bims-obesme 2025-08-31 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–08–31
twelve papers selected by
Xiong Weng, University of Edinburgh

KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart.
Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.
Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.
DNMT1-mediated SPINT2 expression drives early senescence by suppressing c-Met signaling in human fibroblasts.
Epigenetic Programming of Estrogen Receptor in Adipocytes by High Fat Diet Regulates Obesity-Induced Inflammation.
Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications.
Lipodystrophy Syndromes: One Name but Many Diseases Highlighting the Importance of Adipose Tissue in Metabolism.
LYVAC/PDZD8 is a lysosomal vacuolator.
Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.
DNA Methylation Biomarkers Predict Offspring Metabolic Risk From Mothers With Hyperglycemia in Pregnancy.
Metabolome-Wide Mendelian Randomization and Observational Study Reveal Causal Links Between Circulating Metabolites and Youth-Onset Type 2 Diabetes.

Mol Metab. 2025 Aug 25. pii: S2212-8778(25)00146-2. [Epub ahead of print] 102239

KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart.

Mariko Aoyagi Keller, Andreas Ivessa, Tong Liu, Hong Li, Peter J Romanienko, Michinari Nakamura.

  Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.

Keywords:  AMPK; KAT6A; acetylation; acetyltransferase; cardiac hypertrophy; heart failure; hypertensive cardiomyopathy; ketogenic diet; ketone body; lysine acetyltransferase 6A

DOI:  https://doi.org/10.1016/j.molmet.2025.102239
Cell Metab. 2025 Aug 19. pii: S1550-4131(25)00356-0. [Epub ahead of print]

Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.

Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan.

  The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to diet in mice, while single-nucleotide polymorphisms (SNPs) associated with rhythmic gene expression are enriched in E-PIs in steatotic human livers and correlate with lipid metabolism traits. These findings reveal a previously underappreciated temporal aspect of genetics-environment interaction in regulating lipid metabolic traits, with implications for individual variations in obesity-associated disease susceptibility and personalized chronotherapy.

Keywords:  3D enhancer-promoter interaction; diurnal rhythm; genetic variation; human metabolic traits; metabolic disorders

DOI:  https://doi.org/10.1016/j.cmet.2025.07.010
Nat Genet. 2025 Aug 20.

Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.

Zeyuan Johnson Chen, Sankha Subhra Das, Asha Kar, Seung Hyuk T Lee, Kevin D Abuhanna, Marcus Alvarez, Mihir G Sukhatme, Zitian Wang, Kyla Z Gelev, Matthew G Heffel, Yi Zhang, Oren Avram, Elior Rahmani, Sriram Sankararaman, Markku Laakso, Sini Heinonen, Hilkka Peltoniemi, Eran Halperin, Kirsi H Pietiläinen, Chongyuan Luo, Päivi Pajukanta.

The cell-type-level epigenomic landscape of human subcutaneous adipose tissue (SAT) is not well characterized. Here, we elucidate the epigenomic landscape across SAT cell types using snm3C-seq. We find that SAT CG methylation (mCG) displays pronounced hypermethylation in myeloid cells and hypomethylation in adipocytes and adipose stem and progenitor cells, driving nearly half of the 705,063 differentially methylated regions (DMRs). Moreover, TET1 and DNMT3A are identified as plausible regulators of the cell-type-level mCG profiles. Both global mCG profiles and chromosomal compartmentalization reflect SAT cell-type lineage. Notably, adipocytes display more short-range chromosomal interactions, forming complex local 3D genomic structures that regulate transcriptional functions, including adipogenesis. Furthermore, adipocyte DMRs and A compartments are enriched for abdominal obesity genome-wide association study (GWAS) variants and polygenic risk, while myeloid A compartments are enriched for inflammation. Together, we characterize the SAT single-cell-level epigenomic landscape and link GWAS variants and partitioned polygenic risk of abdominal obesity and inflammation to the SAT epigenome.

DOI: https://doi.org/10.1038/s41588-025-02300-4
Nat Commun. 2025 Aug 25. 16(1): 7671

Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.

Kayleigh M Voos, Joyce Tzeng, Priya Patel, Sophie Rubinsky, Ha E Choi, Trevor Pharr, Sebastian Sookram, Joseph A Baur, Erik J Soderblom, Damaris N Lorenzo.

Mitochondrial dynamics enable cellular adaptation to fluctuations in energy demand, such as those imposed on skeletal muscle by exercise, metabolic disorders, or aging. Here, we report a novel pathway that modulates mitochondria dynamics in skeletal muscle involving the scaffolding protein ankyrin-B. Rare variants in ankyrin-B, encoded by ANK2, increase risk for cardio-metabolic syndrome in humans and mice. We show that mice selectively lacking skeletal muscle ankyrin-B have reduced endurance exercise capacity without alterations in muscle strength or systemic glucose regulation. Muscle fibers in these mice have increased oxidative stress, reduced fatty acid oxidation, and enlarged and hyperconnected mitochondria. We found that ankyrin-B interacts with and is required for efficient mitochondria recruitment of fission modulators and sarcoplasmic reticulum-mitochondria coupling. Thus, we conclude that ankyrin-B enables substrate adaptability and bioenergetic homeostasis under energetic stress, and exercise capacity by promoting efficient mitochondrial fission in skeletal muscle.

DOI: https://doi.org/10.1038/s41467-025-62977-3
Aging (Albany NY). 2025 Aug 20. 17

DNMT1-mediated SPINT2 expression drives early senescence by suppressing c-Met signaling in human fibroblasts.

Min Seok Sim, Hae-Ok Byun, Seongki Min, Jiwon Hong, Su Bin Lim, Kyoung Sook Choi, Gyesoon Yoon.

  Cellular senescence is a critical process involved in aging and related disorders, yet the molecular triggers of early senescence remain elusive. Here, we identify DNA methyltransferase 1 (DNMT1) downregulation as a key trigger of early senescence and establish serine protease inhibitor Kunitz type 2 (SPINT2) as its critical downstream effector. Using replicative and oxidative stress-induced senescence models of primary human diploid fibroblast, we observed persistent upregulation of SPINT2 and inverse downregulation of DNMT1, preceding senescence-associated β-galactosidase activity, a conventional senescence marker. Pharmacological inhibition and siRNA-mediated knockdown of DNMT1 significantly increased SPINT2 expression and induced senescence, showing mitigated effects by SPINT2 knockdown. Furthermore, SPINT2 overexpression alone induced senescence. Methylation-specific sequencing identified four CpG sites in SPINT2 promoter, that became hypomethylated at early transition of senescence and upon DNMT1 suppression. Functional analyses revealed that DNMT1-mediated SPINT2 expression induced c-Met inhibition, triggering senescence. Transcriptomic profiling identified 17 commonly deregulated c-Met signaling genes in both senescence models, with COL27A1, STAM2, and CBL validated as key downstream targets of SPINT2/c-Met signaling. These findings establish DNMT1-mediated SPINT2 upregulation as a novel epigenetic mechanism driving senescence initiation via c-Met inhibition, providing insights into the early stage of senescence and potential therapeutic targets for aging-related diseases.

Keywords:  DNA methyltransferase 1 (DNMT1); aging; cellular senescence; senescence; serine protease inhibitor Kunitz type 2 (SPINT2)

DOI:  https://doi.org/10.18632/aging.206303
JCI Insight. 2025 Aug 26. pii: e173423. [Epub ahead of print]

Epigenetic Programming of Estrogen Receptor in Adipocytes by High Fat Diet Regulates Obesity-Induced Inflammation.

Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi.

  Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α (Esr1) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrated that DNA methylation at Esr1 promoter played an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

Keywords:  Adipose tissue; Endocrinology; Epigenetics; Metabolism; Obesity

DOI:  https://doi.org/10.1172/jci.insight.173423
J Adv Res. 2025 Aug 21. pii: S2090-1232(25)00644-7. [Epub ahead of print]

Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications.

Meng-Ting Yin, Liang Guo.

   BACKGROUND: Mitochondrial DNA (mtDNA), a circular genome essential for cellular energy production, is increasingly recognized to exhibit aberrant methylation under pathological conditions. Dysregulated methylation in regulatory regions can impair mtDNA replication, transcription, and metabolic homeostasis, thereby promoting disease progression, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, as well as aging. Despite challenges posed by nuclear pseudogene interference, advanced detection technologies have significantly improved the resolution of mtDNA methylation analysis.
AIM OF REVIEW: This review focuses on three key mtDNA methylation patterns, 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and N6-methyladenine (6mA), summarizing the evidence for their existence as well as their molecular mechanisms in diseases and offering insights into recent advances in mtDNA detection techniques. Key Scientific Concepts of Review: Under pathological conditions, the dysregulation of mtDNA methylation highlights its emerging promise as both a biomarker and therapeutic target. Therefore, this epigenetic aberration provides a foundational framework for elucidating the molecular mechanisms underlying mitochondrial dysfunction across diverse diseases and advancing precision medicine strategies.

Keywords:  5-hydroxymethylcytosine; 5-methylcytosine; MtDNA methylation; N6-methyladenine

DOI:  https://doi.org/10.1016/j.jare.2025.08.029
Curr Diab Rep. 2025 Aug 21. 25(1): 46

Lipodystrophy Syndromes: One Name but Many Diseases Highlighting the Importance of Adipose Tissue in Metabolism.

Maria Foss-Freitas, Donatella Gilio, Elif A Oral.



Keywords:  Adipose tissue; Atypical diabetes; Genotype-phenotype; Lipoatrophic diabetes; Lipodystrophy; Metabolic abnormalities

DOI:  https://doi.org/10.1007/s11892-025-01602-5
Science. 2025 Aug 21. 389(6762): eadz0972

LYVAC/PDZD8 is a lysosomal vacuolator.

Haoxiang Yang, Jinrui Xun, Yajuan Li, Awishi Mondal, Bo Lv, Simon C Watkins, Lingyan Shi, Jay Xiaojun Tan.

Lysosomal vacuolation is commonly found in many pathophysiological conditions, but its molecular mechanisms and functions remain largely unknown. Here, we show that the endoplasmic reticulum (ER)-anchored lipid transfer protein PDZ domain-containing 8 (PDZD8), which we propose to be renamed as lysosomal vacuolator (LYVAC), is a general mediator of lysosomal vacuolation. Using human cell lines, we found that diverse lysosomal vacuolation inducers converged on lysosomal osmotic stress, triggering LYVAC recruitment through multivalent interactions. Stress-induced lysosomal lipid signaling contributed to both the recruitment and activation of LYVAC. By directly sensing lysosomal phosphatidylserine and cholesterol, the lipid transfer domain of LYVAC mediated directional ER-to-lysosome lipid movement, leading to osmotic membrane expansion of lysosomes. These findings uncover an essential mechanism for lysosomal vacuolation with broad implications in pathophysiology.

DOI: https://doi.org/10.1126/science.adz0972
Aging (Albany NY). 2025 Aug 25. 17

Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.

Anna Panfilova, Tatiana Zubareva, Ekaterina Mironova, Gianluigi Mazzoccoli, Maria Greta Pia Marasco, Sofya Balazovskaia, Peter Yablonsky, Igor Kvetnoy.

  Research in the field of mitochondrial biomarkers plays an important role in understanding the processes of cellular aging. Mitochondria are not only the energy centers of the cell, but also key regulators of signaling within the cell. They significantly affect the life and function of the cell. The aging process of cells is associated with various factors, including DNA damage, disruption of the cell cycle, changes in mitochondria, and problems with signal transmission. Mitochondrial dysfunction is a major contributor to cellular and organismal aging. As we age, there is an accumulation of dysfunctional mitochondria, leading to decreased efficiency of oxidative phosphorylation and increased production of reactive oxygen species. This review focuses on the main mitochondrial markers involved in the mechanisms of cell aging: DRP1, Prohibitin, Parkin, PINK1, MFF, VDAC, TOM. These signaling molecules are involved in mitochondrial fission and the mechanisms of mitochondria-dependent apoptosis, in the regulation of mitochondrial respiratory activity, ensuring the stability of the organization and copying of mitochondrial DNA, protecting cells from oxidative stress, in the process of autophagy of damaged mitochondria, in protective mechanisms during stress-induced mitochondrial dysfunction. Analysis of mitochondrial markers can provide valuable information about the state of cells and their functional significance at various stages of aging, which could promote our understanding of cellular aging mechanisms and developing corrective methods. These insights highlight mitochondrial proteins as potential therapeutic targets to combat age-related diseases.

Keywords:  age-associated diseases; biomarkers; cellular senescence; mitochondria; mitochondrial proteins

DOI:  https://doi.org/10.18632/aging.206305
Diabetes. 2025 Sep 01. 74(9): 1695-1707

DNA Methylation Biomarkers Predict Offspring Metabolic Risk From Mothers With Hyperglycemia in Pregnancy.

Johnny Assaf, Ishant Khurana, Ram Abou Zaki, Claudia H T Tam, Ilana Correa, Scott Maxwell, Julie Kinnberg, Malou Christiansen, Caroline Frørup, Heung Man Lee, Harikrishnan Kaipananickal, Jun Okabe, Safiya Naina Marikar, Kwun Kiu Wong, Cadmon K P Lim, Lai Yuk Yuen, Xilin Yang, Chi Chiu Wang, Juliana C N Chan, Kevin Y L Yip, William L Lowe, Wing Hung Tam, Ronald C W Ma, Assam El-Osta.

ARTICLE HIGHLIGHTS: Maternal hyperglycemia is linked to 19 cord blood DNA methylation biomarkers that predict offspring metabolic dysfunction. These methylation changes, associated with maternal glycemic status, improved the prediction of β-cell dysfunction at 7, 11, and 18 years of age compared with clinical factors alone. Validation in human β-cells and pancreatic ductal epithelial cells confirmed that hyperglycemia influences methylation-dependent gene expression. These findings highlight the role of epigenetic modifications at birth as early indicators of diabetes risk, suggesting that in utero hyperglycemic exposure may mediate long-term metabolic outcomes in offspring.

DOI: https://doi.org/10.2337/db25-0105
Diabetes. 2025 Aug 27. pii: db250093. [Epub ahead of print]

Metabolome-Wide Mendelian Randomization and Observational Study Reveal Causal Links Between Circulating Metabolites and Youth-Onset Type 2 Diabetes.

Kaossarath Fagbemi, Raphael Avocegamou, Nahid Yazdanpanah, Mojgan Yazdanpanah, Basile Jumentier, Isabel Gamache, Despoina Manousaki.

ARTICLE HIGHLIGHTS: Metabolism is key in the pathogenesis of type 2 diabetes in both children and adults, and large-scale metabolomic studies offer a unique source for discovery of biomarkers for these conditions. Leveraging human genetics, we explored whether altered levels of circulating metabolites in the blood are causally linked to type 2 diabetes in youth across different ancestries. Our Mendelian randomization analysis identified causal associations for 34 metabolites, and, among these, Mendelian randomization replication and colocalization prioritized 23 metabolites. Observational evidence from the Avon Longitudinal Study of Parents and Children (ALSPAC) study validated effects on glucose homeostasis for six of these metabolites, among which phosphatidylcholine ae C42:3 emerged as the most promising biomarker. These findings highlight the role of metabolism in glucose homeostasis pathophysiology in youth.

DOI: https://doi.org/10.2337/db25-0093