Daily Endocrinology Research Analysis
Three mechanistic studies advance endocrinology across metabolism, circadian biology, and reproductive aging. Epitranscriptomic control of adipogenesis via NAT10–ac4C–KLF9 suggests a druggable axis for obesity, BMAL1–HIF coupling in skeletal muscle links circadian timing to glucose intolerance in diet-induced obesity, and MSC-secreted BDNF restores oocyte quality via ERK1/2 with human validation.
Summary
Three mechanistic studies advance endocrinology across metabolism, circadian biology, and reproductive aging. Epitranscriptomic control of adipogenesis via NAT10–ac4C–KLF9 suggests a druggable axis for obesity, BMAL1–HIF coupling in skeletal muscle links circadian timing to glucose intolerance in diet-induced obesity, and MSC-secreted BDNF restores oocyte quality via ERK1/2 with human validation.
Research Themes
- Epitranscriptomic regulation of metabolism
- Circadian clock–metabolism cross-talk in obesity
- Stem cell paracrine factors for reproductive aging
Selected Articles
1. NAT10-mediated N4-acetylcytidine modification in KLF9 mRNA promotes adipogenesis.
The study identifies an epitranscriptomic pathway in which NAT10 installs ac4C on KLF9 mRNA to stabilize it, thereby activating CEBPA/B–PPARG and promoting adipogenesis. Genetic knockdown of NAT10 in adipose tissue and pharmacologic inhibition with Remodelin reduced adipose expansion and weight gain in high-fat diet mice.
Impact: This work uncovers a druggable epitranscriptomic mechanism of adipogenesis with in vivo efficacy, pointing to NAT10–ac4C–KLF9 as a therapeutic axis for obesity.
Clinical Implications: NAT10 inhibition (e.g., Remodelin) or downstream KLF9 targeting may represent novel anti-obesity strategies; ac4C/KLF9 signatures could serve as biomarkers to stratify or monitor therapy.
Key Findings
- NAT10 expression is upregulated in adipose tissue from obese humans and high-fat diet mice.
- NAT10 overexpression promotes, while silencing inhibits, adipogenesis in hADSCs and 3T3‑L1 cells.
- acRIP‑seq/RNA‑seq identified KLF9 as an ac4C-modified NAT10 target; NAT10 enhances KLF9 mRNA stability and activates the CEBPA/B–PPARG pathway.
- Adipose-targeted AAV shRNA against NAT10 reduced adipose expansion in mice.
- Remodelin, a NAT10 inhibitor, lowered body weight, adipocyte size, and adipose expansion in HFD mice by inhibiting KLF9 mRNA ac4C.
Methodological Strengths
- Multi-omics integration (acRIP-seq and RNA-seq) with mechanistic target validation (acRIP-PCR, dual-luciferase).
- Convergent in vitro (hADSCs, 3T3‑L1) and in vivo (AAV-shRNA, pharmacologic inhibition) evidence.
Limitations
- Preclinical models; human clinical safety and efficacy of NAT10 inhibition remain unknown.
- Potential off-target effects of Remodelin and chronic inhibition of RNA acetylation need evaluation.
Future Directions: Define safety/PK and metabolic efficacy of selective NAT10 inhibitors in large animals; develop adipose-targeted delivery; assess ac4C/KLF9 biomarkers in human obesity trials.
Dysfunctional adipogenesis is a major contributor of obesity. N-acetyltransferase 10 (NAT10) plays a crucial role in regulating N4-acetylcysteine (ac4C) modification in tRNA, 18SrRNA, and mRNA. As the sole "writer" in the ac4C modification process, NAT10 enhances mRNA stability and translation efficiency. There are few reports on the relationship between NAT10 and adipogenesis, as well as obesity. Our study revealed a significant upregulation of NAT10 in adipose tissues of obese individuals and high-fat diet-fed mice. Furthermore, our findings revealed that the overexpression of NAT10 promotes adipogenesis, while its silencing inhibits adipogenesis in both human adipose tissue-derived stem cells (hADSCs) and 3T3-L1 cells. These results indicate the intimate relationship between NAT10 and obesity. After silencing mouse NAT10 (mNAT10), we identified 30 genes that exhibited both hypo-ac4C modification and downregulation in their expression, utilizing a combined approach of acRIP-sequencing (acRIP-seq) and RNA-sequencing (RNA-seq). Among these genes, we validated KLF9 as a target of NAT10 through acRIP-PCR. KLF9, a pivotal transcription factor that positively regulates adipogenesis. Our findings showed that NAT10 enhances the stability of KLF9 mRNA and further activates the CEBPA/B-PPARG pathway. Furthermore, a dual-luciferase reporter assay demonstrated that NAT10 can bind to three motifs of mouse KLF9 and one motif of human KLF9. In vivo studies revealed that adipose tissue-targeted mouse AAV-NAT10 (AAV-shRNA-mNAT10) inhibits adipose tissue expansion in mice. Additionally, Remodelin, a specific NAT10 inhibitor, significantly reduced body weight, adipocyte size, and adipose tissue expansion in high-fat diet-fed mice by inhibiting KLF9 mRNA ac4C modification. These findings provide novel insights and experimental evidence of the prevention and treatment of obesity, highlighting NAT10 and its downstream targets as potential therapeutic targets.
2. BDNF secreted by mesenchymal stem cells improves aged oocyte quality and development potential by activating the ERK1/2 pathway.
Human umbilical cord MSC secretome improves key hallmarks of aged oocyte quality in mice and identifies BDNF as the active component. BDNF activates ERK1/2 to upregulate DAZL and BTG4, improving spindle integrity, maternal RNA clearance, and reducing aneuploidy; it also enhanced fertilization and blastocyst rates in aged human oocytes.
Impact: This study provides mechanistic and translational evidence—including human oocyte data—that a defined paracrine factor (BDNF) can reverse age-related oocyte defects via ERK1/2, opening a pathway to targeted adjuncts for IVF in advanced maternal age.
Clinical Implications: BDNF or MSC-derived biologics could be explored as adjuncts to improve oocyte competence in older patients undergoing IVF; pathway markers (ERK1/2 activation, DAZL/BTG4) may guide responder selection.
Key Findings
- MSC secretome improved first polar body emission, spindle assembly, maternal mRNA degradation, and reduced aneuploidy in aged mouse oocytes.
- Neutralizing BDNF abrogated MSC-secretome effects; recombinant BDNF replicated benefits.
- Mechanism: ERK1/2 activation increased DAZL and BTG4 expression in aged oocytes.
- In situ ovarian injection of MSC-secretome or BDNF enhanced oocyte quality and early embryonic development in aged mice.
- BDNF increased fertilization and blastocyst formation rates in aged human oocytes in vitro.
Methodological Strengths
- Mechanistic dissection with neutralization and recombinant rescue pinpointing BDNF.
- Cross-species validation including in vivo mouse injections and human oocyte culture readouts.
Limitations
- Preclinical; clinical safety, dosing, and delivery methods for ovarian administration remain to be established.
- Sample sizes and long-term offspring outcomes were not reported.
Future Directions: Optimize dosing and delivery (local vs systemic), assess safety and efficacy in large animals, and design early-phase clinical trials integrating molecular response biomarkers.
BACKGROUND: Reduced oocyte quality is a key factor in age-related fertility decline, and there are no effective treatments available. The secretome of mesenchymal stem cells (MSC-sec) contains various bioactive factors and has the potential to improve oocyte quality. This study aimed to investigate the effective component and molecular mechanism of MSC-sec involved in improving oocyte quality from aged mice and humans. METHODS: Immunofluorescence and chromosome spread were performed to investigate the effects of secretome from human umbilical cord-MSC on spindle assembly and aneuploidy in aged mouse oocytes. Brain-derived neurotrophic factor (BDNF) and its neutralization antibody was supplemented in both in vitro and in vivo experiments to verify the effective component in MSC-sec. RNA-seq analysis was used to reveal the alterations in maternal mRNA degradation in aged mouse oocytes after MSC-sec treatment. In vitro culture of oocytes from aged women was also used to verify the effectiveness of BDNF in improving oocyte quality. RESULTS: MSC-sec treatment significantly increased first polar body emission, improved spindle assembly, promoted maternal RNA degradation, and reduced aneuploidy rate in aged mouse oocytes. While the addition of BDNF neutralization antibody blocked the effects of MSC-sec, BDNF alone also increased the oocyte quality from aged mice. Mechanistically, both MSC-sec and BDNF rescued the quality of aged mouse oocytes by activating the ERK1/2 signaling pathway to increase the expression of DAZL and BTG4. In situ injection of MSC-sec or BDNF into aged mouse ovaries significantly improved oocyte quality and early embryonic development. Finally, we demonstrated that BDNF treatment increased both the fertilization rate and blastocyst formation rate of aged human oocytes. CONCLUSION: These findings demonstrate that BDNF secreted by mesenchymal stem cells can improve the quality and development potential of oocytes from both aged mice and humans by activating the ERK1/2 signaling pathway, suggesting that it has the potential to mitigate age-related declines in oocyte quality.
3. Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
Muscle-specific BMAL1 loss worsened glucose tolerance under high-fat diet without increased weight gain, implicating circadian control of skeletal muscle glucose metabolism in diet-induced obesity. The study identifies a BMAL1–HIF axis as a regulatory node linking clock function to metabolic reprogramming.
Impact: Revealing a BMAL1–HIF axis in skeletal muscle provides mechanistic insight into how circadian disruption worsens metabolic disease and suggests time- and pathway-targeted interventions.
Clinical Implications: Chronotherapy and modulation of HIF signaling in muscle may improve glucose tolerance in obesity; aligning feeding/exercise with muscle clock function could be therapeutically beneficial.
Key Findings
- Muscle-specific BMAL1 knockout mice showed worsened glucose tolerance under high-fat diet despite similar weight gain.
- Data support a BMAL1–HIF axis controlling circadian regulation of skeletal muscle glucose metabolism in obesity.
- Metabolite profiling indicates altered metabolic programs consistent with HIF-mediated reprogramming.
Methodological Strengths
- Tissue-specific genetic model isolating muscle clock effects in diet-induced obesity.
- Systems-level metabolite profiling to map pathway changes.
Limitations
- Preclinical mouse study; human translational relevance needs confirmation.
- Abstracted data are incomplete; details of interventions and temporal dynamics are not provided here.
Future Directions: Test whether timed exercise/nutrition or HIF-targeted modulators improve glucose tolerance in obesity; validate BMAL1–HIF signatures in human muscle.
Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from