Endocrinology Research Analysis
April’s endocrinology research converged on spatial and cellular reprogramming in adipose and liver metabolism, alongside a sharpened neuroendocrine link between peripheral metabolic state and behavior. A Science study uncovered age-enriched adipose progenitors (CP‑A) dependent on LIFR signaling that drive visceral adipogenesis, while two liver studies revealed plastic zonation of gluconeogenesis and a hepatoprotective ketogenesis axis extending beyond fat oxidation. A Nature Metabolism report d
Summary
April’s endocrinology research converged on spatial and cellular reprogramming in adipose and liver metabolism, alongside a sharpened neuroendocrine link between peripheral metabolic state and behavior. A Science study uncovered age-enriched adipose progenitors (CP‑A) dependent on LIFR signaling that drive visceral adipogenesis, while two liver studies revealed plastic zonation of gluconeogenesis and a hepatoprotective ketogenesis axis extending beyond fat oxidation. A Nature Metabolism report defined an adipose-to-brain endocrine circuit (GDF15→GFRAL) connecting lipolysis to anxiety-like behavior. Diagnostic modernization advanced in parallel, with LC‑MS/MS solutions for AVS discrepancies and receptor/AI-enhanced imaging poised to reduce invasive testing.
Selected Articles
1. Distinct adipose progenitor cells emerging with age drive active adipogenesis.
Lineage tracing, transplantation, and single-cell RNA-seq identify an age-enriched committed preadipocyte (CP‑A) population that expands in mid-life and autonomously drives visceral adipogenesis, with activity dependent on LIFR signaling.
Impact: Reveals a druggable, age-enriched progenitor pool and signaling dependency that mechanistically explains age-related visceral fat gain and opens intervention windows against mid-life cardiometabolic risk.
Clinical Implications: Human validation could enable LIFR pathway inhibitors or progenitor-directed strategies to prevent or reverse visceral adiposity; CP‑A activity biomarkers may guide patient selection.
Key Findings
- Mid-life visceral adipogenesis is extensive despite low turnover in youth.
- CP‑A progenitors display high proliferation/adipogenesis and expand with age.
- LIFR signaling is required for CP‑A–driven adipogenesis; perturbation reduces fat formation.
2. Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.
Single-cell and spatial analyses show that gluconeogenesis shifts from periportal dominance in early fasting to include robust pericentral activity during prolonged fasting/starvation, accompanied by suppression of β-catenin signaling and reprogramming of glutamine flux.
Impact: Challenges static zonation models and connects signaling and substrate flux to state-dependent hepatic glucose output, reshaping therapeutic strategies and tracer study interpretation.
Clinical Implications: Supports interventions that modulate β-catenin and glutamine flux to reduce hepatic glucose output without worsening other metabolic endpoints.
Key Findings
- Gluconeogenic programs are spatially and temporally plastic across the liver lobule.
- Starvation suppresses canonical β‑catenin signaling throughout the lobule.
- Glutamine pathway reprogramming enhances incorporation into glucose under starvation.
3. Ketogenesis mitigates metabolic dysfunction-associated steatotic liver disease through mechanisms that extend beyond fat oxidation.
Human stable-isotope fluxomics integrated with genetic mouse models shows that maintaining hepatic ketogenesis (HMGCS2 activity) protects against MASLD/MASH via mechanisms beyond total fat oxidation; BDH1 disruption reduces oxidation without worsening injury.
Impact: Reframes ketogenesis as a hepatoprotective signaling axis, elevating it from a metabolic byproduct to a therapeutic and biomarker candidate in fatty liver disease.
Clinical Implications: Motivates trials of pharmacologic or nutritional strategies enhancing hepatic ketogenesis and development of ketone flux biomarkers for patient stratification.
Key Findings
- Hepatic injury in MASH correlates with ketogenesis and total fat oxidation but not TCA turnover.
- Hepatic HMGCS2 loss induces MASLD/MASH-like injury with impaired oxidation.
- BDH1 disruption lowers oxidation without exacerbating liver injury, implying protective ketone signaling.
4. GDF15 links adipose tissue lipolysis with anxiety.
β-adrenergic–driven lipolysis in white adipose tissue induces GDF15 via M2-like macrophages, and stress-induced anxiety-like behavior requires the GDF15 receptor GFRAL, defining a peripheral adipose-to-brain endocrine circuit.
Impact: Establishes a causal neuroendocrine pathway connecting peripheral metabolic mobilization to behavior, with therapeutic implications for both metabolic and psychiatric conditions.
Clinical Implications: Suggests monitoring for neuropsychiatric effects when elevating GDF15 therapeutically and exploring GDF15–GFRAL antagonism to mitigate stress-related anxiety without central β-blockade.
Key Findings
- Stress and β3-agonism induce adipose GDF15 secretion.
- GDF15 induction is lipolysis-dependent via M2-like macrophage activation.
- GFRAL is necessary for anxiety-like behavior in mice.
5. Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.
Zonally targeted disruption reveals periportal versus pericentral hepatocyte insulin resistance produce divergent phenotypes, nominating strategies to reduce steatosis without aggravating glycemia.
Impact: Reframes hepatic insulin resistance as spatially heterogeneous with actionable zonal targets, enabling decoupling of steatosis from systemic glycemia.
Clinical Implications: Supports development of pericentral-selective signaling modulators or downstream adaptations to treat fatty liver in T2D while preserving glucose control.
Key Findings
- Periportal insulin resistance increases gluconeogenesis but reduces lipogenesis and steatosis.
- Pericentral insulin resistance lowers pericentral steatosis while preserving systemic glucose control.
- Metabolic flux reallocation (e.g., to muscle) contributes to preserved glycemia.