bims-obesme 2026-09-20 papers

Issue of 2026–09–20
four papers selected by
Xiong Weng, University of Edinburgh

Cell Rep. 2026 Sep 15. pii: S2211-1247(26)01087-9. [Epub ahead of print]45(10): 118009

ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.

Songnan Wang, Yingjie Guo, Weidong An, J Michelle Lee, Yu Li, Valentino Sudaryo, Jacqueline A Carozza, Gabriel Grenot, Gemini Skariah, Saranya C Reghupaty, Sonny Young, Xiaochen Bai, Katrin J Svensson, Lingyin Li.

The mechanism underlying the role of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in metabolic disease remains unsolved. Using a 2'3'-cyclic GMP-AMP (cGAMP)-hydrolysis-deficient mouse (Enpp1H362A), we show that selective loss of this activity exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An in vivo glucose-uptake screen identifies brown adipose tissue (BAT) as a key site of metabolic impairment, marked by extracellular cGAMP accumulation and defective insulin-stimulated glucose uptake. Mechanistically, nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP synthesis and export. Excess extracellular cGAMP directly suppresses glucose uptake in brown adipocytes via stimulator of interferon genes (STING) pathway. Furthermore, impaired cGAMP clearance acts as a paracrine signal that recruits and polarizes BAT macrophages toward a pro-inflammatory M1-like phenotype. Finally, the human ENPP1 K173Q variant associated with obesity and diabetes displays reduced cGAMP hydrolysis activity. Together, these findings establish ENPP1 as an immunometabolic checkpoint that buffers extracellular cGAMP to maintain metabolic homeostasis.

Keywords: CP: immunology; CP: metabolism; ENPP1; STING; brown adipose tissue; diabetes; extracellular cGAMP; immune checkpoint; immunometabolism; insulin resistance; obesity

DOI: https://doi.org/10.1016/j.celrep.2026.118009

Aging Cell. 2026 Sep;25(9): e70718

Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.

Renin Chang, Andy P Tsai, Boyang Wang, Kuan-Hao Tsui, Cheng-Yoong Pang, Chia-Jung Li.

The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue-specific molecular clock of aging. We trace foundational single-cell and multi-tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single-cell and population-scale studies that have transformed the field: deep multi-tissue surveys revealing tissue-specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ-specific disease, and a two-step mechanism in which cryptic replication-error mutations become detectable through age-related clonal mosaicism. We discuss technologies such as single-cell mtDNA genotyping, duplex and long-read sequencing, and droplet digital PCR that now read the clock at single-molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA-driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood-based biomarker of biological age.

Keywords: aging; clonal expansion; heteroplasmy; mitochondrial DNA; molecular clock; respiratory chain deficiency; somatic mutation

DOI: https://doi.org/10.1111/acel.70718

Nature. 2026 Sep 15.

Quality control of glycogen through direct ubiquitylation by RNF213.

Matthew C J Yip, Katerina Naydenova, Elsje G Otten, Alexander Heatley, Agnes Moe, Leonie Anton, Lucía de Los Reyes-Ramírez, Helen E Jolin, Frederic Langevin, Michal Wiacek, Catarina Franco, Anne Bertolotti, Wanda Kukulski, Andrew N J McKenzie, Felix Randow.

Quality control of biomolecules is vital for organismal health. While DNA repair and protein quality control are well understood, how cells monitor other important biomolecules such as glycogen remains ill-defined. The accumulation of aberrant, poorly branched glycogen into insoluble polyglucosan bodies causes severe disease1,2. Here, we discover autophagy of ubiquitylated aberrant glycogen as a previously unrecognized quality control mechanism safeguarding the brain from polyglucosan buildup. This mechanism depends on the E3 ubiquitin ligase RNF213. Mice lacking ligase activity in RNF213 accumulate polyglucosan in cerebellum, pons, and hippocampus. Using cells engineered to produce polyglucosan, we show that RNF213 selectively ubiquitylates abnormal glycogen. Cryo-EM analysis of RNF213 bound to glycogen-derived maltoheptaose revealed its CBM20 domain binds linear oligosaccharides. Disrupting carbohydrate binding results in gain of E3 ligase activity towards physiological glycogen, indicating the CBM20 domain limits RNF213 activity towards physiological glycogen. Epistasis analysis places RNF213 upstream of LUBAC, suggesting a hierarchical network of multiple E3 ligases surveying glycogen quality. Ubiquitylated polyglucosan recruits the autophagy receptors SQSTM1, TAX1BP1, and optineurin, thereby triggering uptake into autophagosomes. These findings identify RNF213 as a quality control factor preventing polyglucosan accumulation in astrocytes through direct ubiquitylation of polyglucosan, revealing an essential role for non-protein ubiquitylation in glycogen quality control.

DOI: https://doi.org/10.1038/s41586-026-11139-6

Nat Rev Genet. 2026 Sep 17.

Gene regulatory mechanisms downstream of DNA methylation.

Tyler J Buckley, Mannix J Burns, Lucas Jarry, Shuya Wang, Su May Lei Soe, Steven E Jacobsen.

Cytosine DNA methylation is a conserved epigenetic modification that regulates gene expression, represses transposable elements and maintains genome stability across diverse eukaryotes. Although major advances have uncovered the pathways involved in the establishment, maintenance and removal of DNA methylation, the downstream mechanisms by which this mark influences transcriptional programmes and shapes chromatin structure are less well understood. Here, we review how specialized reader proteins and transcription factors interpret DNA methylation to preserve methylation patterns, recruit effector complexes, regulate chromatin accessibility and interact with parallel epigenetic systems to mediate transcriptional silencing and activation across mammals and plants. We highlight that robust transcriptional and epigenetic states emerge from overlapping, layered and partially redundant DNA methylation-dependent mechanisms. Together, these insights provide a framework for understanding how DNA methylation shapes the epigenome to regulate development, differentiation and disease progression.

DOI: https://doi.org/10.1038/s41576-026-01008-3