Daily Endocrinology Research Analysis
Analyzed 81 papers and selected 3 impactful papers.
Summary
Three mechanistic studies advance endocrine science: an in vivo enhancer-screening approach maps growth hormone–regulated, sex-biased hepatocyte enhancers linked to metabolic disease risk; β-hydroxybutyrate drives histone β-hydroxybutyrylation to activate PPARα and mitigate steatosis; and hypothyroidism is shown to impair skeletal muscle regeneration via coordinated myogenic cell-cycle control and inflammatory–stromal signaling. Together, these papers underscore sex differences, metabolite-epigenetic crosstalk, and thyroid hormone–dependent tissue repair.
Research Themes
- Sex-biased endocrine regulation and hepatocyte enhancer function
- Metabolite-driven epigenetic control of hepatic lipid metabolism (Kbhb–PPARα axis)
- Thyroid hormone signaling in muscle regeneration and immune–stromal crosstalk
Selected Articles
1. HDI-STARR-seq Identifies Functional GH-regulated Sex-Biased Hepatocyte Enhancers Linked to Liver Metabolism and Disease.
Using a tiled HDI-STARR-seq library delivered to mouse liver, the authors functionally validated hundreds of GH-responsive, sex-biased hepatocyte enhancers that mirror chromatin accessibility changes and are enriched for activating histone marks and transcription factor motifs. These enhancers link to both MASLD-enabling and -protective genes, providing a mechanistic substrate for sex differences in hepatic metabolism and disease susceptibility.
Impact: This study pioneers an in vivo, high-throughput functional mapping of endocrine-regulated enhancers, directly linking GH-driven, sex-biased chromatin regulation to metabolic disease pathways. It reframes sex differences in hepatic disease risk as enhancer-level phenomena.
Clinical Implications: While preclinical, these findings suggest that sex-specific enhancer regulation under GH may inform sex-aware risk stratification for MASLD and identify enhancer–TF axes (e.g., STAT5/BCL6/CUX2/HNF4A) as potential therapeutic entry points.
Key Findings
- Constructed a 23,912-reporter HDI-STARR-seq library spanning 1,839 liver ATAC regions and validated 840 GH-regulated and/or sex-biased enhancers in vivo.
- Regulated enhancers mirrored chromatin accessibility, were enriched for H3K27ac/H3K4me1 and motifs for sex-specific repressors (BCL6, CUX2) and HNF4A.
- Linked sex-biased/GH-regulated enhancers to genes influencing MASLD susceptibility, implicating enhancer-level control in sex-differential disease risk.
Methodological Strengths
- Integrated single-nucleus multiomic chromatin accessibility with in vivo HDI-STARR-seq functional assays.
- Hydrodynamic delivery allowed condition-specific enhancer activity readouts within intact liver tissue.
Limitations
- Mouse-based enhancer validation may not fully capture human hepatocyte regulatory architecture.
- Reporter-based assays may not completely recapitulate native chromatin context for all enhancers.
Future Directions: Validate conserved human enhancers, test GH/STAT5 pathway modulation on enhancer activity and metabolic phenotypes, and integrate with human genetic variation to prioritize therapeutic targets.
Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional cis-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with in vivo functional enhancer assays to identify and validate GH-resp
2. β-Hydroxybutyrate upregulates hepatic histone β-hydroxybutyrylation modification, promotes the expression of PPARα, and alleviates the hepatic steatosis in MASLD.
BHB reduced hepatic lipid accumulation in db/db mice and PA-loaded AML12 cells, while increasing total protein Kbhb and H3K9bhb marks. PPARα and downstream β-oxidation genes were upregulated, and pharmacologic blockade of Kbhb (p300 inhibitor A485 or ACSS2 inhibition) diminished these effects, supporting a causal Kbhb–PPARα axis in alleviating steatosis.
Impact: This work delineates a metabolite-epigenetic mechanism by which BHB remodels hepatic chromatin to activate PPARα programs and counter steatosis, highlighting actionable epigenetic nodes in MASLD.
Clinical Implications: The findings support exploration of nutritional or pharmacologic strategies that elevate hepatic Kbhb or directly enhance PPARα via epigenetic modulation to treat MASLD, while emphasizing careful translation and safety evaluation.
Key Findings
- BHB alleviated hepatic lipid accumulation in db/db mice and PA-induced AML12 hepatocytes.
- BHB increased total protein Kbhb and histone H3K9bhb, concomitant with upregulation of PPARα and β-oxidation genes.
- Inhibition of Kbhb (p300 inhibitor A485 or ACSS2 inhibition) reduced PPARα pathway induction, implicating Kbhb as a mechanistic mediator.
Methodological Strengths
- Convergent in vivo (db/db MASLD model) and in vitro (AML12) validation with orthogonal readouts (qPCR, Western, histology).
- Causal testing using pharmacologic inhibition of Kbhb writers to dissect the epigenetic dependency.
Limitations
- Preclinical mouse and cell models; human validation is needed.
- Potential off-target effects of epigenetic inhibitors (e.g., p300 inhibition) may confound specificity.
Future Directions: Map Kbhb at PPARα target loci genome-wide, define dose–response and safety of BHB or Kbhb modulators, and conduct translational studies in human MASLD.
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) stands as the most widespread chronic liver disorder globally. Histone β-hydroxybutyrylation (Kbhb)-a novel post-translational modification of histones driven by β-hydroxybutyrate (BHB)-has recently been recognized as a key epigenetic modulator. Our study aimed to explore how BHB influences the expression of hepatic lipid metabolism-associated genes in MASLD, and to determine whether histone Kbhb acts as the mechanistic mediator underlying these effects. METHODS: For in vivo experiments, db/db mice fed a high-fat diet were utilized as the MASLD model. Following BHB intervention,
3. Hypothyroidism impairs skeletal muscle regeneration after injury by altering myogenic and nonmyogenic pathways.
Hypothyroidism impaired muscle repair by reducing myogenic-lineage diversity, stalling satellite cells at G1/S, and sustaining proinflammatory and fibro-adipogenic niches. Triiodothyronine exerts dual actions—direct transcriptional control of myogenic and oxidative programs and indirect paracrine remodeling via FAPs and immune cells—illuminating mechanisms of hypothyroid myopathy and sarcopenia.
Impact: This is a comprehensive, multi-omic dissection of thyroid hormone actions in regenerating muscle, defining dual-mode regulation across myogenic and stromal–immune compartments with direct relevance to hypothyroid myopathy.
Clinical Implications: Findings support timely thyroid hormone normalization in injury or surgery settings and motivate trials targeting FAP/immune remodeling to improve muscle recovery in hypothyroid patients.
Key Findings
- Hypothyroid muscles exhibited smaller myofibers and a shift toward slower oxidative fiber types up to 2 months post-injury.
- scRNA-seq showed reduced myogenic-lineage diversity and satellite cell G1/S stalling with delayed differentiation.
- Nonmyogenic dynamics were altered with early FAP activation and persistent proinflammatory macrophages; T3 acted via direct transcriptional control and indirect paracrine remodeling.
Methodological Strengths
- Combined scRNA-seq with FUCCI cell-cycle reporters for temporal resolution of regeneration under hypothyroidism.
- Integrated regulon and ligand–receptor analyses to map myogenic and stromal–immune cross-communication.
Limitations
- Mouse injury model; clinical extrapolation requires human validation.
- No interventional rescue experiments in vivo to test targeted modulation of FAP/immune pathways.
Future Directions: Translate signatures to human biopsies, test T3 timing/dosing and niche-targeted therapies, and define biomarkers predicting regenerative response in hypothyroid states.
Thyroid hormone signaling is an essential regulator of skeletal muscle development, function, and metabolism, yet the specific signaling pathways required for muscle regeneration are not yet defined. We used scRNA-seq and the FUCCI (fluorescent ubiquitination-based cell cycle indicator) reporter mouse model to examine how hypothyroidism impacts repair processes after cardiotoxin-induced injury in mice. During regeneration, and up to 2 months after injury, hypothyroid muscles displayed smaller myofibers and a shift to slower oxidative fiber types. scRNA-seq of tibialis anterior muscle during regeneration revealed that hypothyroidism reduced myogenic-lineage diversity. Cell cycle analysis confirmed delayed cell cycle progression at 5 and 14 days after injury, with skeletal muscle stem cells stalled at the G1/S transition, hindering differentiation. Transcriptomic data revealed altered nonmyogenic dynamics, including elevated activated fibro-adipogenic progenitors (FAPs) early in repair and persistent proinflammatory macrophages. Integrative regulon and ligand-receptor analysis further demonstrated that triiodothyronine acted through dual modes: a direct transcriptional control of myogenic cell cycle and oxidative programs and an indirect paracrine remodeling mediated by FAP and immune signaling networks. This study identified what we believe to be novel effects of hypothyroidism on myogenic heterogeneity and impaired tissue repair, offering insights into muscle-wasting mechanisms relevant to hypothyroidism-associated myopathy and sarcopenia.