methods: Images for 21 femoropopliteal CTO lesions treated endovascularly between May 2018 and December 2019 were used for analysis. IVUS images after guidewire passage and those after balloon angioplasty were evaluated at 1 cm intervals. Cross sectional images were obtained (n = 219) and divided into two groups by the guidewire route: those in which the guidewire passed through the inner half of the luminal radius (central wiring group, 139 cross sectional images) and those in which the guidewire passed through the outer half of the luminal radius (eccentric wiring group, 80 cross sectional images). Angiographically severe dissection was defined as Type C or greater according to the National Heart, Lung, and Blood Institute classification, to which six dissection morphology patterns were applied based on IVUS images (Types A - E2).

Results: Central wiring was achieved in an average of 69.6 ± 28.0% of the CTO length from per limb analysis. Among the IVUS assessed dissection morphology patterns, Types D - E2 were more frequently correlated with angiographically severe dissection than were Types A - C (57.5% vs. 13.7%, p < .001). Multivariable analysis showed that soft plaque was a predictive factor for (odds ratio [OR] 2.14; 95% confidence interval [CI] 1.007 - 4.72; p = .048) and central wiring was a protective factor (OR 0.27; 95% CI 0.14 - 0.49; p < .001) against Type D - E2 dissection patterns assessed by IVUS after balloon angioplasty.

Conclusion: Lesions with Type D - E2 dissection patterns assessed by IVUS were correlated with angiographically severe dissection. Central wiring may be useful for preventing severe dissection after balloon angioplasty for femoropopliteal CTO lesions.
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http://dx.doi.org/10.1016/j.ejvs.2021.01.014DOI Listing
February 2021

Hip fractures among the elderly in Kyoto, Japan: a 10-year study.

Arch Osteoporos 2021 02 12;16(1):30. Epub 2021 Feb 12.

Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

In Kyoto Prefecture, Japan, the number of hip fractures increased during 2013-2017 compared to 2008-2012. However, the estimated overall incidence rate increased only in femoral neck fractures in men aged ≥75 and women aged ≥85.

Purpose: The incidence rate of hip fractures in Japan has plateaued or decreased. We investigated the annual hip fracture occurrences in Kyoto Prefecture, Japan, from 2008 to 2017.

Methods: Patients aged 65 years and above who sustained hip fractures between 2008 and 2017 and were treated at one of the participating 11 hospitals were included. The total number of beds in these institutions was 3701, accounting for 21.5% of the 17,242 acute-care beds in Kyoto Prefecture. The change in incidence rate was estimated utilizing the population according to the national census conducted in 2010 and 2015.

Results: The total number of hip fractures was 10,060, with 47.5% femoral neck fractures and 52.5% trochanteric fractures. A decrease in number was seen only in trochanteric fractures in the group of 75- to 84-year-old women. The population-adjusted numbers of femoral neck fractures showed a significant increase in all age groups in men, whereas in women, there was an increase in femoral neck fractures in the ≥85 group and trochanteric fractures in the age group 65-74, and a decrease in trochanteric fractures in the age group 75-84. The estimated change in incidence rate showed an increase in femoral neck fractures in men aged ≥75 and women aged ≥85.

Conclusion: In Kyoto Prefecture, the number of hip fractures increased in the second half of the study period (2013-2017) compared to the first half (2008-2012). However, the incidence rate had not increased, except in femoral neck fractures in men aged ≥75 and women aged ≥85.
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http://dx.doi.org/10.1007/s11657-021-00888-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880939PMC
February 2021

Three-dimensional optical coherence tomography versus intravascular ultrasound in percutaneous coronary intervention for the left main coronary artery.

Heart Vessels 2021 May 2;36(5):630-637. Epub 2021 Jan 2.

Department of Cardiology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.

We aimed to compare the intravascular imaging findings, and clinical outcomes between three-dimensional optical coherence tomography (OCT)- and intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) for the left main coronary artery (LMCA). We enrolled 331 patients underwent OCT- or IVUS-guide single crossover stenting across the side branch (SB) and subsequent kissing balloon inflation (KBT) for LMCA bifurcation. Primary endpoint was defined as a composite of cardiac death, myocardial infarction, and target lesion revascularization. Of 331 patients, 58 patients (17.5%) underwent OCT-guide PCI. OCT-guide PCI associated with higher frequency of proximal optimization technique (POT) (98.3% vs 85.3%, P = 0.013) and smaller balloon size of POT (4.29 ± 0.44 mm vs 4.43 ± 0.42, P = 0.02) than IVUS-guide PCI. Although maximal stent area at LMCA and minimal stent area at main vessel were significantly smaller in OCT-guide PCI in intravascular imaging (P = 0.01, and P = 0.002, respectively), the restenosis rate at follow-up angiography was comparable in both groups (15.2% vs. 9.4%, P = 0.387). Cumulative rate of primary endpoint was not significantly different between 2 groups both before and after propensity score adjustment (7.0% vs. 7.4%, P = 0.98 and 2.6% vs. 7.3%, P = 0.18). In conclusion, the clinical outcomes at 1 year were comparable, suggesting OCT- and IVUS-guided PCI for LMCA were similarly feasible. The balloon size of POT in OCT-guide PCI might be influenced by the limited visibility in the proximal LMCA.
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http://dx.doi.org/10.1007/s00380-020-01742-6DOI Listing
May 2021

Comparative Analysis of the Preventive Effects of Canagliflozin, a Sodium-Glucose Co-Transporter-2 Inhibitor, on Body Weight Gain Between Oral Gavage and Dietary Administration by Focusing on Fatty Acid Metabolism.

Diabetes Metab Syndr Obes 2020 16;13:4353-4359. Epub 2020 Nov 16.

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.

Purpose: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have various pleiotropic effects, including body weight reduction, and therefore have the potential to be used in various applications. However, such effects have not been fully investigated; thus, non-clinical studies using animal models are needed. In animal experiments, SGLT2 inhibitors are usually administered by oral or dietary methods. However, the detailed characteristics of these dosing methods, especially to induce their pleiotropic effects, have not been reported. Therefore, we compared the preventive effects of canagliflozin, an SGLT2 inhibitor, on body weight gain following oral gavage and dietary administration methods in a mouse model of diet-induced obesity.

Methods: Canagliflozin was dosed by oral gavage or dietary administration for 9 weeks to 6-week-old C57BL/6N mice fed a high-fat diet, and parameters related to obesity were evaluated.

Results: The suppression of body weight gain, fat mass, and hepatic lipid content was observed following both dosing methods, whereas the effect on body weight tended to be stronger in the dietary administration group. In adipose tissue, fatty acid synthase expression was significantly decreased in the dietary administration group, and its expression was significantly correlated with fat mass. However, the expression of genes related to fatty acid oxidation was unchanged, indicating that the preventive effect on body weight gain was mediated mainly through the suppression of lipid synthesis rather than the promotion of lipid oxidation.

Conclusion: Canagliflozin prevented body weight gain through the suppression of lipid synthesis via both dosing methods, although there were some differences in the efficacy. The findings of our study can help to identify new mechanisms of action of SGLT2 inhibitors and potential applications.
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http://dx.doi.org/10.2147/DMSO.S269916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678695PMC
November 2020

Clinical Outcomes in Patients Treated With a Repositionable and Fully Retrievable Aortic Valve - REPRISE Japan Study.

Circ J 2020 Nov 14. Epub 2020 Nov 14.

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine.

Background: The REPRISE Japan study, a prospective multicenter single-arm trial, was undertaken to confirm the safety and effectiveness of transcatheter aortic valve replacement (TAVR) with the LOTUS valve in Japanese subjects with severe symptomatic calcific aortic stenosis at extreme or high surgical risk.Methods and Results:REPRISE Japan enrolled 40 subjects in the transfemoral (TF) cohort (mean age 84 years; mean [±SD] Society of Thoracic Surgeons [STS] score 6.4±2.9%); 10 additional subjects were treated with a transaortic (TAo) approach (mean age 84 years; mean STS score 6.3±3.3%). A subanalysis was also performed on subjects treated with the 21-mm LOTUS valve (n=15; mean age 84 years; mean STS score 5.3±2.1%). The primary safety endpoint (a composite of all-cause mortality, stroke, life-threatening or major bleeding events, acute kidney injury [Stage 2/3], and major vascular complications at 30 days) occurred in 15% of TF subjects. The primary effectiveness endpoint (a composite of all-cause mortality, disabling stroke, and moderate or greater paravalvular leak [PVL; core laboratory assessed] at 6 months) occurred in 5.3% of TF subjects. Across the TF, TAo, and 21-mm LOTUS valve cohorts, no subjects exhibited moderate or greater PVL at 6 months. The 30-day rate of pacemaker implantation was 22.5% in the TF cohort (TAo: 20%; 21 mm: 13.3%).

Conclusions: Data from REPRISE Japan confirm the safety and efficacy of the LOTUS Valve when used in Japanese clinical practice.
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http://dx.doi.org/10.1253/circj.CJ-20-0064DOI Listing
November 2020

Clinical Outcomes and Angiographic Results of Bailout Stenting for Guide Catheter-Induced Iatrogenic Coronary Artery Dissection - Impact of Stent Type.

Circ J 2020 09 4;84(10):1746-1753. Epub 2020 Sep 4.

Department of Cardiology, Kurashiki Central Hospital.

Background: Guide catheter-induced iatrogenic coronary artery dissection is a rare but feared complication. When it occurs, bailout stenting is widely performed; however, its prognosis and the impact of stent type remains unclear.Methods and Results:The study population consisted of 77,257 consecutive patients (coronary angiography, 55,864; percutaneous coronary intervention, 21,393) between 2000 and 2015. We investigated the incidence, clinical outcomes, and angiographic results after bailout stenting and compared by stent type: bare-metal stent (BMS) and drug-eluting stent (DES). Iatrogenic coronary artery dissection occurred in 105 patients (incidence rate, 0.14%). All cases of iatrogenic coronary artery dissection that were recognized as requiring bailout procedure could be managed by stent implantation, and no patients died during bailout procedure. The 5-year cumulative incidences of cardiac death, target lesion revascularization, and major adverse cardiac events were 11.3%, 10.3%, and 21.0%, respectively. The binary restenosis rate was 10.4%, and it was not significantly different between BMS and DES implantation. In lesions with preprocedural stenosis, however, it was significantly lower in the DES group than in the BMS group. On the other hand, coronary artery dissection recurred in 8 patients, which was observed only after DES implantation.

Conclusions: The immediate and long-term outcomes of bailout stenting for iatrogenic coronary artery dissection were acceptable. Although DES may be favorable for stenotic lesions, coronary artery dissection can recur after DES implantation.
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http://dx.doi.org/10.1253/circj.CJ-20-0123DOI Listing
September 2020

Impact of high-dose statin on cardiovascular outcomes in real-world patients with ST-elevation acute myocardial infarction.

Heart Vessels 2021 Mar 3;36(3):297-307. Epub 2020 Sep 3.

Department of Cardiology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama, 710-8602, Japan.

Little is known about the impact of a high-dose statin on cardiovascular outcomes after ST-elevation acute myocardial infarction (STEMI) in real-world Japanese patients. Between July 2011 and June 2017, 1110 consecutive STEMI patients underwent primary percutaneous coronary intervention at our hospital and were discharged. A high-dose statin was administered in 117 patients (10.5%) and non-high-dose statin was administered in 947 patients (85.3%). The low-density lipoprotein cholesterol level was significantly higher in the high-dose statin group at admission (129.8 ± 44.9 vs. 110.4 ± 32.7, p < 0.0001), but the levels were not significantly different at follow-up (86.7 ± 25.7 vs. 85.0 ± 25.0, p = 0.52). The cumulative 2-year incidence of a composite of cardiac death, myocardial infarction, ischemic stroke, and any unplanned coronary revascularization was significantly lower in the high-dose statin group (6.2% vs. 16.9%, log-rank p = 0.004). Propensity score matched analysis indicated similar results. Among the types of coronary revascularization, a high-dose statin was significantly correlated with a lower rate of de novo lesion revascularization (hazard ratio 0.31; 95% confidence interval 0.08-0.83; p = 0.02). The results of our analyses indicate that administration of a high-dose statin may result in better cardiovascular outcomes after STEMI mainly by reducing the rate of revascularization for de novo lesions regardless of the achieved low-density lipoprotein cholesterol level in real-world patients.
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http://dx.doi.org/10.1007/s00380-020-01696-9DOI Listing
March 2021

Stiffness of the extracellular matrix regulates differentiation into beige adipocytes.

Biochem Biophys Res Commun 2020 11 26;532(2):205-210. Epub 2020 Aug 26.

Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto, 606-8502, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Sakyo, Kyoto, 606-8501, Japan. Electronic address:

Beige/brite adipocytes, which express high levels of uncoupling protein 1 (UCP1) to generate heat using stored triglycerides, are induced under specific stimuli such as cold exposure in inguinal white adipose tissue (iWAT). Although extracellular microenvironments such as extracellular matrix (ECM) stiffness are known to regulate cell behaviors, including cell differentiation into adipocytes, the effect on iWAT cells is unknown. In this study, we show that rigid ECM promotes the cell spreading of iWAT-derived preadipocytes. Furthermore, the expression of UCP1 and other thermogenic genes in iWAT cells is promoted when the cells are cultured on rigid ECM. The expression of mTOR, a kinase known to regulate the differentiation to beige adipocytes, is decreased on rigid substrates. These results suggest that ECM stiffness plays an important role in the differentiation to beige adipocytes.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.032DOI Listing
November 2020

Prevalence of the Academic Research Consortium for High Bleeding Risk Criteria and Prognostic Value of a Simplified Definition.

Circ J 2020 08 16;84(9):1560-1567. Epub 2020 Jul 16.

Department of Cardiology, Kurashiki Central Hospital.

Background: The Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria have been suggested as the standard definition of HBR. However, the prevalence of individual criteria and their prognostic value for long-term bleeding events after percutaneous coronary intervention are scarcely studied.Methods and Results:The study population comprised 1,193 patients treated with everolimus-eluting stents between 2010 and 2011. Data on all 17 major and minor criteria of the ARC-HBR definition were retrospectively collected, and applied to this study population. Major bleeding was defined as the occurrence of a BARC type 3 or 5 bleeding event. A simplified definition was developed by excluding the low-frequency criterion, and the prognostic value was assessed by a receiver-operating characteristic curve. Mean follow-up was 2,996±433 days and there were 656 HBR patients (55.0%). The cumulative incidence of major bleeding was significantly higher in the HBR group than in the non-HBR group (16.2% vs. 5.7% at 8 years, P<0.001). The frequencies of 6 of the 17 criteria were less than 1%. The prognostic value of the simplified definition made by excluding these 6 criteria for major bleeding was comparable to that of the original (c-statistic=0.598 and 0.600, P=0.08).

Conclusions: Some risk criteria of the ARC-HBR definition are observed infrequently. Our simplified definition identified patients with long-term bleeding risk as successfully as the original definition.
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http://dx.doi.org/10.1253/circj.CJ-20-0395DOI Listing
August 2020

Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells.

iScience 2020 Jul 24;23(7):101299. Epub 2020 Jun 24.

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan. Electronic address:

The proteasome is a therapeutic target in cancer, but resistance to proteasome inhibitors often develops owing to the induction of compensatory pathways. Through a genome-wide siRNA screen combined with RNA sequencing analysis, we identified hexokinase and downstream O-GlcNAcylation as cell survival factors under proteasome impairment. The inhibition of O-GlcNAcylation synergistically induced massive cell death in combination with proteasome inhibition. We further demonstrated that O-GlcNAcylation was indispensable for maintaining proteasome activity by enhancing biogenesis as well as proteasome degradation in a manner independent of Nrf1, a well-known compensatory transcription factor that upregulates proteasome gene expression. Our results identify a pathway that maintains proteasome function under proteasome impairment, providing potential targets for cancer therapy.
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http://dx.doi.org/10.1016/j.isci.2020.101299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338785PMC
July 2020

Investigating Anti-Obesity Effects by Oral Administration of Aloe vera Gel Extract (AVGE): Possible Involvement in Activation of Brown Adipose Tissue (BAT).

J Nutr Sci Vitaminol (Tokyo) 2020 ;66(2):176-184

Graduate School of Agriculture, Kyoto University.

The aim of this study is to investigate the mechanism of anti-obesity effects of Aloe vera gel extract (AVGE) containing Aloe sterols. Previously, we reported that oral intake of Aloe vera components has an anti-diabetic and anti-obesity effect. This study was designed to assess the role of brown adipose tissue (BAT) in the anti-obesity effect of AVGE. Six-week-old male mice were divided into three groups; STD (standard diet), HFD (60% high fat diet) and AVGE (60% high fat diet with AVGE treatment). During 11 wk of AVGE administration, body weight has been monitored. Tissue samples were obtained to be measured the weight and evaluated the gene expressions. Mice treated with AVGE had suppressed body weight, and liver and fat weight gain. To investigate BAT activation, we measured the expression of mRNA related to BAT thermogenesis. Mice in the AVGE group had higher expression of Ucp1, Adrb3, and Cidea in BAT compared to HFD. Next, to investigate the possibility that AVGE induced hepatic FGF21, which is an important factor for nutrient and energy homeostasis including BAT regulation, in vitro study was conducted. HepG2 cell stimulated by AVGE were highly expressed FGF21. These results suggested that BAT activation partially contributes to mechanism of anti-obesity effect of Aloe sterols in diet-induced obesity (DIO) models. However, further study is needed to determine the predominant mechanism.
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http://dx.doi.org/10.3177/jnsv.66.176DOI Listing
February 2021

Anti-Inflammatory and Antioxidative Properties of Isoflavones Provide Renal Protective Effects Distinct from Those of Dietary Soy Proteins against Diabetic Nephropathy.

Mol Nutr Food Res 2020 05 27;64(10):e2000015. Epub 2020 Apr 27.

Division of Food Science and Biotechnology, Laboratory of Molecular Function of Food, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan.

Scope: Dietary soy reportedly protects from diabetic nephropathy (DN), but its active components and mechanism of action remain unknown.

Methods And Results: In this study, KKAy mice are fed three types of diet: Dietary soy isoflavones with soy protein (Soy-IP) diet, reduced isoflavones soy protein (RisoP), and oral administration of isoflavones aglycones (IsoAgc). Albuminuria and glycosuria are decreased only in the soy-IP group. The risoP group show reduced expansion of mesangial matrix and renal fibrosis, the IsoAgc group show renal anti-fibrotic and anti-inflammatory effects; however, these renal pathological changes are repressed in the soy-IP group, suggesting the distinct protective roles of soy protein or isoflavones in DN. The isoflavone genistein has a better inhibitory effect on the inflammatory response and cellular interactions in both mouse tubular cells and macrophages when exposed to high glucose and albumin (HGA). Genistein also represses HGA-induced activator protein 1 activation and reactive oxidases stress generation, accompanied by reduced NADPH oxidase (NOX) gene expression. Finally, diabetic mice show a decrease in lipid peroxidation levels in both plasma and urine, along with lower NOXs gene expression.

Conclusion: The data elucidate the detailed mechanism by which isoflavones inhibit renal inflammation and provide a potential practical adjunct therapy to restrict DN progression.
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http://dx.doi.org/10.1002/mnfr.202000015DOI Listing
May 2020

Glycerol kinase stimulates uncoupling protein 1 expression by regulating fatty acid metabolism in beige adipocytes.

J Biol Chem 2020 05 9;295(20):7033-7045. Epub 2020 Apr 9.

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan

Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced up-regulation in inguinal white adipose tissue (iWAT) was partially abolished by knockdown (KD) Consistently, the KD inhibited expression induced by treatment with the β-adrenergic receptors (βAR) agonist isoproterenol (Iso) and resulted in impaired uncoupled respiration. KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element-binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore KD related to Iso-induced cAMP products. In Iso-treated KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the KD-induced down-regulation and POA treatment down-regulated Iso-activated Our findings suggest that stimulates expression via a mechanism that partially depends on the βAR-cAMP-CREB pathway and -mediated regulation of fatty acid metabolism.
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http://dx.doi.org/10.1074/jbc.RA119.011658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242690PMC
May 2020

A semi-rigid thoracolumbar orthosis fitted immediately after spinal surgery : stabilizing effects and patient satisfaction.

J Med Invest 2019 ;66(3.4):275-279

Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

Purpose : To evaluate the stabilizing effects of a Fit Cure-Spine® semi-rigid thoracolumbar orthosis and wearer satisfaction after lumbar surgery. Methods : In study 1, the spinal angle, spinal motion angle, and distribution of load were measured in 8 adult male volunteers when the orthosis was worn (1) with no custom-made stay (CMS), (2) with a CMS in the prone position (P-CMS), and (3) with a CMS in the prone position and decreased lordosis (DP-CMS). In study 2, pain scale scores and responses to a questionnaire were recorded in 40 consecutive patients who underwent lumbar spinal surgery in our hospital. Results : In study 1, the mean lumbar lordosis when standing was similar to that in the prone position. When the trunk was bent forward, loads on the back support in P-CMS and DP-CMS were concentrated at the center of the CMS, unlike those for No-CMS. In study 2, there was a significant decrease in postoperative wound pain after wearing the Fit Cure-Spine orthosis for 2 weeks. Most patients who wore the orthosis were satisfied with their pain outcome. Conclusion : Adjustment to lumbar lordosis and the prone position was restricted in volunteers wearing the Fit Cure-Spine with a CMS. J. Med. Invest. 66 : 275-279, August, 2019.
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http://dx.doi.org/10.2152/jmi.66.275DOI Listing
June 2020

Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence.

Genes Cells 2019 Dec 6;24(12):801-813. Epub 2019 Nov 6.

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

The proteasome degradation machinery is essential for a variety of cellular processes including senescence and T-cell immunity. Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4 T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4 T cells upon T-cell receptor (TCR) stimulation underlie T-cell senescence. Proteasome dysfunction promotes senescence-associated phenotypes, including defective proliferation, cytokine production and increased levels of PD-1 CD44 CD4 T cells. Proteasome induction by TCR signaling via MEK-, IKK- and calcineurin-dependent pathways is attenuated with age and decreased in PD-1 CD44 CD4 T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4 T-cell senescence.
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http://dx.doi.org/10.1111/gtc.12728DOI Listing
December 2019

Long non-coding RNA 2310069B03Rik functions as a suppressor of Ucp1 expression under prolonged cold exposure in murine beige adipocytes.

Biosci Biotechnol Biochem 2020 Feb 10;84(2):305-313. Epub 2019 Oct 10.

Laboratory of Molecular Functions of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.

Specific conditions, such as exposure to cold, can induce the production of brown-like adipocytes in white adipose tissue. These adipocytes express high levels of uncoupling protein 1 (UCP1) and energy expended by generating heat. Thus, these are a potential target for the prevention or treatment of obesity. The present study involved a comprehensive analysis of the adipose tissue to understand the relationship between long non-coding RNA (lncRNA) 2310069B03Rik and UCP1. Cold exposure increased both and expression in inguinal white adipose tissue (iWAT). However, overexpression of lncRNA 2310069B03Rik suppressed the mRNA expression and the promoter activity of UCP1 in the iWAT primary adipocytes. In addition, compared to the early induction of expression by cold stimulation, the induction of lncRNA 2310069B03Rik expression was later. These results suggest that lncRNA 2310069B03Rik functions as a suppression factor of expression.
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http://dx.doi.org/10.1080/09168451.2019.1677451DOI Listing
February 2020

Long-Term Incidence and Details of Bleeding Events After Everolimus-Eluting Stent Implantation - 7-8-Year Outcomes.

Circ J 2019 10 7;83(11):2242-2249. Epub 2019 Sep 7.

Department of Cardiology, Kurashiki Central Hospital.

Background: To date, the long-term incidence and details of major bleeding (MB) and coronary thrombotic events (CTE) in patients with everolimus-eluting stent (EES) implantation have not been made clear.Methods and Results:The study population comprised 1,193 patients treated with EES without in-hospital events between 2010 and 2011. MB was defined as the occurrence of a Bleeding Academic Research Consortium type 3 or 5 bleeding event. The mean follow-up period was 2,996±433 days. Cumulative rate of MB was 7.4% and 10.8% at 5 and 8 years, respectively. Of 46 patients with intracranial bleeding, 20 had trauma-related intracranial bleeding. Cumulative rates of definite stent thrombosis and CTE at 8 years were 0.4% and 5.9%, respectively. Multivariate analysis revealed low body mass index (<23) (hazard ratio (HR), 1.57; 95% confidence interval (CI), 1.03-2.36; P=0.03) and concomitant use of oral anticoagulants (HR, 2.17; 95% CI, 1.30-3.50; P=0.004) as independent risk factors of MB and previous PCI (HR, 2.47; 95% CI, 1.29-1.00; P=0.006) as the factor for CTE.

Conclusions: MB is not uncommon and is a long-term hazard, but the occurrence of stent thrombosis is very low after EES implantation. Approximately half of the cases involving intracranial bleeding were associated with trauma.
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http://dx.doi.org/10.1253/circj.CJ-19-0494DOI Listing
October 2019

β-Cryptoxanthin Induces UCP-1 Expression via a RAR Pathway in Adipose Tissue.

J Agric Food Chem 2019 Sep 11;67(38):10595-10603. Epub 2019 Sep 11.

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture , Kyoto University , Uji , Kyoto 611-0011 , Japan.

While β-cryptoxanthin is hypothesized to have a preventive effect on lifestyle-related diseases, its underlying mechanisms are unknown. We investigated the effect of β-cryptoxanthin on energy metabolism in adipose tissues and its underlying mechanism. C57BL/6J mice were fed a high-fat diet (60% kcal fat) containing 0 or 0.05% β-cryptoxanthin for 12 weeks. β-cryptoxanthin treatment was found to reduce body fat gain and plasma glucose level, while increasing energy expenditure. The expression of uncoupling protein (UCP) 1 was elevated in adipose tissues in the treatment group. Furthermore, the in vivo assays showed that the mRNA expression was higher in the β-cryptoxanthin treatment group, an effect that disappeared upon cotreatment with a retinoic acid receptor (RAR) antagonist. In conclusion, we report that β-cryptoxanthin reduces body fat and body weight gain and that β-cryptoxanthin increases the expression of UCP1 via the RAR pathway.
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http://dx.doi.org/10.1021/acs.jafc.9b01930DOI Listing
September 2019

Dash-Associated Spondylolysis Hypothesis.

Spine Surg Relat Res 2019 Apr 25;3(2):146-150. Epub 2018 Aug 25.

Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

Introduction: In past biomechanical studies, repetitive motion of lumbar extension, rotation, or a combination of both, frequently seen in batting or pitching practice in baseball, shooting practice in soccer, and spiking practice in volleyball, have been considered important risk factors of lumbar spondylolysis. However, clinically, these have been identified in many athletes performing on a running track or on the field, which requires none of the practices described above. The purpose of this study was to verify how much impact running has on the pathologic mechanism of lumbar spondylolysis.

Methods: In study 1, 89 consecutive pediatric patients diagnosed with lumbar spondylolysis at a single outpatient clinic between January 2012 and February 2017 were retrospectively analyzed. In study 2, motion analysis was performed on 17 male volunteers who had played on a soccer team without experiencing low back pain or any type of musculoskeletal injury. A Vicon motion capture system was used to evaluate four movements: maximal effort sprint (Dash), comfortable running (Jog), instep kick (Shoot), and inside kick (Pass).

Results: In study 1, 13 of the 89 patients with lumbar spondylolysis were track and field athletes. In study 2, motion analysis revealed that the hip extension angle, spine rotation angle, and hip flexion moment were similar in Dash and Shoot during the maximum hip extension phase. The pelvic rotation angle was significantly greater in the kicking conditions than in the running conditions.

Conclusions: Kinematically and kinetically, the spinopelvic angles in Dash were considered similar to those in Shoot. Dash could cause mechanical stress at the pars interarticularis of the lumbar spine, similar to that caused by Shoot, thus leading to spondylolysis.
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http://dx.doi.org/10.22603/ssrr.2018-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690085PMC
April 2019

Bony Healing of Discontinuous Laminar Stress Fractures Due to Contralateral Pars Defect or Spina Bifida Occulta.

Spine Surg Relat Res 2019 Jan 25;3(1):67-70. Epub 2018 Jul 25.

Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

Introduction: Although there has been a dramatic improvement in the outcomes of conservative treatment to achieve bony healing due to advances in diagnostic and therapeutic tools, in some patients, the results continue to be unfavorable. The purpose of this study was to investigate the outcomes of conservative treatment in pediatric patients with stress fractures occurring in the lamina that are discontinuous due to a contralateral pars defect or spina bifida occulta (SBO).

Methods: The medical records at our outpatient clinic for 103 consecutive patients (83 boys, 20 girls) with lumbar spondylolysis (LS) were reviewed to identify those who had presented with a stress fracture and a contralateral pars defect or with SBO at the affected lamina level.

Results: Twelve patients (11 boys, 1 girl) of mean age 12.3 (range 8-16) years were identified. Except for 1 stress structure that occurred at L4, all the stress fractures occurred at L5. Six patients had a pars defect, 5 had SBO, and 1 had both. Two of the 6 patients with a contralateral pars defect had early LS, 3 had progressive LS, and 1 had a pedicle fracture. The fracture healed in 1 (50%) of the 2 patients with early LS and in the patient with the pedicle fracture, but did not heal in any of the patients with progressive LS. Two of the 5 patients with SBO at the affected lamina level had early LS and 3 had progressive LS. The bony healing rate was 100% in the 2 patients with early LS and 66.7% in the 3 patients with progressive LS. The fracture healed in the patient with progressive LS and both a pars defect and SBO at the affected lamina.

Conclusions: Contralateral pars defect remains an unfavorable factor for bony healing discontinuous laminar stress fractures.
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http://dx.doi.org/10.22603/ssrr.2018-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690129PMC
January 2019

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Nature 2019 08 21;572(7771):614-619. Epub 2019 Aug 21.

UCSF Diabetes Center, San Francisco, CA, USA.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.
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http://dx.doi.org/10.1038/s41586-019-1503-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715529PMC
August 2019

Long-term outcomes of three-vessel coronary artery disease after coronary revascularization by percutaneous coronary intervention using second-generation drug-eluting stents versus coronary artery bypass graft surgery.

Cardiovasc Interv Ther 2020 Apr 10;35(2):194-202. Epub 2019 Jul 10.

Department of Cardiology, Kurashiki Central Hospital, 1-1-1, Miwa, Kurashiki, Okayama, 710-8602, Japan.

Studies on the outcomes of de novo three-vessel coronary artery disease (3VD) are limited. This study evaluated the outcomes after coronary revascularization in patients with 3VD treated by percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (2ndDES) in comparison with coronary artery bypass grafting (CABG). We analyzed 853 patients undergoing either PCI or CABG for 3VD between 2010 and 2014. Of them, this study included 298 undergoing PCI with 2ndDES alone (PCI group) and 171 undergoing CABG (CABG group). The primary outcome measure was a composite of all-cause death, non-fatal myocardial infarction (MI), or stroke. The secondary outcome measures were cardiac death, MI, stroke, and target vessel revascularization (TVR). Propensity matching was used to adjust a cohort of patients with similar baseline characteristics. Between the PCI and CABG groups, no significant differences were found in the 3-year cumulative incidence of the primary outcome measure (14.9% vs. 12.9%, p = 0.60). After propensity score matching, no significant differences were found in the incidences of primary outcome measure (13.0% vs. 12.8%, p = 0.95), cardiac death, MI, and stroke (3.5% vs. 2.7%, p = 0.72; 1.2% vs. 0.0%, p = 0.31; and 4.9% vs. 3.1%, p = 0.35), whereas that of TVR was significantly higher in the PCI group (24.5 vs. 7.1%, p < 0.01). Compared with CABG, PCI with second-generation DES was not associated with higher risk of clinical outcomes, but was associated with a higher risk of TVR in the treatment of 3VD.
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http://dx.doi.org/10.1007/s12928-019-00599-5DOI Listing
April 2020

A new mouse model for noninvasive fluorescence-based monitoring of mitochondrial UCP1 expression.

FEBS Lett 2019 06 20;593(11):1201-1212. Epub 2019 May 20.

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Japan.

Mitochondrial uncoupling protein 1 (UCP1) is well known for its thermogenic function in brown adipose tissue (BAT). Since UCP1 expends energy on thermogenesis, UCP1 activation has been considered an approach to ameliorate obesity. As a tool for uncovering yet unknown mechanisms of UCP1 activation, we generated a transgenic mouse model in which UCP1 expression levels are reflected in fluorescence derived from monomeric red fluorescent protein 1 (mRFP1). In these UCP1-mRFP1 BAC transgenic mice, fluorescence intensity mimics the change in UCP1 expression levels evoked through physiological or pharmacological stimulation. This transgenic mouse model will be useful in the search for bioactive compounds with the ability to induce UCP1 and for revealing undiscovered mechanisms of BAT activation.
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http://dx.doi.org/10.1002/1873-3468.13430DOI Listing
June 2019

An Adolescent Athlete with Low Back Pain Associated with Spina Bifida Occulta at the Thoracolumbar Junction : A Case Report.

J Med Invest 2019 ;66(1.2):199-200

Department of Orthopedics, Institute ofBiomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

Introduction: Spina bifida occulta (SBO) is a common malformation of lamina of the spine, most commonly occurring in the sacrum or lower lumbar spine. Athletes with anatomical abnormalities such as SBO may be vulnerable to discoordination of muscles and/or skeletal structures.

Case Report: We present a case of a 15- year-old male adolescent who presented with persistent low back pain (LBP) associated with SBO at T11-L1 that had been overlooked for several years. He participated in karate as a top-level competitor at the nationallevel, but the LBP interfered with his play. Dynamic X-ray films showed limited range of motion (ROM) in his lower lumbar spine (L3-S1). Instead, the thoracolumbar junction compensated for the lack of ROM in the lumbar spine,enabling trunk flexion and extension. To restore normal coordination, he was treated with a 2-week rehabilitation program including flexibility and core conditioning for the trunk to improve coordination of spinal movement. Two weeks later, his LBP resolved.

Conclusion: These results suggest that evaluation of the coordination of the muscles and skeletal structures has an important role in the treatment of cases with an anatomical abnormality such as SBO. J.Med.Invest.66:199-200, February, 2019.
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http://dx.doi.org/10.2152/jmi.66.199DOI Listing
December 2019

Soy hydrolysate enhances the isoproterenol-stimulated lipolytic pathway through an increase in β-adrenergic receptor expression in adipocytes.

Biosci Biotechnol Biochem 2019 Sep 2;83(9):1782-1789. Epub 2019 May 2.

a Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Uji , Japan.

Activation of the adipose lipolytic pathway during lipid metabolism is mediated by protein kinase A (PKA), which responds to β-adrenergic stimulation, leading to increased lipolysis. Soy is well known as a functional food and it is able to affect lipolysis in adipocytes. However, the mechanism by which soy components contribute to the lipolytic pathway remains to be fully elucidated. Here, we show that hydrolyzed soy enhances isoproterenol-stimulated lipolysis and activation of PKA in 3T3-L1 adipocytes. We also found that the expression of β-adrenergic receptors, which coordinate the activation of PKA, is elevated in adipocytes differentiated in the presence of soy hydrolysate. The activity of the soy hydrolysate towards β-adrenergic receptor expression was detected in its hydrophilic fraction. Our results suggest that the soy hydrolysate enhances the PKA pathway through the upregulation of β-adrenergic receptor expression and thereby, increase lipolysis in adipocytes.
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http://dx.doi.org/10.1080/09168451.2019.1611413DOI Listing
September 2019

Heme oxygenase-1 prevents glucocorticoid and hypoxia-induced apoptosis and necrosis of osteocyte-like cells.

Med Mol Morphol 2019 Sep 31;52(3):173-180. Epub 2019 Jan 31.

Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Glucocorticoids and hypoxia is considered to promote osteocyte apoptosis and necrosis, which are observed in glucocorticoid-associated osteonecrosis and osteoporosis. Heme oxygenase-1 (HO-1) induced by hemin is reported to have cytoprotective effects in ischemic diseases. The objective of this study was to evaluate the effect of HO-1 on osteocyte death caused by glucocorticoids and hypoxia. We confirmed that hemin induced HO-1 expression in MLO-Y4 mouse osteocytes. MLO-Y4 was cultured with dexamethasone (Dex) under hypoxia (DH group). Furthermore, these cells were cultured with hemin (DH-h group) or hemin and zinc protoporphyrin IX (an HO-1 inhibitor) (DH-h-PP group). The rates of apoptosis and necrosis of these groups were analyzed by flow cytometry and compared with cells cultured under normal condition. Both apoptosis and necrosis increased in the DH group. Hemin administration significantly reduced cell death caused by glucocorticoids and hypoxia in the DH-h group, and its effect was attenuated by the HO-1 inhibitor in DH-h-PP group. Capase-3 activity significantly decreased in the DH-h group. This implied that the cell death inhibition effect due to hemin is mediated by HO-1 and caspase-3. HO-1 induction may be useful in the treatment of glucocorticoid-associated osteonecrosis and osteoporosis.
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http://dx.doi.org/10.1007/s00795-018-00215-0DOI Listing
September 2019

Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes.

Int J Mol Sci 2019 Jan 11;20(2). Epub 2019 Jan 11.

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.

Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 () involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of and peroxisome proliferator-activated receptor γ (), which is known as a transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the enhancer, thereby downregulating expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on expression via Pparγ suppression in beige adipocytes.
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http://dx.doi.org/10.3390/ijms20020274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359291PMC
January 2019

A review of the studies on food-derived factors which regulate energy metabolism via the modulation of lipid-sensing nuclear receptors.

Authors:
Tsuyoshi Goto

Biosci Biotechnol Biochem 2019 Apr 20;83(4):579-588. Epub 2018 Dec 20.

a Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture , Kyoto University , Kyoto , Japan.

Obesity is one of the most important risk factors for chronic metabolic disorders. Molecular mechanisms underlying obesity-related metabolic disorders have not been completely elucidated. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and are key metabolic regulators of the whole-body energy metabolism. Certain enzymes involved in carbohydrate and lipid metabolism are directly regulated by PPARs via their interaction with specific response elements in their gene promoters. Many food factors act as ligands of PPARs and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors, leading to the attenuation of obesity-related metabolic disorders. In this review, we describe our current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities. Abbreviations: WAT: white adipose tissue; PPAR: Peroxisome proliferators-activated receptor; RXR: retinoid X receptors; mTORC1: mechanistic target of rapamycin complex 1; PPRE: PPAR-responsive regulatory elements; NAFLD: nonalcoholic fatty liver disease; LPL: lipoprotein lipase; FGF21: fibroblast growth factor 21; BAT: brown adipose tissue; UCP1: uncoupling protein 1; LPC(16:0): 1-palmitoyl lysophosphatidylcholine; C/EBP: CCAAT-enhancer binding proteins; STAT5A: signal transduction and activator of transcription 5A; APO apolipoptotein; CBP: cAMP response element-binding protein-binding protein; PGC1A: PPARγ coactivator protein 1a; HFD: high-fat diet; TG: triglyceride; VLDL: very low density lipoprotein; HDL: high density lipoprotein.
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http://dx.doi.org/10.1080/09168451.2018.1559025DOI Listing
April 2019

Apo-12'-lycopenal, a Lycopene Metabolite, Promotes Adipocyte Differentiation via Peroxisome Proliferator-Activated Receptor γ Activation.

J Agric Food Chem 2018 Dec 4;66(50):13152-13161. Epub 2018 Dec 4.

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture , Kyoto University , Uji , Kyoto 611-0011 , Japan.

Apo-lycopenals, lycopene metabolites produced by an initial cleavage by β,β-carotene-9',10'-oxygenase, exhibit diverse biologically active effects. In this study, we investigated the effect of apo-lycopenals on the activation of nuclear receptors involved in glucose and lipid metabolism. Only apo-12'-lycopenal exhibited selective and dose-dependent transactivation activity for peroxisome proliferator-activated receptor γ (PPARγ), whereas neither apo-6'- nor apo-8'-lycopenals displayed this activity ((7.83 ± 0.66)-, (1.32 ± 0.10)-, and (1.31 ± 0.37)-fold higher activity relative to control, respectively). Additionally, apo-12'-lycopenal promoted adipocyte differentiation of 3T3-L1 cells and subsequently increased the mRNA levels of PPARγ (a (2.36 ± 0.07)-fold increase relative to control; p < 0.01) and its target genes, as well as enhanced adiponectin secretion (a (3.25 ± 0.27)-fold increase relative to control; p < 0.01) and insulin-stimulated glucose uptake (1486 ± 85 pmol/well; p < 0.001) in 3T3-L1 cells. Our results indicated that apo-12'-lycopenal promoted adipocyte differentiation by direct binding and activation of PPARγ.
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http://dx.doi.org/10.1021/acs.jafc.8b04736DOI Listing
December 2018