Daily Endocrinology Research Analysis
Analyzed 48 papers and selected 3 impactful papers.
Summary
Analyzed 48 papers and selected 3 impactful articles.
Selected Articles
1. Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.
This mechanistic study uncovers AUH as a dual regulator of thermogenesis by (1) enabling PPARγ HMGylation via HMG-CoA to boost UCP1 transcription and (2) stabilizing Ucp1 mRNA through RNA binding. AUH promotes white adipose browning and protects male mice from diet-induced obesity, with human adipose AUH inversely correlated with adiposity.
Impact: Identifies a previously unknown post-translational modification (HMGylation) of PPARγ linking amino acid catabolism to adipose thermogenesis, opening a therapeutic avenue for obesity.
Clinical Implications: Pharmacologic enhancement of AUH activity or targeted modulation of PPARγ HMGylation could augment thermogenesis and browning as anti-obesity strategies, pending validation in both sexes and humans.
Key Findings
- AUH knockdown reduces, and overexpression increases, thermogenesis in brown adipocytes in vitro and in vivo.
- HMG-CoA mediates direct HMGylation of PPARγ at Lys386, enhancing transcriptional activity and UCP1 expression.
- AUH binds and stabilizes Ucp1 mRNA via its RNA-binding function.
- AUH promotes browning of white adipose tissue; its expression inversely correlates with adiposity in human WAT.
- Adipose AUH overexpression protects male mice from high-fat diet–induced obesity.
Methodological Strengths
- Integrated in vitro and in vivo validation with human adipose tissue correlation.
- Identification and site-specific mapping of a novel post-translational modification on PPARγ.
Limitations
- Most in vivo protection data are in male mice; sex-specific effects require evaluation.
- Translational relevance and safety of modulating PPARγ HMGylation in humans remain untested.
Future Directions: Define the HMGylation landscape across adipose depots and sexes; develop AUH modulators or PPARγ HMGylation mimetics; test efficacy and safety in large animal models and early-phase trials.
A strong association between leucine and obesity has been well established; however, the role of leucine catabolic enzymes in adipose tissue remains largely unknown. Here, we show that knockdown of the leucine catabolic enzyme AU RNA-binding methylglutaconyl-CoA hydratase (AUH) in brown adipocytes reduces thermogenesis, while AUH over-expression has the opposite effect both in vivo and in vitro. Mechanistically, AUH partially promotes uncoupling protein 1 (UCP1) expression through its metabolite 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). HMG-CoA directly HMGylates peroxisome proliferator-activated receptor gamma (PPARγ) on lysine 386, enhancing its transcriptional activity to increase UCP1 expression. In addition, AUH binds to and stabilizes Ucp1 mRNA via its RNA-binding function. Moreover, we discovered that AUH promotes white adipose tissue browning; AUH expression in human white adipose tissue is inversely correlated with adiposity, and over-expression of AUH in adipose tissue protects male mice against high-fat diet-induced obesity. Collectively, these results provide new insights into the crosstalk between amino acid metabolism and thermogenesis and identify a novel post-translational modification of PPARγ.
2. Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism.
Across 17 individuals from 14 families, bi-allelic hypomorphic WDHD1 variants were linked to microcephalic primordial dwarfism with systemic manifestations. Patient fibroblasts exhibited reduced WDHD1 protein, slowed replication forks, DNA damage, G1–S transition defects, abnormal nuclear morphology, and premature sister chromatid separation, implicating replisome failure in human growth disorders.
Impact: Defines WDHD1 as a new human disease gene for MPD and mechanistically ties replisome dysfunction to impaired organismal growth, expanding diagnostic panels and biological understanding.
Clinical Implications: WDHD1 should be included in genetic testing for severe proportionate growth failure with microcephaly. Anticipatory guidance is warranted for potential complications (e.g., acute liver failure), and mechanistic insights may inform future targeted therapies.
Key Findings
- Identified bi-allelic hypomorphic WDHD1 variants in 17 subjects with microcephalic primordial dwarfism across 14 families.
- Subject-derived fibroblasts showed markedly reduced WDHD1 protein and aberrant splicing for intronic variants.
- Observed globally reduced replication fork speed, spontaneous DNA damage, and a G1-to-S transition defect.
- Detected abnormal nuclear morphology (micronuclei, multilobed, enlarged nuclei) and increased premature sister chromatid separation.
- Establishes WDHD1 as essential for replisome assembly, fork stability, and sister chromatid cohesion in humans.
Methodological Strengths
- Multi-family genetic discovery with functional validation in patient-derived fibroblasts.
- Comprehensive cellular phenotyping (replication dynamics, DNA damage, cell cycle, chromosomal cohesion).
Limitations
- No in vivo animal models to corroborate organismal phenotypes and mechanisms.
- Therapeutic strategies were not explored; longitudinal natural history data are limited.
Future Directions: Develop in vivo models to dissect tissue-specific consequences of WDHD1 deficiency; delineate genotype-phenotype correlations; explore replication stress modulators as therapeutic candidates.
DNA replication is carried out by the replisome and is essential for maintaining genome integrity and cell proliferation. Pathogenic variants in genes encoding various replisome components cause microcephalic primordial dwarfism (MPD), characterized by growth retardation, microcephaly, and developmental abnormalities. Here, we report bi-allelic hypomorphic variants in WDHD1 as a cause of MPD with a broad spectrum of additional abnormalities, including acute liver failure, in 17 subjects from 14 families. WDHD1 encodes a replisome scaffolding protein (also known as AND-1 and Ctf4), which is essential for replisome assembly, replication fork stability, and sister chromatid cohesion. We found aberrant splicing of WDHD1 pre-mRNAs for all intronic variants tested and markedly reduced WDHD1 protein levels in subject-derived fibroblasts. Fibroblasts with bi-allelic WDHD1 variants showed globally reduced replication fork speed and impaired replication control, accompanied by spontaneous DNA damage and a G1-to-S transition defect. Using various cell biology approaches, we show that subject fibroblasts displayed reduced proliferation, abnormal nuclear morphology, including micronuclei, multilobed, and enlarged nuclei, as well as an increased number of metaphases with premature sister chromatid separation. Together, our findings establish WDHD1 as a protein required for normal organismal growth and development in humans and underscore its multiple functions in maintaining genome integrity.
3. Metformin suppresses β-cell apoptosis under ER stress by inhibiting protein translation.
Metformin prevents thapsigargin-induced β-cell apoptosis by reprogramming stress and translational pathways: it dampens UPR gene induction, modulates eIF2 signaling, and suppresses cap-dependent translation via 4E-BP1 dephosphorylation downstream of mTOR. The anti-apoptotic effect requires 4E-BP1, positioning translational control as a key β-cell protective mechanism of metformin.
Impact: Provides a β-cell-intrinsic mechanistic basis for metformin’s cytoprotection, extending its role beyond insulin sensitization and highlighting translational control as a therapeutic axis.
Clinical Implications: Supports early metformin use to preserve β-cell mass by mitigating ER stress–induced apoptosis; suggests combination strategies that reinforce mTOR–4E-BP1–mediated translational control. In vivo validation and dose–exposure bridging to human therapeutics are needed.
Key Findings
- Metformin dose-dependently prevents thapsigargin-induced β-cell apoptosis in mouse islets.
- Suppresses UPR gene upregulation and modulates eIF2 signaling during ER stress.
- Reduces cap-dependent protein translation via 4E-BP1 dephosphorylation; 4E-BP1 knockdown abolishes cytoprotection.
- Mitigates mTOR pathway activation in ER-stressed islets, aligning with translational restraint.
- Multi-omics (transcriptomic, proteomic, phosphoproteomic) and polysome/puromycin assays converge on translational control.
Methodological Strengths
- Convergent multi-omics and functional assays (polysome profiling, puromycin incorporation, 4E-BP1 knockdown).
- Use of primary mouse islets increases physiological relevance over immortalized lines alone.
Limitations
- Lacks in vivo diabetic models to confirm β-cell protection and metabolic benefits.
- Pharmacologic exposures vs. human therapeutic concentrations were not bridged.
Future Directions: Test β-cell preservation and glycemic durability in in vivo diabetes models; quantify translational control biomarkers in humans on metformin; explore synergistic combinations targeting mTOR–4E-BP1.
Endoplasmic reticulum (ER) stress is a critical driver of pancreatic β-cell dysfunction and apoptosis. Although metformin, a drug used to treat type 2 diabetes, primarily decreases blood glucose levels by improving insulin sensitivity, its direct effects on β-cell survival remain unclear. Here, we investigated the effect of metformin on β-cell stress responses under ER stress conditions. Thapsigargin (Tg)-induced ER stress increased β-cell apoptosis in mouse islets, which was prevented by metformin in a dose-dependent manner. Treatment with metformin for 24 h suppressed the Tg-induced upregulation of unfolded protein response (UPR)-related genes, as confirmed by transcriptomic and pathway analyses. Quantitative proteomics revealed that Tg inhibited eIF2 signaling and protein translation, both of which were partially restored by metformin. Enrichment analysis further indicated the attenuation of apoptotic pathways in metformin-treated islets. Polysome profiling and puromycin incorporation assays demonstrated that metformin reduced protein translation independently of ER stress. Metformin promoted the dephosphorylation of 4E-BP1, a key initiator of cap-dependent protein translation that is activated by phosphorylation, and the antiapoptotic effect of metformin was abolished by 4E-BP1 knockdown in MIN6 cells. Phosphoproteomic analysis indicated that the activation of mTOR signaling, a kinase of 4E-BP1, in Tg-treated islets was mitigated by metformin. Taken together, these findings reveal a cytoprotective mechanism of metformin in β-cells, in which metformin suppresses ER stress-induced apoptosis through 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling. This study highlights a β-cell-intrinsic action of metformin that may contribute to its long-term therapeutic benefits in diabetes management.