Daily Endocrinology Research Analysis
Three mechanistic studies advance endocrine-metabolic science: adipocyte FMO3-derived TMAO drives white adipose tissue dysfunction via inflammasome activation; PAD4 in macrophages promotes tubulointerstitial injury in diabetic kidney disease and is targetable; and the endocrine disruptor PCB126 accelerates endometriosis through an ESR2/AXL/DNMT3A epigenetic axis. Together, they highlight immunometabolism and epigenetic reprogramming as actionable nodes across endocrine disorders.
Summary
Three mechanistic studies advance endocrine-metabolic science: adipocyte FMO3-derived TMAO drives white adipose tissue dysfunction via inflammasome activation; PAD4 in macrophages promotes tubulointerstitial injury in diabetic kidney disease and is targetable; and the endocrine disruptor PCB126 accelerates endometriosis through an ESR2/AXL/DNMT3A epigenetic axis. Together, they highlight immunometabolism and epigenetic reprogramming as actionable nodes across endocrine disorders.
Research Themes
- Immunometabolism and inflammasome signaling in metabolic disease
- Innate immunity and macrophage-driven injury in diabetic kidney disease
- Endocrine disruptors, estrogen receptor signaling, and epigenetic regulation in endometriosis
Selected Articles
1. Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
This mechanistic study shows that adipocyte FMO3 drives TMAO production, which directly binds ASC to activate inflammasomes, leading to WAT senescence, fibrosis, and inflammation and worsening metabolic homeostasis with age. Adipocyte-specific FMO3 ablation lowers TMAO in fat and plasma and improves glucose, energy, and lipid homeostasis in ageing and obese mice.
Impact: It identifies adipocyte FMO3 as a previously underappreciated cellular source controlling TMAO and reveals a direct molecular mechanism—TMAO–ASC binding—linking diet–microbiome metabolites to inflammasome-driven metabolic inflammation.
Clinical Implications: Therapeutically, targeting adipocyte FMO3, lowering TMAO (diet, microbiome, enzyme inhibition), or blocking ASC inflammasome activation could mitigate age-related metabolic dysfunction and obesity-associated inflammation.
Key Findings
- Ageing or p53 activation upregulates adipocyte FMO3 and increases TMAO levels.
- Adipocyte-specific FMO3 deletion reduces TMAO in WAT and plasma and improves glucose, energy, and lipid homeostasis with reduced WAT senescence, fibrosis, and inflammation.
- Proteomics identified TMAO-interacting proteins; mechanistically, TMAO binds ASC to promote caspase-1 activation and IL-1β production, activating inflammasomes in adipocytes and macrophages.
Methodological Strengths
- Adipocyte-specific genetic ablation with in vivo ageing and obesity models.
- Proteomics and biochemical evidence for direct TMAO–ASC interaction mechanistically linking metabolite to inflammasome activation.
Limitations
- Preclinical mouse and cellular models require human validation for translational relevance.
- The relative contribution of adipocyte versus hepatic FMO3 to systemic TMAO in diverse human phenotypes remains to be quantified.
Future Directions: Validate adipocyte FMO3/TMAO/ASC axis in human tissues and cohorts; test pharmacological FMO3 inhibition, TMAO-lowering, or ASC blockade in translational models; dissect diet–microbiome modifiers of adipocyte TMAO signaling.
2. PAD4 promotes macrophage migration to aggravate tubulointerstitial injury in diabetic kidney disease.
Human genetic analyses linked PADI4 loss-of-function to better kidney function, while DKD tissues and models showed increased PAD4 in the tubulointerstitium. Genetic or pharmacologic PAD4 inhibition curtailed macrophage infiltration and injury via a p65–Cmklr1 axis, positioning PAD4 as a translational target in DKD.
Impact: It integrates population-scale human genetics with mechanistic in vivo validation to nominate PAD4 as a causally relevant target for diabetic kidney disease.
Clinical Implications: PAD4 inhibitors (e.g., GSK484-class) or strategies reducing PAD4-driven macrophage migration could attenuate tubulointerstitial injury in DKD, warranting early-phase clinical evaluation and biomarker development.
Key Findings
- Functional analysis of 48 PADI4 variants from UK Biobank showed most were loss-of-function and associated with higher eGFR.
- PAD4 expression is elevated in the renal tubulointerstitium in DKD patients and mouse models.
- Macrophage-specific PAD4 deficiency and PAD4 inhibitor GSK484 reduced macrophage infiltration and tubulointerstitial injury via a p65–Cmklr1 transcriptional mechanism that enhances macrophage migration.
Methodological Strengths
- Integration of population-scale human genetics with mechanistic animal models and pharmacological inhibition.
- Clear molecular mechanism linking PAD4 to NF-κB (p65)–Cmklr1-driven macrophage migration.
Limitations
- Clinical efficacy and safety of PAD4 inhibition in DKD remain untested in humans.
- Extent of PAD4 pathway variability across DKD etiologies and patient subgroups requires clarification.
Future Directions: Develop selective, drug-like PAD4 inhibitors with renal exposure; validate PAD4 activity biomarkers; and design early-phase trials enriched for macrophage-driven tubulointerstitial inflammation.
3. Polychlorinated Biphenyls Alter Estrogen Receptor β-mediated Epigenetic Regulation, Promoting Endometriosis.
Environmental PCB126 promotes endometriosis by enhancing ESR2 signaling, upregulating AXL/GAS6, and increasing DNMT3A to reprogram gene expression and immunity. Pharmacologic AXL inhibition and Dnmt3a loss curtailed lesion growth, defining an actionable ESR2–AXL–DNMT3A axis.
Impact: This work mechanistically links an endocrine-disrupting chemical to estrogen receptor β-driven epigenetic and immune reprogramming in endometriosis and validates druggable nodes (AXL, DNMT3A).
Clinical Implications: Risk mitigation may include reducing PCB exposure; therapeutically, AXL inhibitors or epigenetic modulators downstream of ESR2 warrant exploration for refractory endometriosis.
Key Findings
- PCB126 exposure significantly increased growth of ectopic endometriotic lesions in mouse and humanized models.
- Mechanistically, PCB126 enhanced ESR2 activity and upregulated AXL/GAS6 and DNMT3A, driving epigenetic and immune reprogramming.
- AXL inhibition and tissue-specific Dnmt3a knockout reduced lesion growth and inflammatory cytokine production.
Methodological Strengths
- Convergent validation across mouse models, human endometrial cells, pharmacologic inhibition, and genetic knockout.
- Multi-omic profiling (RNA-seq) and signaling analyses linking ESR2 to DNMT3A and AXL pathways.
Limitations
- Translational dosing and exposure levels of PCB126 in humans remain to be defined.
- Clinical efficacy of AXL inhibition or epigenetic modulation in endometriosis is untested.
Future Directions: Epidemiologic–mechanistic bridging studies in exposed populations, biomarker development for ESR2/AXL/DNMT3A activation, and early-phase trials of AXL inhibitors in endometriosis.