Chang‐Myung Oh

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.

Introduction: One of the most common sleep disorders, insomnia is a significant public health concern. Several psychiatric disorders, such as anxiety disorders and depression, have shown strong relationships with insomnia. However, the clinical impact of the combination of these two conditions on insomnia severity and sleep quality remains unknown. We investigated the relationship between sleep disturbance and psychiatric comorbidities in subjects with high risk for insomnia. Methods: We analyzed data from a nation-wide cross-sectional survey of Korean adults aged 19~69 years conducted from November 2011 to January 2012. The survey was performed via face-to-face interviews using a structured questionnaire. We used the insomnia severity index (ISI) to evaluate insomnia and defined respondents with ISI scores of ≥10 as subject having a high risk for insomnia. To diagnose anxiety and depression, we used the Goldberg anxiety scale (GAS) and Patient Health Questionnaire-9 (PHQ-9), respectively. Results: Of the 2,762 respondents, 290 (10.5%) were classified as subjects with high risk for insomnia; anxiety (odds ratio [OR], 9.8; 95% confidence interval [CI]. 7.3 - 13.1) and depression (OR, 19.7; 95% CI ,13.1 - 29.6) were more common in this population than in participants without insomnia. Of the participants with insomnia, 152 (52.4%) had neither anxiety nor depression, 63 (21.7 %) only had anxiety, 21 (7.2%) only had depression, and 54 (18.6%) had both anxiety and depression. The group with both anxiety and depression was associated with worse scores on sleep-related scales than the other groups (high ISI, Pittsburgh Sleep Quality Index [PSQI], and Epworth Sleepiness Scale). The relationship between outcome measures (ISI and PSQI) and psychiatric problems was significant only when anxiety and depression were present. The PSQI has a significant mediation effect on the relationship between psychiatric comorbidities and insomnia severity. Conclusion: Among the respondents with insomnia, psychiatric comorbidities may have a negative impact on daytime alertness, general sleep quality, and insomnia severity, especially when the two conditions are present at the same time. Clinicians should therefore consider psychiatric comorbidities when treat insomnia.

Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis.

Various behavioral and physiological pathways follow a pre-determined, 24 hour cycle known as the circadian rhythm. Metabolic homeostasis is regulated by the circadian rhythm. Time-restricted eating (TRE) is a type of intermittent fasting based on the circadian rhythm. In this study, we aim to analyze systemically the effects of TRE on body weight, body composition, and other metabolic parameters. We reviewed articles from PubMed, EMBASE, and the Cochrane Library to identify clinical trials that compared TRE to a regular diet. We included 19 studies for meta-analysis. Participants following TRE showed significantly reduced body weight (mean difference (MD), -0.90; 95% confidence interval (CI): -1.71 to -0.10) and fat mass (MD: -1.58, 95% CI: -2.64 to -0.51), while preserving fat-free mass (MD, -0.24; 95% CI: -1.15 to 0.67). TRE also showed beneficial effects on cardiometabolic parameters such as blood pressure (systolic BP, MD, -3.07; 95% CI: -5.76 to -0.37), fasting glucose concentration (MD, -2.96; 95% CI, -5.60 to -0.33), and cholesterol profiles (triglycerides, MD: -11.60, 95% CI: -23.30 to -0.27). In conclusion, TRE is a promising therapeutic strategy for controlling weight and improving metabolic dysfunctions in those who are overweight or obese. Further large-scale clinical trials are needed to confirm these findings and the usefulness of TRE.