AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.

The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

Dietary factors in relation to the risk of cognitive impairment and physical frailty in Chinese older adults: a prospective cohort study.

PURPOSE: The study aimed to investigate the independent associations of dietary factors with cognitive impairment (CI) and physical frailty (PF) among Chinese older adults. METHODS: This study included 10,734 participants (mean age = 78.7 years) free of CI and PF at baseline from the Chinese Longitudinal Health Longevity Survey. Dietary intake was collected using a simplified food frequency questionnaire every 3-4 years. The Chinese version Mini-Mental State Examination was used to assess cognition function, participants with a score below 18 were defined as CI. PF was defined using the activities of daily living, instrumental activities of daily living, and functional limitation-related questions. The outcome was defined as the first onset of either CI or PF. Competing risk models were used to estimate the corresponding hazard ratios (HRs) and the 95% confidence intervals (95% CIs). RESULTS: During the study follow-up (mean = 8.1 years), a total of 1220 CI cases and 1451 PF cases were newly identified. Higher frequency of fruits intake was associated with a lower hazard of CI (HR = 0.75, 95% CI 0.58-0.97), whereas higher intake of preserved vegetables demonstrated an opposite association (HR = 1.23, 95% CI 1.07-1.42). In terms of PF, we observed a lower risk associated with higher meat and poultry intake (HR = 0.72, 95% CI 0.61-0.88). In particular, a significant protective association of fish and aquatic products intake with PF was observed among participants with ≥ 28 natural teeth (HR = 0.52, 95% CI 0.27-0.99). CONCLUSION: Our findings suggest divergent roles of major dietary factors in the development of CI and PF among Chinese older adults.

Activation of METTL3 Promotes White Adipose Tissue Beiging and Combats Obesity.

The induction of beige adipocytes in white adipose tissue (WAT), also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of the Mettl3 gene undermines WAT beiging and impairs the metabolic capability of mice fed with a high-fat diet. Mechanistically, METTL3-catalyzed m6A installation on thermogenic mRNAs, including Krüppel-like factor 9 (Klf9), prevents their degradation. Activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate promotes WAT beiging, reduces body weight, and corrects metabolic disorders in diet-induced obese mice. These findings uncover a novel epitranscriptional mechanism in WAT beiging and identify METTL3 as a potential therapeutic target for obesity-associated diseases. ARTICLE HIGHLIGHTS: METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging. Depletion of Mettl3 undermines WAT beiging and impairs thermogenesis. METTL3-mediated m6A installation promotes the stability of Krüppel-like factor 9 (Klf9). KLF9 rescues impaired beiging elicited by Mettl3 depletion. Pharmaceutical activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate induces WAT beiging. Methyl piperidine-3-carboxylate corrects obesity-associated disorders. The METTL3-KLF9 pathway may serve as a potential therapeutic target for obesity-associated diseases.

Adipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice.

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. N(6)-methyladenosine (m6A) RNA modification has been recently identified as a key regulator of obesity, while the detailed mechanism is elusive. Here, we find that YTH RNA binding protein 1 (YTHDF1), an m6A reader, acts as an essential regulator of white adipose tissue metabolism. The expression of YTHDF1 decreases in adipose tissue of male mice fed a high-fat diet. Adipocyte-specific Ythdf1 deficiency exacerbates obesity-induced metabolic defects and inhibits beiging of inguinal white adipose tissue (iWAT) in male mice. By contrast, male mice with WAT-specific YTHDF1 overexpression are resistant to obesity and shows promotion of beiging. Mechanistically, YTHDF1 regulates the translation of diverse m6A-modified mRNAs. In particular, YTHDF1 facilitates the translation of bone morphogenetic protein 8b (Bmp8b) in an m6A-dependent manner to induce the beiging process. Here, we show that YTHDF1 may be an potential therapeutic target for the management of obesity-associated diseases.

Bidirectional association between physical multimorbidity and subclinical depression in Chinese older adults: Findings from a prospective cohort study.

BACKGROUND: Both physical multimorbidity and subclinical depression pose a significant threat to aging population worldwide. The association between these conditions appeared to be in a bidirectional way, however the joint causal relationship yet to be fully understood in elderly Chinese population. METHODS: A total of 4605 Chinese elders from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2015) were included for the present study. Physical multimorbidity was defined as having two or more self-reported chronic physical conditions. Subclinical depression was defined by ≥ 12 scores assessed using the 10-item Centre for Epidemiological Studies Depression Scale. The bidirectional association between physical multimorbidity and subclinical depression was examined using multivariable logistic regression models, adjusting for covariates. RESULTS: During study period, 23.99% of participant reported incident episode of subclinical depression and 21.36% reported physical multimorbidity. In fully adjusted model, those with physical multimorbidity were two times more likely to have subclinical depression (OR = 2.05, 95% CI: 1.71-2.46). Besides that, subclinical depression was associated with physical multimorbidity (OR = 1.84, 95% CI: 1.50-2.46), but in slightly less magnitude. Furthermore, the bidirectional association remains statistically significant across different subgroups. LIMITATIONS: Chronic conditions were all self-reported and we couldn't adjust for all confounders, which may be subject to measurement error. CONCLUSIONS: Physical multimorbidity and subclinical depression was associated in a bidirectional way in elderly Chinese population, which highlights the necessary of covering a broad spectrum of aspects of clinical management among adults with physical multimorbidity or subclinical depression.

The role of ATF3 in ZnO nanoparticle-induced genotoxicity and cytotoxicity in bronchial epithelial cells.

ZnO nanoparticle (ZnO NP) exposure causes oxidative stress in the respiratory system, leading to pulmonary damage. Activating transcription factor 3 (ATF3) participates in a variety of cellular stress responses. However, the role of ATF3 in ZnO NP genotoxicity and cytotoxicity remains to be explored. Here we reported that ZnO NP treatment dramatically induced the expression of ATF3 in human bronchial epithelial (HBE) cells, which was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2). ATF3 was required for the repair of ZnO NP-induced DNA damage as gamma foci number increased when endogenous ATF3 was silenced. Moreover, ATF3 also contributed to ZnO NP-induced cell apoptosis. Mechanistic study revealed that ATF3 interacted with the p53 protein and upregulated its expression under ZnO NP treatment. Collectively, our findings demonstrated ATF3 as an important regulator of epithelial homeostasis by promoting both DNA repair and the death of damaged cells under ZnO NP-induced genotoxic stress.

Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis.

BACKGROUND: Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis. METHODS: The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET). RESULTS: Triptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (ApcMin/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA. CONCLUSIONS: Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.