bims-obesme 2025-12-21 papers

Issue of 2025–12–21
six papers selected by
Xiong Weng, University of Edinburgh

Nat Aging. 2025 Dec 15.

GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging.

In Hwa Jang, Anna Carey, Victor Kruglov, Katie Nguyen, Jeffrey R Misialek, Stephanie H Cholensky, Declan M Smith, Suxia Bai, Timothy Nottoli, David A Bernlohr, Pamela L Lutsey, Christina D Camell.

Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3-SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3-SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3-SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging.

DOI: https://doi.org/10.1038/s43587-025-01034-6

Nat Commun. 2025 Dec 16.

Multi-layered transcriptional control of glycogen metabolism coordinates thermogenic remodeling of white adipocytes in male mice.

Haipeng Fu, Seoyeon Lee, Nathan R Zemke, Weiwei Fan, Yunqing Wang, James Garza, David Tin, Bryce Villao, Bichen Zhang, Xianda Ma, Jinyang Zhang, Tangran Dong, Yuyao Ren, Michael Downes, Ronald M Evans, Bing Ren, Alan R Saltiel.

Thermogenic activation of subcutaneous white adipocytes requires glycogen synthesis and turnover. Here we show that β-adrenergic stimulation induces a distinct glycogen metabolism gene program in inguinal white adipose tissue in a cell-autonomous and adipocyte-specific manner. Among these, Gys2 and Ppp1r3c are rapidly induced following acute β3-adrenergic receptor activation. We identify Gys2 as a direct transcriptional target of PKA-CREB signaling. In contrast, sustained expression of glycogen metabolism genes under chronic β3-adrenergic activation requires the coactivator PGC1α, whose loss blunts glycogen accumulation and thermogenic capacity. Mechanistically, PGC1α cooperates with estrogen-related receptors (ERRs) to regulate chromatin accessibility and gene transcription. Although deletion of ERRα is compensated by ERRγ, combined deletion of ERRα/β/γ abolishes expression of glycogen metabolism and thermogenic genes. Chromatin profiling confirm that ERRs directly control the glycogen metabolic program in beige adipocytes. Together, our results identify a multilayered transcriptional axis that sustains glycogen metabolism during β-adrenergic activation in male mice.

DOI: https://doi.org/10.1038/s41467-025-67515-9

Nat Commun. 2025 Dec 16.

TRIM37-PARP1-TET1 axis maintains stemness and prevents osteoporosis by inhibiting DNMT1 alternative splicing via 5hmC regulation.

Chun-Te Ho, Ling-Hui Li, Wei-Chao Chang, Heng-Hsiung Wu, Ya-Huey Chen, Shih-Chieh Hung.

The significance of DNA hydroxymethylation in replicative senescence of mesenchymal stem cells (MSCs) and aging-related osteoporosis remains unknown. Here, we reveal 5hmC levels positively regulate MSC self-renewal and osteoblast differentiation. Mechanistically, PARP1 recruits TET1 to hydrolyze methylated nucleotides on DNMT1 exons, aiding CTCF in preventing DNMT1 alternative splicing in early MSCs. Additionally, ATM phosphorylates TRIM37 at Th203, promoting its nuclear entry and the monoubiquitination of PARP1, stabilizing the protein. CTCF or TRIM37 knockdown induces replicative senescence of MSCs with loss of full-length DNMT1. Co-treatment with resveratrol (ATM activator) and vitamin C (TET1 activator) rejuvenates late MSCs via the TRIM37/PARP1/DNMT1 pathway and alleviates osteoporosis in aged mice. Gene knockout experiments further reveal the participation of TRIM37 and PARP1 in MSC aging, contributing significantly to bone maintenance and repair in vivo. This study emphasizes the role of DNA hydroxymethylation in stemness, suggesting therapeutic strategies, especially for osteoporosis.

DOI: https://doi.org/10.1038/s41467-025-66281-y

Cell Mol Gastroenterol Hepatol. 2025 Dec 11. pii: S2352-345X(25)00248-6. [Epub ahead of print] 101706

Prevention of cholestatic liver disease through BCL6-FXR enterohepatic crosstalk.

Ellen Fruzyna, Meredith A Sommars, Yasu Omura, Kristine M Yarnoff, Janice C Wang, Christopher R Futtner, Richard M Green, Grant D Barish.

Bile acid (BA) metabolism must be tightly regulated because BAs serve as metabolic signaling molecules but become cytotoxic at high levels. The farnesoid X receptor (FXR) is a crucial BA sensor, yet our understanding of its regulation and coordination with other transcription factors is limited. Here, we found that hepatic B cell lymphoma 6 (Bcl6) integrates with FXR to control BA homeostasis. Mice lacking hepatic Bcl6 (Bcl6LKO) have increased BA synthesis and levels, as well as reduced expression of the hepatic BA re-uptake transporter sodium-taurocholate cotransporting polypeptide (NTCP), particularly among males. Furthermore, loss of Bcl6 reduced hepatic fibroblast growth factor receptor 4 (FGFR4) expression, attenuating FXR-controlled entero-hepatic BA feedback signaling. To understand the mutual contributions of BCL6 and FXR to BA homeostasis, we generated animals with combined deletion of hepatic Bcl6 and Fxr (Bcl6LKOFxrKO mice). Remarkably, combined ablation caused almost complete loss of hepatic Shp expression, upregulation of the rate-limiting BA synthesis enzyme CYP7A1, severe elevation in BA levels, and cholestatic liver damage. Together, these findings reveal BCL6 as a key modulator of FXR enterohepatic signaling to maintain BA homeostasis and protect the liver from cholestatic injury.

DOI: https://doi.org/10.1016/j.jcmgh.2025.101706

Circulation. 2025 Dec 18.

Macrophage-Specific E3 Ubiquitin Ligase TRIM31 Reduces Atherosclerotic Plaque Formation by Targeting LOX-1.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease marked by lipid accumulation and immune cell infiltration in arterial walls. Macrophages contribute by internalizing oxidized low-density lipoprotein, forming foam cells, and driving inflammation. The ubiquitin-proteasome system regulates immune and inflammatory responses in atherosclerosis. This study investigated the protective role of TRIM31 (tripartite motif-containing 31), an E3 ubiquitin ligase, in macrophage lipid metabolism and inflammation through selective regulation of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1).
METHODS: Transcriptomic profiling, macrophage-specific Trim31 knockout (Trim31fl/flLyz2cre) and overexpression (Trim31Lyz2-KI) mice, and LOX-1 knockout (Lox-1-/-) models were used to examine the impact of TRIM31 in vivo (n=8 per group). TRIM31 substrates were identified using single-cell RNA sequencing of atherosclerotic aortas and proteomic/immunoprecipitation-mass spectrometry analyses. Functional assays were performed in both mouse and human macrophages (n=5-6 per group). Ubiquitination mechanisms were clarified through immunoprecipitation and site-directed mutagenesis. Rescue experiments involved LOX-1 knockdown or reconstitution with wild-type and lysine 12 to arginine variant (K12R) LOX-1 and TRIM31 overexpression in Lox-1-/- or Apoe-/-Lox-1-/- mice to evaluate the functional importance of LOX-1 ubiquitination in vivo (n=8 per group) and in vitro (n=5 per group).
RESULTS: TRIM31 was selectively upregulated in macrophages under oxidized low-density lipoprotein stimulation and in atherosclerosis plaques. TRIM31 deficiency exacerbated plaque burden, foam cell formation, and inflammatory signaling (n=8 per group). Single-cell analysis revealed enrichment of lipid transport and inflammatory pathways in TRIM31-deficient plaques. LOX-1 was identified as a key TRIM31 substrate. TRIM31 promoted K48-linked ubiquitination of LOX-1 at lysine 12, facilitating its degradation. The atheroprotective effects of TRIM31 were abolished in Lox-1-/- or K12R-variant rescue models. The TRIM31-LOX-1 axis was also confirmed by human macrophages in regulating lipid uptake and inflammation.
CONCLUSIONS: TRIM31, an inducible, macrophage-enriched protective factor in atherosclerosis, restricts foam cell formation and inflammation by targeting LOX-1 for proteasomal degradation. These findings position TRIM31 as a promising therapeutic target for macrophage-driven atherogenesis.

Keywords: atherosclerosis; foam cells; inflammation; macrophages; ubiquitination

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.076514