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Objective: Non-alcoholic fatty liver disease (NAFLD) with excessive triglyceride accumulation in the liver prevails in approximately 24% of adults worldwide. Prolonged fasting rapidly causes hepatic steatosis. However, the etiology of hepatic steatosis during starvation is unclear. During starvation, skeletal muscle, the central tissue for metabolism, physical exercise, and storage for protein/amino acids, adapts to energy deficit by promoting muscle proteolysis, which leads to muscle atrophy. The critical factors that cause muscle atrophy are the Forkhead Box O family transcription factors (FoxO1, 3 and 4). Although skeletal muscle FoxOs are necessary to adapt to starvation, the specific function of skeletal muscle FoxOs at the whole-body level is unclear. We hypothesized that skeletal muscle atrophy and/or metabolism would be associated with the etiology of starvation-induced fatty liver and aimed to elucidate the inter-organ crosstalk from skeletal muscle to liver via FoxOs signaling pathway. Methods: We previously generated skeletal muscle-specific FoxO1,3,4-triple knockout mice (mFoxO1,3,4-/-) using human skeletal α-actin promoter-driven Cre recombinase expression (Oyabu et al. 2022. FASEB J 36: e22152). The control FoxO1,3,4flox/flox mice (wild-type mice) and mFoxO1,3,4-/- mice were fasted for 48 h to mimic prolonged fasting. Results: Skeletal muscle mass was significantly reduced in 48 h-fasted wild-type mice. This reduction was prevented by the skeletal muscle FoxO-triple deletion. Fasted mFoxO1,3,4-/- mice showed reduced blood glucose levels, suggesting the lack of energy in 48 h-fasted mFoxO1,3,4-/- mice. Interestingly, starvation-induced lipid-droplet formation in the liver, accumulation of hepatic triglyceride, and the expression of hepatic lipid-droplet-marker protein (Plin2) were significantly increased in 48 h-fasted mFoxO1,3,4-/- mice compared to fasted wild-type mice, indicating that hepatic steatosis was accelerated by skeletal muscle FoxO-triple deletion, despite of the retention from skeletal muscle loss. This suggests that skeletal muscle FoxOs are essential for protection against starvation-induced hepatic steatosis for adaptation to starvation. Starvation induced the upregulation of genes involved in not only muscle proteolysis, but also triglyceride uptake and metabolism in skeletal muscle, which were abrogated by the skeletal muscle-specific FoxO-triple deletion. In addition, the muscle triglyceride level was lower in 48 h-fasted mFoxO1,3,4-/- mice than fasted wild-type mice. Conclusion: Here, we demonstrated a critical connection between liver and skeletal muscle via FoxOs transcription factors. Our data indicate that healthy skeletal muscle atrophy and/or metabolism via FoxOs signaling pathway is critical for prevention of starvation-induced hepatic steatosis. This study sheds light on the skeletal muscle-liver inter-organ crosstalk as the potential therapeutic targets of malnutrition-induced NAFLD. This study was supported by Grants-in-Aids for Scientific Research KAKENHI from the Japan Society for the Promotion of Science. This study was also supported by Mishima Kaiun Memorial Foundation and Grants-in-Aids for the Second Dream Challenge Planning Awards from JSBBA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Soy isoflavones have been shown to have anti-inflammatory properties; however, the anti-inflammatory effects of isoflavone metabolites produced during soybean germination remain unclear. We found that the daidzein and genistein derivatives, 8-prenyl daidzein (8-PD) and 8-prenyl genistein (8-PG), demonstrated a more potent effect than daidzein and genistein on repressing inflammatory responses in macrophages. Although IkB protein levels were unaltered, 8-PD and 8-PG repressed nuclear factor kappa B (NF-κB) activation, which was associated with reduced ERK1/2, JNK, and p38 MAPK activation and suppressed mitogen- and stress-activated kinase 1 phosphorylation. Inflammatory responses induced by the medium containing hypertrophic adipocyte secretions were successfully suppressed by 8-PD and 8-PG treatment. In the ex vivo study, 8-PD and 8-PG significantly inhibited proinflammatory C–C motif chemokine ligand 2 (CCL2) secretion from the adipose tissues of mice fed a long-term high-fat diet. The data suggest that 8-PD and 8-PG could regulate macrophage activation under obesity conditions.

Mergers of local governments, commonly referred to as municipal mergers, have been widely implemented to internalize spillover effects. Many empirical studies point out that municipalities change the intertemporal budget allocation by increasing their debt issuance before mergers and they consider that this debt issuance is induced by the “fiscal common pool problem” because of pooled budgets after mergers. However, this phenomenon has yet to be analyzed theoretically. Therefore, this paper examines the mechanism of increased debt issuance before municipal mergers. We compare the debt issuance in the merger case with the level in the socially optimal and nonmerger cases. We find that the amount of debt issuance is larger in the merger case than in both other cases. The difference vanishes when spillovers are perfect.

We report that Gs signaling in melanocortin 4 receptor (MC4R)-expressing cells regulates energy expenditure, appetite, and locomotor activity. These findings shed light on the mechanism underlying the regulation of energy metabolism and locomotor activity by MC4R/cAMP signaling.

Purpose To compare diffusion tensor imaging (DTI) parameters in healthy adult human lower leg muscles and to determine the correlation between DTI parameters and muscle power measurements among different types of muscle contraction. Materials and methods DTI measurements of the unilateral lower leg muscles having three different types of contraction (non-contraction state, isometric contraction, and soleus shortening) were obtained from 10 healthy adults using a 3-T MRI scanner. DTI parameters (λ1, λ2, λ3, mean diffusivity, and fractional anisotropy) were calculated. The values of the DTI parameters and correlation between the DTI parameters and muscle power measurements (maximum power and maximum amount of work) obtained from a dynamometer were statistically compared among the different types of contraction. Intra- and inter-class correlation coefficients were calculated for analysis of reproducibility. Results The λ1, λ2, λ3, and mean diffusivity of the soleus muscle are significantly lower in the non-contraction state as compared with isometric contraction and soleus shortening (p 1, λ2, and mean diffusivity. There was a positive correlation between the maximum amount of work and fractional anisotropy in the non-contraction state for the soleus muscle. A negative correlation for the tibialis anterior muscle in the non-contraction state was seen between the maximum amount of work and fractional anisotropy. Overall reproducibility of the DTI parameters was excellent. Conclusions DTI parameters were significantly changed depending on the ankle joint position and type of muscle contraction.

Melanocortin-4 receptor (MC4R) is a critical regulator of appetite and energy expenditure in rodents and humans. MC4R deficiency causes hyperphagia, reduced energy expenditure, and impaired glucose metabolism. Ligand binding to MC4R activates adenylyl cyclase, resulting in increased levels of intracellular cyclic adenosine monophosphate (cAMP), a secondary messenger that regulates several cellular processes. Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cAMP and is reportedly involved in obesity. However, the precise mechanism through which CRTC1 regulates energy metabolism remains unknown. Additionally, there are no reports linking CRTC1 and MC4R, although both CRTC1 and MC4R are known to be involved in obesity. Here, we demonstrate that mice lacking CRTC1, specifically in MC4R cells, are sensitive to high-fat diet (HFD)-induced obesity and exhibit hyperphagia and increased body weight gain. Moreover, the loss of CRTC1 in MC4R cells impairs glucose metabolism. MC4R-expressing cell-specific CRTC1 knockout mice did not show changes in body weight gain, food intake, or glucose metabolism when fed a normal-chow diet. Thus, CRTC1 expression in MC4R cells is required for metabolic adaptation to HFD with respect to appetite regulation. Our results revealed an important protective role of CRTC1 in MC4R cells against dietary adaptation.

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.

Target of rapamycin (TOR) forms two distinct complexes, TORC1 and TORC2, to exert its essential functions in cellular growth and homeostasis. TORC1 signaling is regulated in response to nutrients such as amino acids and glucose; however, the mechanisms underlying the activation of TORC2 signaling are still poorly understood compared to those for TORC1 signaling. In the budding yeast Saccharomyces cerevisiae, TORC2 targets the protein kinases Ypk1 and Ypk2 (hereafter Ypk1/2), and Pkc1 for phosphorylation. Plasma membrane stress is known to activate TORC2–Ypk1/2 signaling. We have previously reported that methylglyoxal (MG), a metabolite derived from glycolysis, activates TORC2–Pkc1 signaling. In this study, we found that MG activates the TORC2–Ypk1/2 and TORC2–Pkc1 signaling, and that phosphatidylserine is involved in the activation of both signaling pathways. We also demonstrated that the Rho family GTPase Cdc42 contributes to the plasma membrane stress-induced activation of TORC2–Ypk1/2 signaling. Furthermore, we revealed that phosphatidylinositol-specific phospholipase C, Plc1, contributes to the activation of both TORC2–Ypk1/2 and TORC2–Pkc1 signaling.

Data on long-term outcomes of transcatheter aortic valve replacement (TAVR) in Japanese patients beyond 5 years are limited.Between June 2010 and December 2014, 55 consecutive inoperable or high surgical risk patients underwent TAVR with SAPIEN XT valves (Edwards Lifesciences, Irvine, CA, USA) for severe aortic stenosis at our institution. Among them, 2 patients were excluded from the analysis because one was converted to open surgery during the TAVR procedure and the other could not undergo TAVR due to device delivery failure. We retrospectively analyzed long-term clinical outcomes of these 53 patients (mean age: 84.1 years; mean STS score: 8.4) who had at least a 7-year follow-up after TAVR.The rates of freedom from all-cause and cardiovascular deaths at 7 years were 35.8 % and 79.3 %, respectively. The moderate or severe structural valve deterioration (SVD) rate at 5 and 7 years was 7.2 % and 11.4 %, respectively. The rate of bioprosthetic valve failure (BVF) at 7 years was 6.2 %.The 7-year mortality rate of inoperable or high surgical risk patients treated with SAPIEN XT was high, while the cardiovascular mortality rate was acceptable. Although the poor survival rate limited the long-term assessment of SAPIEN XT valve durability, the incidence of SVD and BVF was not rare.

Thermoregulation is a process by which core body temperature is maintained in mammals. Males typically have a lower body temperature than females. However, the effects of androgens, which show higher levels in males, on adrenergic receptor-mediated thermogenesis remain unclear. Here, we demonstrate that androgen-androgen receptor (AR) signaling suppresses the β-adrenergic agonist-induced rise of core body temperature using castrated and AR knockout (ARKO) male mice. Furthermore, in vitro mechanistic studies show that activated AR inhibits cAMP response element (CRE)-mediated transcription by suppressing cAMP response element-binding protein (CREB) phosphorylation. The elevation of body temperature induced by the β-adrenergic agonist CL316243 was higher in ARKO and castrated mice than in the control mice. Similarly, CL316243 induced a greater increase in Uncoupling protein 1 (Ucp1) expression and CREB phosphorylation in the brown adipose tissue of ARKO mice than in that of controls. We determined that activation of AR by dihydrotestosterone suppressed β3-agonist- or forskolin-induced CRE-mediated transcription, which was prevented by AR antagonist. AR activation also suppressed CREB phosphorylation induced by forskolin. Moreover, we found AR nuclear localization, but not transcriptional activity, was necessary for the suppression of CRE-mediated transcription. Finally, modified mammalian two-hybrid and immunoprecipitation analyses suggest nuclear AR and CREB form a protein complex both in the presence and absence of dihydrotestosterone and forskolin. These results suggest androgen-AR signaling suppresses β-adrenoceptor-induced UCP1-mediated brown adipose tissue thermogenesis by suppressing CREB phosphorylation, presumably owing to a protein complex with AR and CREB. This mechanism explains sexual differences in body temperature, at least partially.

The melanocortin 4 receptor (MC4R) plays an important role in the regulation of appetite and energy expenditure in humans and rodents. Impairment of MC4R signaling causes severe obesity. MC4R mainly couples to the G-protein G

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.

Satoko Kawarasaki,1 Honami Sawazaki,1 Hiroaki Iijima,2 Su-Ping Ng,1 Jungin Kwon,1 Shinsuke Mohri,1 Mari Iwase,1 Huei-Fen Jheng,1 Haruya Takahashi,1 Wataru Nomura,1,3 Kazuo Inoue,1,3 Teruo Kawada,1,3 Tsuyoshi Goto1,3 1Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan; 2Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 3Research Unit for Physiological Chemistry, The Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8317, JapanCorrespondence: Tsuyoshi GotoLaboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, JapanTel +81-774-38-3753Fax +81-774-38-3752Email goto.tsuyoshi.6x@kyoto-u.ac.jpPurpose: 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.Keywords: SGLT2 inhibitor, obesity, dosing method

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 lncRNA 2310069B03Rik and Ucp1 expression in inguinal white adipose tissue (iWAT). However, overexpression of lncRNA 2310069B03Rik suppressed the Ucp1 mRNA expression and the promoter activity of UCP1 in the iWAT primary adipocytes. In addition, compared to the early induction of Ucp1 expression by cold stimulation, the induction of lncRNA 2310069B03Rik expression was later. These results suggest that lncRNA 2310069B03Rik functions as a suppression factor of Ucp1 expression.

Methylglyoxal (MG) is a metabolite derived from glycolysis whose levels in the blood and tissues of patients with diabetes are higher than those of healthy individuals, suggesting that MG is associated with the development of diabetic complications. However, it remains unknown whether high levels of MG are a cause or consequence of diabetes. Here, we show that MG negatively affects the expression of uncoupling protein 1 (UCP1), which is involved in thermogenesis and the regulation of systemic metabolism. Decreased Ucp1 expression is associated with obesity and type 2 diabetes. We found that MG attenuated the increase in Ucp1 expression following treatment with isoproterenol in beige adipocytes. However, MG did not affect protein kinase A signaling, the core coordinator of isoproterenol-induced Ucp1 expression. Instead, MG activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases. We found that JNK inhibition, but not p38, recovered isoproterenol-stimulated Ucp1 expression under MG treatment. Altogether, these results suggest an inhibitory role of MG on the thermogenic function of beige adipocytes through the JNK signaling pathway., Highlights • Methylglyoxal suppresses isoproterenol-induced Ucp1 expression in beige adipocytes. • Methylglyoxal activates JNK in beige adipocytes. • Inhibition of JNK recovers methylglyoxal-suppressed Ucp1 expression.

Cyclic adenosine monophosphate responsive element–binding protein-1-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 the hypothalamus, which plays an important role for appetite regulation, SF1 cells are only found in ventromedial hypothalamus. RNA sequencing analysis of microdissected 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.

Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid, an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil, a prodrug of mycophenolic acid, to mice and demonstrated that mycophenolate mofetil induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.

Paclitaxel has the potential for inducing lumen enlargement by vessel enlargement, healing of dissection, and plaque regression. This study was carried out to determine the possibility of and the relevant factors of delayed stenosis regression after drug-coated balloon (DCB) angioplasty for femoropopliteal (FP) artery lesions. A total 105 de novo FP lesions were finalized with DCB angioplasty in our institute between May 2018 and June 2020. Among them, cases in which residual stenosis was detected by duplex ultrasonography (DUS) after the procedure were included in this study. Significant stenosis was defined as peak systolic velocity ratio ≥ 2.4 by DUS. Follow-up DUS was routinely performed 6 months after the procedure, and we defined cases without stenosis as cases of delayed stenosis regression according to the follow-up DUS. DUS showed that 26 (25.5%) of 102 lesions had residual stenosis after DCB angioplasty, and delayed stenosis regression was observed in 12 (57.1%) of 21 lesions 6 months after the procedure. The percentage of lesions containing calcified plaque as detected by intravascular ultrasound analysis was significantly higher in the non-regression group than in the regression group (18.2% vs. 77.8%, p = 0.02). Vessel remodeling and dissection patterns were not associated with delayed stenosis regression. The results of our analyses indicate that delayed stenosis regression may occur after DCB angioplasty for FP lesions in more than half of cases with residual stenosis. Delayed stenosis regression may be difficult in cases of calcified lesions.

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.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulatinglevels 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.

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

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.

The onset of sleep has been reported to be accompanied by a decline in the core body temperature (CBT) at the onset of night. The stimulation of hepatic FGF21 by PPARα agonist influences the central nervous system and decreases the CBT. The present study aimed to evaluate the effect of food-derived PPARα activator on hepatic FGF21 expression and CBT regulation using Lactobacillus helveticus-MIKI-020 (LH). The treatment with LH stimulated FGF21 expression in a PPARα-dependent manner in hepatocytes. Furthermore, two weeks of LH treatment decreased the CBT only during sleep in mice. The expression of FGF21 in the liver and the plasma content of FGF21 were significantly higher in the LH feeding group than in the control group. The results present a novel approach to decrease the CBT during sleep, which can potentially improve sleep disorders.

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.

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.

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.

Adiponectin, an adipokine, regulates glucose metabolism and insulin sensitivity through the adiponectin receptor (AdipoR). In this study, we searched for metabolites that activate the adiponectin signaling pathway from tomato (Solanum lycopersicu). Metabolites of mature tomato were separated into 55 fractions by liquid chromatography, and then each fraction was examined using the phosphorylation assay of AMP-protein kinase (AMPK) in C2C12 myotubes and in AdipoR-knockdown cells by small interfering RNA (siRNA). Several fractions showed AMPK phosphorylation in C2C12 myotubes and siRNA-mediated abrogation of the effect. Non-targeted metabolite analysis revealed the presence of 721 diverse metabolites in tomato. By integrating the activity of fractions on AMPK phosphorylation and the 721 metabolites based on their retention times of liquid chromatography, we performed a comprehensive screen for metabolites that possess adiponectin-like activity. As the screening suggested that the active fractions contained four carotenoids, we further analyzed β-carotene and lycopene, the major carotenoids of food. They induced AMPK phosphorylation via the AdipoR, Ca2+/calmodulin-dependent protein kinase kinase and Ca2+ influx, in addition to activating glucose uptake via AdipoR in C2C12 myotubes. All these events were characteristic adiponectin actions. These results indicated that the food-derived carotenoids, β-carotene and lycopene, activate the adiponectin signaling pathway, including AMPK phosphorylation.

Aims The aim of the study was to assess the long-term outcomes of coronary chronic total occlusion (CTO) lesions after retrograde percutaneous coronary intervention (PCI) in comparison with those after antegrade PCI alone. Methods and results A total of 842 consecutive patients (928 CTO lesions) undergoing PCI and subsequent follow-up were classified into two groups: retrograde PCI for at least one CTO (n=302, retrograde group) and antegrade PCI alone (n=540, antegrade group). The total procedural success rate was 89.7%. The retrograde group had significantly higher incidences of periprocedural myocardial infarction and coronary perforation (7.3% vs. 3.7%, p=0.01; 7.9% vs. 4.4%, p=0.04, respectively). Median follow-up duration was 7.7 (interquartile range 5.6-8.7) years. Seven-year relative risk comparing the retrograde and antegrade groups was neutral in all-cause death (adjusted HR [aHR] 1.06, 95% CI: 0.75-1.49; p=0.745), cardiac death (aHR 0.85, 95% CI: 0.47-1.55; p=0.598), coronary artery bypass grafting (aHR 1.62, 95% CI: 0.74-3.54; p=0.229), and non-target vessel revascularisation (aHR 0.96, 95% CI: 0.78-1.17; p=0.663). Conclusions Retrograde CTO PCI did not lead to worse long-term outcomes despite increased risk in periprocedural myocardial infarction and coronary perforation.

Purpose : To analyze extraosseous signal changes (ESCs) on magnetic resonance imaging (MRI) in pediatric patients with stress fractures occurring in the lamina. Methods : This study was a retrospective review of 69 consecutive pediatric patients with stress fractures occurring in the lamina. We analyzed MRI scans obtained at the first presentation. Results : We used mainly axial short tau inversion recovery images acquired through the pedicle of these 84 fracture sites to identify the ESCs. These were then divided into three groups: "invisible" when no ESC was detected, "periosteal" for ESC seen on only the dorsal side of the lamina, and "perimuscular" for ESC distinctly spread around / in the paravertebral muscles. In total, 78 (92.9%) fracture sites showed ESCs on the dorsal side of the lamina among which 72 ESCs were located on only the "dorsal" side, while 6 ESCs were on the ventral side against the transverse process. Conclusion : ESCs on MRI were detected in more than 90% of patients before stress fracture became apparent in the lamina, which was considered similar to findings of periosteal thickening / edema detected at the onset of stress fracture in long bone. J. Med. Invest. 68 : 136-139, February, 2021.

Secular changes in the incidence rate of hip fractures were estimated to vary by fracture type, i.e., femoral neck or trochanteric fractures, age, and sex, in urban or rural areas in Kyoto Prefecture, Japan from 2008 to 2017. PURPOSE Our survey in Kyoto Prefecture from 2008 to 2017 showed that the incidence rate of femoral neck fractures is generally increasing. We investigated the differences between urban and rural areas in the changes of the incidence rate over time of femoral neck and trochanteric fractures during the same period. 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 ratio of sick beds for acute-term care at the investigated hospitals to total number of beds in the urban area was 16.5% (1863/11,158) and 30.6% (1863/5623) in the rural area. The change in incidence rate was estimated utilizing the population according to the national census conducted in 2010 and 2015. RESULTS There were 3559 and 6474 hip fractures in the urban and rural areas, respectively. Femoral neck fractures were 1936 (54.4%) and 2813 (43.5%) in each area. The increase of the population-adjusted numbers was marked by neck fractures in males, in both areas. In women, there was a significant increase in femoral neck fractures in the urban area in those aged 85 years and over. For trochanteric fractures, a significant increase was only found in women aged 65 to 74 years in the rural area. CONCLUSION A regional difference in the secular changes in incidence rate of hip fractures was found in women, not in men, mostly because neck fractures in women increased in the over 85 group in the urban area.

The clinical outcomes of patients undergoing percutaneous coronary intervention (PCI) for left main coronary artery (LMCA) malperfusion caused by acute type A aortic dissection (AAAD) remains largely unexplored. The aim of this study was to determine the clinical outcomes of patients undergoing PCI for LMCA malperfusion caused by AAAD. We examined nine consecutive patients undergoing PCI for LMCA malperfusion caused by AAAD between 1995 and 2020. The mean age was 55.4 ± 7.7 years. Eight patients presented cardiogenic shock, and five patients cardiopulmonary arrest. Two patients were diagnosed with AAAD before coronary angiography using computed tomography and transthoracic echocardiography, respectively, and in the other seven patients after coronary angiography using other modalities. Four patients underwent PCI on intra-aortic balloon pumping support, and four patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO) support, including one patient on both. PCI was successful in eight patients, with final thrombolysis in myocardial infarction grade 2 or 3. The four patients on VA-ECMO did not undergo aortic dissection repair due to poor recovery of cardiac function and died during the hospital stay, and the other five patients had successful PCI, underwent aortic dissection repair, and remained alive at 5 year follow-up. In conclusion, LMCA malperfusion caused by AAAD seemed to have clinical presentations and electrocardiogram changes similar to acute coronary syndrome. PCI and subsequent surgical aortic repair saved the lives of all AAAD patients with LMCA malperfusion who had not required VA-ECMO.

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities. Bonora et al. identify a new mitochondrial recessive disorder caused by biallelic variants in the LIG3 gene encoding DNA ligase III, which is responsible for mitochondrial DNA repair. Clinical signs include gut dysmotility and neurological features such as leucoencephalopathy, epilepsy and stroke-like episodes.

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.

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

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.

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

Brown adipose tissue (BAT) is a key organ that produces heat and dissipates energy, and may be clinically relevant to the treatment of obesity and diabetes. Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis including that of norepinephrine (NA) and nitric oxide (NO) synthase. Although both NA and NO are well-known factors in BAT differentiation, the role of BH4 in the differentiation of BAT is poorly understood. We investigated the role of BH4 in differentiation of BAT using a mouse model of BH4 deficiency, the Hph-1 mouse. Hph-1 neonatal mice exhibit dysplasia of BAT as well as attenuated thermogenesis-related gene expressions (UCP1, Dio2, Pgc1a) compared with control mice. As differentiation capacity is considered to be at maximum during late gestation, we administered BH4 to fetal Hph-1 mice via placental transfer using intraperitoneal injection to pregnant Hph-1 mice for 6 days just before birth. Maternal BH4 supplementation ameliorated dysplasia of neonatal BAT and restored thermogenesis-related genes expression. Intriguingly, offspring of the maternal BH4-supplementation group showed less weight gain, ameliorated glucose intolerance, and improved cold tolerance after growth under high fat chow diet. We then evaluated the direct effect of BH4 on brown adipocyte differentiation using brown pre-adipocytes isolated from control and Hph-1 mice. Compared with control mice, brown pre-adipocytes from Hph-1 mice showed reduced differentiation capacity, while BH4 supplementation in brown pre-adipocytes from Hph-1 mice ameliorated differentiation capacity nitric oxide-dependently. Taking these findings together, BH4 plays an integral role in the differentiation of BAT, especially in the fetal period, and may represent a novel target for prevention of metabolic disorders such as obesity and diabetes. Disclosure H. Minamino: None. Y. Fujita: None. Y. Oguri: None. T. Goto: None. A. Ohashi: None. F. Furuya: None. N. Isomura: None. T. Kohei: None. Y. Li: None. S. Kawarasaki: None. T. Kawada: None. H. Hasegawa: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Summary 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., Graphical Abstract, Highlights • O-GlcNAcylation suppresses cell death under proteasome impairment • Combined inhibition of O-GlcNAcylation and proteasome induces massive tumor cell death • O-GlcNAcylation maintains proteasome activity independently of Nrf1 • O-GlcNAcylation enhances proteasome turnover under the proteasome impairment, Biological Sciences; Cell Biology; Functional Aspects of Cell Biology; Cancer

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.

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.