酪酸ナトリウム誘導アポトーシスにおけるCaspase-10の重要な役割

博士（医学）神戸大

Manipulating the Circadian and Sleep Cycles to Protect Against Metabolic Disease

Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g. obesity) involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude enhancing small molecules (CEMs) identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep and metabolism will also have far-reaching implications for various chronic human diseases and aging

Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α

1132Nsciescopu

The Important Role of Caspase-10 in Sodium Butyrate-Induced Apoptosis

Butyrate, a short chain fatty acid, exhibits a wide variety of biological effects including theinhibition of cell growth, change of cellular morphology and the induction of apoptosis. Sodiumbutyrate-induced apoptosis has been reported to associate with the up-regulation ofpro-apoptotic Bax expression, and the down-regulation of anti-apoptotic Bcl-2 and Bcl-XLexpressions. However, in some cases, butyrate has also been shown to cause apoptosis withoutchange in Bcl-2, Bcl-XL and/or Bax. This study investigates the detailed mechanisms of sodiumbutyrate-induced apoptosis. The effect of sodium butyrate was analyzed in the induction ofcaspase activities, formation of caspase active forms and mRNA levels in human breast cancercell line MRK-nu-1. Induction of activities of caspase-3, -10 and, to some extent, -8 and formationof DNA fragmentation were observed with sodium butyrate in a dose- and/or time-dependentmanner. The levels of caspase-10 mRNA expression markedly increased in a time-dependentmanner by the treatment of sodium butyrate, whereas caspase-8 mRNA expression was notchanged. Inhibitors of caspase-8 and caspase-10 reduced caspase-3 activity and subsequent DNAfragmentation induced by sodium butyrate. These caspase inhibitors also inhibited the cleavageof pro-caspase-3 to the active forms indicated by Western blotting analysis. Pyrrolidinedithiocarbamate also inhibited the induction of caspase-10 mRNA expression and caspase-3activation. Contrary to other reports, levels of Bcl-2, Bcl-XL and Bax mRNA expressions werenot distinctly changed by even 5 mM sodium butyrate treatment. Our results suggest that sodiumbutyrate may trigger apoptosis via the induction of the caspase-10 expression

Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice

Cholesterol and bile acid (BA) homeostasis plays a central role in systemic metabolism. Accumulating evidence suggests a key regulatory function of the circadian clock, our biological timer, in lipid metabolism, particularly cholesterol and bile acid flux. Previously, we showed that Nobiletin (NOB), a natural compound targeting the ROR (Retinoic acid receptor-related orphan receptor) nuclear receptors in the circadian oscillator, strongly protects lipid homeostasis, including normal serum cholesterol levels in high-fat (HF) fed mice at both young and old ages. In this study, we further examined the role of NOB in cholesterol metabolism in HF-fed aged mice, and found that NOB lowered the serum LDL/VLDL cholesterol levels and consequently the LDL/HDL ratio. BA levels in the serum were markedly reduced in the HF.NOB group, and examination of additional hepatic markers further indicate a protective role of NOB in the liver. At the molecular level, whereas HF feeding downregulated hepatic expression of several ROR target genes involved in bile acid synthesis, NOB treatment (HF.NOB) was able to rescue it. In accordance, fecal BA excretion was enhanced by NOB, and microbial 16S sequencing revealed alteration of several taxa known to be involved in secondary BA production in the gut. Together, these results demonstrate concerted effects of the clock-modulating compound NOB in cholesterol and BA metabolism, suggesting pharmacological manipulation of the clock as a novel therapeutic strategy against metabolic disorders and age-related decline

Cardiolipin Synthesis in Skeletal Muscle Is Rhythmic and Modifiable by Age and Diet

Circadian clocks regulate metabolic processes in a tissue-specific manner, which deteriorates during aging. Skeletal muscle is the largest metabolic organ in our body, and our previous studies highlight a key role of circadian regulation of skeletal muscle mitochondria in healthy aging. However, a possible circadian regulation of cardiolipin (CL), the signature lipid class in the mitochondrial inner membrane, remains largely unclear. Here, we show that CL levels oscillate during the diurnal cycle in C2C12 myotubes. Disruption of the Ror genes, encoding the ROR nuclear receptors in the secondary loop of the circadian oscillator, in C2C12 cells was found to dampen core circadian gene expression. Importantly, several genes involved in CL synthesis, including Taz and Ptpmt1, displayed rhythmic expression which was disrupted or diminished in Ror-deficient C2C12 cells. In vivo studies using skeletal muscle tissues collected from young and aged mice showed diverse effects of the clock and aging on the oscillatory expression of CL genes, and CL levels in skeletal muscle were enhanced in aged mice relative to young mice. Finally, consistent with a regulatory role of RORs, Nobiletin, a natural agonist of RORs, was found to partially restore transcripts levels of CL synthesis genes in aged muscle under a dietary challenge condition. Together, these observations highlight a rhythmic CL synthesis in skeletal muscle that is dependent on RORs and modifiable by age and diet

Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice.

International audiencePolycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. In this study, we determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropin concentrations. Hypothalamic KiSS1 neurons are believed to be critical to the onset of puberty and are the target of leptin. Adult NTM exhibited lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity, and decreased energy expenditure. They displayed a delayed increase in subcutaneous white adipose tissue amounts. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice