持久運動時の脂肪代謝調節機構に関する研究

京都大学0048新制・課程博士博士(農学)甲第19042号農博第2120号新制||農||1032(附属図書館)学位論文||H27||N4924(農学部図書室)31993京都大学大学院農学研究科食品生物科学専攻(主査)教授 伏木 亨, 教授 保川 清, 教授 金本 龍平学位規則第4条第1項該当Doctor of Agricultural ScienceKyoto UniversityDGA

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Combined pharmacological activation of AMPK and PPARδ potentiates the effects of exercise in trained mice.

The combined activation of the cellular energy sensor AMP‐activated protein kinase (AMPK) and the nuclear transcription factor peroxisome proliferator‐activated receptor delta (PPARδ) has been demonstrated to improve endurance and muscle function by mimicking the effects of exercise training. However, their combined pharmacological activation with exercise training has not been explored. Balb/c mice were trained on a treadmill and administered both the AMPK activator AICAR and the PPARδ agonist GW0742 for 4 weeks. AICAR treatment potentiated endurance, but the combination of AICAR and GW0742 further potentiated endurance and increased all running parameters significantly relative to exercised and nonexercised groups (138–179% and 355% increase in running time, respectively). Despite the lack of change in basal whole‐body metabolism, a significant shift to fat as the main energy source with a decline in carbohydrate utilization was observed upon indirect calorimetry analysis at the period near exhaustion. Increased energy substrates before exercise, and elevated muscle nonesterified fatty acids (NEFA) and elevated muscle glycogen at exhaustion were observed together with increased PDK4 mRNA expression. Citrate synthase activity was elevated in AICAR‐treated groups, while PGC‐1α protein level tended to be increased in GW0742‐treated groups. At exhaustion, Pgc1a was robustly upregulated together with Pdk4, Cd36, and Lpl in the muscle. A robust upregulation of Pgc1a and a downregulation in Chrebp were observed in the liver. Our data show that combined pharmacological activation of AMPK and PPARδ potentiates endurance in trained mice by transcriptional changes in muscle and liver, increased available energy substrates, delayed hypoglycemia through glycogen sparing accompanied by increased NEFA availability, and improved substrate shift from carbohydrate to fat

Mechanism of Soy Isoflavone Daidzein-Induced Female-Specific Anorectic Effect

Epidemiological studies suggest that regular intake of soy isoflavone exerts a preventive effect on postmenopausal obesity and other forms of dysmetabolism. Estrogens inhibit eating behavior. Soy isoflavones may act as estrogen agonist in estrogen-depleted conditions, whereas they may either act as an estrogen antagonist or be ineffective in estrogen-repleted conditions. We investigated the effects of dietary soy isoflavone on food intake under various estrogen conditions using male, ovariectomized (OVX), and non-OVX female rats, and compared the effects with those of estradiol. We found that soy isoflavones reduced food intake in females specifically, regardless of whether ovariectomy had been performed, whereas subcutaneous implantation of estradiol pellet did not reduce food intake in intact female rats, but did so in OVX female and male rats. Contrary to this hypothesis, the reduction in food intake may not be caused by the estrogenic properties of soy isoflavones. It is of great interest to understand the mechanisms underlying the anorectic effects of soy isoflavones. In this non-systematic review, we summarize our recent studies that have investigated the bioactive substances of anorectic action, pharmacokinetic properties of soy isoflavones, and the modification of central and peripheral signals regulating appetite by soy isoflavones, and selected studies that were identified via database mining

Blood Lactate Functions as a Signal for Enhancing Fatty Acid Metabolism during Exercise via TGF-β in the Brain

Moderate-intensity running (treadmill velocity of 21 m/min) increased blood lactate and actived transforming growth factor-β (TGF-β) concentration in rat cerebrospinal fluid (CSF). On the other hand, low-intensity running (15 m/min) did not increase blood lactate and caused no change in CSF TGF-β. Intraperitoneal (i.p.) administration of lactate to anesthetized rats caused an increase in blood lactate similar to that observed after a 21 m/min running exercise and increased the level of active TGF-β in CSF. Intraperitoneal administration of lactate at the same dose to awake and unrestricted rats caused a decrease in the respiratory exchange ratio, that is, enhancement of fatty acid oxidation and depression of spontaneous motor activity (SMA). Given that intracisternal administration of TGF-β to rats has been reported to enhance fatty acid metabolism and to depress SMA, we surmise that the observed changes caused by i.p. lactate administration in this study were mediated, at least in part, by TGF-β in the brain

Effects of Soy Isoflavones, Resistant Starch and Antibiotics on Polycystic Ovary Syndrome (PCOS)-Like Features in Letrozole-Treated Rats

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Recently, various dietary interventions have been used extensively as a novel therapy against PCOS. In the present study, we show that soy isoflavone metabolites and resistant starch, together with gut microbiota modulations, were successful in decreasing the severity of PCOS-like reproductive features while increasing the expression of gut barrier markers and butyric acid in the gut. In the letrozole-induced PCOS model rats, the intake of both 0.05% soy isoflavones and 11% resistant starch, even with letrozole treatment, reduced the severity of menstrual irregularity and polycystic ovaries with a high concentration of soy isoflavones and equol in plasma. Antibiotic cocktail treatment suppressed soy isoflavone metabolism in the gut and showed no considerable effects on reducing the PCOS-like symptoms. The mRNA expression level of occludin significantly increased with soy isoflavone and resistant starch combined treatment. Bacterial genera such as Blautia, Dorea and Clostridium were positively correlated with menstrual irregularity under resistant starch intake. Moreover, the concentration of butyric acid was elevated by resistant starch intake. In conclusion, we propose that both dietary interventions and gut microbiota modulations could be effectively used in reducing the severity of PCOS reproductive features

Dietary Alaska pollack protein improves skeletal muscle weight recovery after immobilization-induced atrophy in rats.

The promotion of muscle recovery after immobilization is important to preserve an optimum health status. Here, we examined the effect of dietary Alaska pollack protein (APP) on skeletal muscle weight after atrophy induced by hind limb immobilization using plaster immobilization technique. Rat left limb was casted with a wetted plaster cast under anesthesia. After 2 weeks of feeding, the cast was removed and the rats were divided into three groups, namely, a baseline group, high-fat casein diet group, and high-fat APP diet group. After 3 weeks of feeding, the skeletal muscles (soleus, extensor digitorum longus [EDL], and gastrocnemius) were sampled. The estimated weight gains of soleus, gastrocnemius, and EDL muscle in the immobilized limbs were significantly larger in the rats fed with APP diet as compared with those fed with casein diet. In soleus muscle, dietary APP increased the expression of Igf1 and Myog genes in the immobilized limbs after the recovery period