Daily Endocrinology Research Analysis
Three impactful endocrinology-related papers span mechanistic discovery, metabolic regulation, and reproductive practice. An AI-assisted pipeline maps gut microbial bile acid enzymes and uncovers a novel bile acid skeleton, a study reveals YAP as a physiological regulator of adipose lipolysis, and a large cohort shows switching frozen embryo transfer protocols after failure does not improve live birth.
Summary
Three impactful endocrinology-related papers span mechanistic discovery, metabolic regulation, and reproductive practice. An AI-assisted pipeline maps gut microbial bile acid enzymes and uncovers a novel bile acid skeleton, a study reveals YAP as a physiological regulator of adipose lipolysis, and a large cohort shows switching frozen embryo transfer protocols after failure does not improve live birth.
Research Themes
- Microbiome enzymology of bile acids and host metabolism
- Adipose tissue lipolysis regulation and obesity biology
- Reproductive endocrinology: protocol effectiveness in frozen embryo transfer
Selected Articles
1. Identification of gut microbial bile acid metabolic enzymes via an AI-assisted pipeline.
Using an AI-assisted workflow (BEAUT), the authors predicted over 600,000 gut microbial bile acid metabolic enzymes and released the HGBME database. They experimentally characterized new enzymes, including MABH and 3-acetoDCA synthetase (ADS); ADS produces a previously unreported skeleton bile acid (3-acetoDCA) via C–C bond extension, which is widespread and modulates gut microbial interactions.
Impact: This work opens an enzymatic map of bile acid transformations and provides validated new enzymes and a novel bile acid skeleton, offering tools and targets for microbiome-informed metabolic interventions.
Clinical Implications: While not immediately clinical, the resource enables targeting of specific microbial bile acid enzymes to modulate host bile acid pools, with potential applications in metabolic, cholestatic, and endocrine diseases.
Key Findings
- Developed the AI-assisted BEAUT workflow and compiled the HGBME database with >600,000 candidate microbial bile acid enzymes.
- Identified and validated previously uncharacterized enzymes, including monoacid acylated bile acid hydrolase (MABH) and 3-acetoDCA synthetase (ADS).
- Discovered a previously unreported skeleton bile acid (3-acetoDCA) produced by ADS via carbon–carbon bond extension; 3-acetoDCA is widespread and modulates gut microbial interactions.
Methodological Strengths
- Integration of AI-driven prediction with experimental enzymology and microbial validation.
- Creation and public release of a comprehensive, queryable enzyme database (HGBME).
Limitations
- Primarily preclinical mechanistic work without direct clinical outcomes.
- Most predicted enzymes remain to be experimentally validated and linked to human disease phenotypes.
Future Directions: Systematic validation of additional predicted enzymes, mapping enzyme–phenotype associations in human cohorts, and developing small-molecule or dietary strategies to modulate bile acid enzymatic activities.
2. Adipose tissue-specific Yap knockout exacerbates diet-induced obesity through suppression of lipolysis.
Adipose-specific Yap knockout male mice exhibited exacerbated high-fat diet-induced obesity due to suppressed lipolysis with reduced ATGL and HSL expression. Consequent decreases in fasting free fatty acids led to cold intolerance and impaired fasted exercise performance, revealing YAP as a physiological regulator of adipose lipolysis.
Impact: Identifies YAP as a new node controlling adipose lipolysis in vivo, linking Hippo pathway signaling to systemic energy homeostasis and offering a potential therapeutic target for obesity.
Clinical Implications: Therapeutic strategies that enhance YAP activity or downstream lipolytic pathways in adipose tissue may increase lipid mobilization and improve obesity-related phenotypes, with attention to sex-specific effects.
Key Findings
- Male adipose-specific Yap knockout mice developed more severe high-fat diet-induced obesity than controls.
- Lipolysis was suppressed with decreased ATGL and HSL expression, lowering fasting free fatty acids.
- Physiological consequences included cold intolerance and impaired exercise capacity in the fasted state.
Methodological Strengths
- Tissue-specific genetic knockout model enabling causal inference in adipose biology.
- Comprehensive phenotyping including metabolic, molecular, and physiological stress tests (cold exposure, exercise).
Limitations
- Findings are in mice with male-specific effects; human translatability requires validation.
- No pharmacologic gain-of-function studies to test therapeutic modulation of YAP signaling.
Future Directions: Clarify upstream regulators and downstream effectors of YAP in adipocytes, test pharmacologic modulators, and examine sex differences and human adipose models.
3. Outcomes after frozen embryo transfer failure: changing the protocol does not improve live birth.
In 17,989 FET cycles following a failed transfer, switching between programmed and natural protocols did not change live birth rates overall, regardless of the direction of change. Clinical pregnancy and pregnancy loss rates were also similar, including in euploid transfers. A planned subgroup suggested higher live birth with a true natural FET after a failed programmed cycle.
Impact: Provides large-scale, practice-informing evidence that changing FET protocol after a failed cycle does not improve live birth, guiding decision-making and resource use.
Clinical Implications: Clinicians should not switch FET protocol solely due to a prior failure when endometrial preparation is adequate; consider maintaining the current approach and focus on other modifiable factors. A true natural FET may merit consideration after a failed programmed cycle in selected patients.
Key Findings
- Across 17,989 subsequent FET cycles, switching between programmed and natural protocols did not improve live birth rates.
- Clinical pregnancy and pregnancy loss did not differ between switching and repeating the same protocol, including in euploid transfers.
- Subgroup analysis suggested higher live birth with a true natural FET after a failed programmed FET (adjusted RR 1.20, 95% CI 1.03–1.39).
Methodological Strengths
- Very large sample size with contemporary practice data over a decade.
- Adjusted analyses and clinically relevant subgroup analyses including euploid transfers.
Limitations
- Retrospective design with potential residual confounding and selection bias.
- Definition and implementation of “true natural” FET may vary and limit generalizability.
Future Directions: Prospective randomized trials comparing true natural vs programmed protocols after failed FET, and mechanistic studies of endometrial receptivity to identify subgroups benefiting from protocol changes.