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.
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.
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.