Weekly Endocrinology Research Analysis
This week’s endocrinology literature prioritized mechanistic discoveries in adipose and hepatic metabolism, reaffirmed the protective and regulatory roles of ketogenesis in fatty liver disease, and advanced spatial and single‑cell approaches that redefine metabolic zonation. Several translational signals emerged: targetable age-enriched adipose progenitors (LIFR/CP-A), spatially plastic hepatic gluconeogenesis with β-catenin and glutamine flux implications, and ketogenesis as a hepatoprotective
Summary
This week’s endocrinology literature prioritized mechanistic discoveries in adipose and hepatic metabolism, reaffirmed the protective and regulatory roles of ketogenesis in fatty liver disease, and advanced spatial and single‑cell approaches that redefine metabolic zonation. Several translational signals emerged: targetable age-enriched adipose progenitors (LIFR/CP-A), spatially plastic hepatic gluconeogenesis with β-catenin and glutamine flux implications, and ketogenesis as a hepatoprotective axis beyond mere fat oxidation. These findings converge on new therapeutic targets and prompt diagnostic/biomarker work to translate into clinical prevention strategies.
Selected Articles
1. Distinct adipose progenitor cells emerging with age drive active adipogenesis.
Using lineage tracing, transplantation, and single-cell RNA‑seq in mice, the study identifies an age-enriched committed preadipocyte population (CP‑A) that expands in middle age and autonomously drives visceral adipogenesis. CP‑A cells show high proliferation and adipogenic potential and require leukemia inhibitory factor receptor (LIFR) signaling for their activity, linking a targetable signaling axis to age-dependent visceral fat accumulation.
Impact: Identifies a previously unappreciated, age‑enriched progenitor population with a druggable signaling dependency (LIFR) that mechanistically explains mid-life visceral adipogenesis and suggests interventions to prevent age‑related metabolic disease.
Clinical Implications: If validated in humans, targeting LIFR signaling or CP‑A biology could prevent or reverse age-related visceral adiposity and downstream cardiometabolic risk; biomarker development to detect CP‑A activity may help select patients for intervention.
Key Findings
- Lineage tracing shows extensive visceral adipogenesis during middle age despite low young‑adult turnover.
- Single-cell RNA‑seq identifies an age‑enriched committed preadipocyte (CP‑A) population with heightened proliferation and adipogenesis.
- LIFR signaling is required for CP‑A–driven adipogenesis and visceral fat expansion; perturbation reduces adipogenesis.
2. Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.
Single‑cell analyses across the liver lobule show that gluconeogenic gene expression shifts dynamically from periportal hepatocytes in early fasting to include robust pericentral activity under prolonged fasting/starvation, accompanied by suppression of canonical β‑catenin signaling and reprogramming of glutamine metabolism to support gluconeogenesis.
Impact: Challenges static models of zonation and hepatic insulin resistance by demonstrating lobule‑wide plasticity of gluconeogenesis and linking signaling (β‑catenin) and substrate flux (glutamine) to state‑dependent glucose production — implications for interpreting tracer studies and targeting hepatic glucose output.
Clinical Implications: Understanding zonation plasticity should refine interpretation of fasting tests and metabolic flux studies; it suggests novel therapeutic approaches to reduce hepatic glucose output (e.g., modulating β‑catenin or glutamine flux) in diabetes and NAFLD.
Key Findings
- Gluconeogenic programs are spatially and temporally plastic across the liver lobule, shifting from periportal dominance to include pericentral hepatocytes under starvation.
- Starvation suppresses canonical β‑catenin signaling across the lobule.
- Starvation reprograms glutamine synthetase/glutaminase expression, enhancing glutamine incorporation into glucose.
3. Ketogenesis mitigates metabolic dysfunction-associated steatotic liver disease through mechanisms that extend beyond fat oxidation.
Integrating human stable‑isotope fluxomics and genetic mouse models, the study shows that maintenance of hepatic ketogenesis (HMGCS2 activity) protects against MASLD/MASH by mechanisms not solely explained by total fat oxidation. HMGCS2 loss causes MASLD/MASH‑like liver injury, whereas disruption of downstream BDH1 impairs oxidation without worsening injury, indicating ketone‑related protective signaling.
Impact: Reframes ketogenesis as a hepatoprotective axis beyond substrate oxidation, combining quantitative human flux data with targeted mouse genetics — this elevates ketogenesis as a candidate therapeutic/biomarker axis in MASLD/MASH.
Clinical Implications: Therapies or diets that enhance or preserve hepatic ketogenesis (pharmacologic or nutritional) deserve testing in MASLD/MASH; ketone flux biomarkers may help stratify patients for such interventions.
Key Findings
- Human MASH correlates with ketogenesis and total fat oxidation, but not with TCA turnover.
- Hepatic HMGCS2 disruption in mice impairs fat oxidation and induces an MASLD/MASH‑like phenotype.
- BDH1 disruption reduces fat oxidation without exacerbating steatotic liver injury, suggesting ketone signaling beyond oxidation is protective.