Search

During periods of fasting, the body undergoes a metabolic shift from carbohydrate utilization to the use of fats and ketones as an energy source, as well as the inhibition of de novo lipogenesis and the initiation of gluconeogenesis in the liver. The transcription factor sterol regulatory element‐binding protein‐1 (SREBP‐1), which plays a critical role in the regulation of lipogenesis, is suppressed during fasting, resulting in the suppression of hepatic lipogenesis. We previously demonstrated that the interaction of fasting‐induced Kruppel‐like factor 15 (KLF15) with liver X receptor serves as the essential mechanism for the nutritional regulation of SREBP‐1 expression. However, the underlying mechanisms of KLF15 induction during fasting remain unclear. In this study, we show that the glucocorticoid receptor (GR) regulates the hepatic expression of KLF15 and, subsequently, lipogenesis through the KLF15‐SREBP‐1 pathway during fasting. KLF15 is necessary for the suppression of SREBP‐1 by GR, as demonstrated through experiments using KLF15 knockout mice. Additionally, we show that GR is involved in the fasting response, with heightened binding to the KLF15 enhancer. It has been widely known that the hypothalamic–pituitary–adrenal (HPA) axis regulates the secretion of glucocorticoids and plays a significant role in the metabolic response to undernutrition. These findings demonstrate the importance of the HPA‐axis‐regulated GR‐KLF15 pathway in the regulation of lipid metabolism in the liver during fasting. [ABSTRACT FROM AUTHOR]

When amino acids are plentiful in the diet, the liver upregulates most enzymes responsible for amino acid degradation. In particular, the activity of urea cycle enzymes increases in response to high-protein diets to facilitate the excretion of excess nitrogen. KLF15 has been established as a critical regulator of amino acid catabolism including ureagenesis and we have recently identified FoxO transcription factors as an important upstream regulator of KLF15 in the liver. Therefore, we explored the role of FoxOs in amino acid metabolism under high-protein diet. Our findings revealed that the concentrations of two urea cycle-related amino acids, arginine and ornithine, were significantly altered by FoxOs knockdown. Additionally, using KLF15 knockout mice and an in vivo Ad-luc analytical system, we confirmed that FoxOs directly regulate hepatic Ass1 expression under high-protein intake independently from KLF15. Moreover, ChIP analysis showed that the high-protein diet increased FoxOs DNA binding without altering the nuclear protein amount. Therefore, FoxOs play a direct role in regulating ureagenesis via a KLF15-independent pathway in response to high-protein intake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: We aimed to determine the effects of exercise on cell-free DNA (cfDNA) levels and concentration changes during the menstrual cycle in participants with regular menstrual cycles and no exercise habits., Methods: Eleven sedentary female students with regular menstrual cycles and ovulation performed bicycle exercises at 60% VO 2max for 30 min during the menstrual, ovulatory, and luteal phases. Blood samples were collected before (Pre), immediately after (Post 0), 30 min after (Post 30), and 60 min after (Post 60) exercise. Blood concentrations of ovarian hormones, cfDNA, prostaglandin F2a (PGF2α), interleukin-6 (IL-6), and aromatase were evaluated., Results: Based on the concentration of ovarian hormones, seven individuals were finally analyzed. No significant phase difference was observed in cfDNA across all time points. cfDNA (menstrual phase: p  = 0.028, ovulatory phase: p  = 0.018, and luteal phase: p  = 0.048) and aromatase concentrations (menstrual phase: p  = 0.040, ovulatory phase: p  = 0.039, and luteal phase: p  = 0.045) significantly increased from Pre to Post 0 in all phases. Serum estradiol (E2) levels were significantly higher in the luteal phase at all time points than in the menstrual phase (Pre: p  < 0.001, Post 0: p  < 0.001, Post 30: p  = 0.005, and Post 60: p  = 0.011); however, serum progesterone (P4) levels were significantly higher in the luteal phase at all time points than in the menstrual (Pre: p  < 0.001, Post 0: p  < 0.001, Post 30: p  < 0.001, and Post 60: p  < 0.001) and ovulatory phases (Pre: p  = 0.005, Post 0: p  = 0.005, Post 30: p  = 0.003, and Post 60: p  = 0.003). E2 levels significantly increased from Pre to Post 0 in the ovulatory and luteal phases, whereas P4 levels increased in the luteal phase. Progesterone to estradiol level ratio (P4/E2) changes from Pre to Post 0 (%baseline) during the luteal phase were significantly negatively correlated ( r  = -0.82, p  = 0.046) with the changes in cfDNA from Pre to Post 0. Furthermore, the repeated measures correlation between P4/E2 and cfDNA level showed a significant negative correlation in ovulatory and luteal phases., Discussion: The results indicate that while resting cfDNA levels are unlikely to be affected by a woman's menstrual cycle, the increase in cfDNA after exercise is higher in the ovulatory phase (when only E2 increases) and lower in the luteal phase (when E2 and P4 increase with exercise) compared to that in the menstrual phase (when E2 and P4 are in low levels), suggesting the contribution of increased ovarian hormone levels after exercise., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Sawai, Shida, Hoshikawa, Hatanaka, Ueda, Kato, Tokinoya, Natsui, Kawakami and Takekoshi.)