bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–03–08
fifteen papers selected by
Xiong Weng, University of Edinburgh
  1. TCL1A mediates DNA methylation defects in recurrent hydatidiform mole with NLRP7 pathogenic variants.
  2. GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.
  3. The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.
  4. Dynamic subcellular proteomics identifies regulators of adipocyte insulin action.
  5. Context-dependent roles of sex hormone signaling in controlling visceral adipose tissue Treg heterogeneity and clonal expansion.
  6. Why timing matters in MASLD: Late-day metabolic control.
  7. Microbiota-mediated induction of beige adipocytes in response to dietary cues.
  8. Adipocyte-specific NR5A2 deficiency ameliorates diet-induced metabolic syndrome by suppressing adipose tissue inflammation.
  9. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  10. LYPLAL1 Rare Loss-of-Function Variants in Humans and Deletion in Human Hepatoma Cells Protect Against MASLD.
  11. Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
  12. STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
  13. Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants.
  14. Nutrient-driven histone acetylation underlies energy storage and mobilization.
  15. α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models.
  1. Nat Commun. 2026 Mar 05. pii: 2160. [Epub ahead of print]17(1):
    TCL1A mediates DNA methylation defects in recurrent hydatidiform mole with NLRP7 pathogenic variants.
    Zheng Gao, Qingting Liu, Lei Li, Ting Hu, Xukun Lu, Yu Wu, Dandan Qin, Xiaoxiao Wang, Chen Gu, Jinhong Li, Chengpeng Xu, Dan Zhou, Fan Zhou, YanLing Bai, Xiangjin Kang, Jianqiao Liu, Dong Deng, Lei Li.
      Pathogenic variants in NLRP7, implicated in 55% of recurrent hydatidiform mole characterized by hypomethylation at maternally methylated imprinted regions, are proposed to disrupt de novo DNA methylation in human oocytes. However, the precise mechanism remains unclear. Here, we identify TCL1A, a DNMT3A inhibitor, as an endogenous NLRP7-interacting partner. The cryo-EM structure of the NLRP7-TCL1A complex reveals its fundamental architecture. Comprehensive analysis demonstrates that the majority of recurrent hydatidiform mole-causing NLRP7 variants impair its interaction with TCL1A. Mechanistically, NLRP7 potentially safeguards oocyte methylome by sequestering TCL1A in the cytoplasm, thereby preventing its nuclear entry and subsequent suppression of DNMT3A-mediated de novo methylation. Combining in silico predictions and interaction analysis, we identify L766R as a pathogenic variant. These findings propose a cytoplasmic regulatory mechanism governing nuclear DNA methylation, explaining the hypomethylation pathogenesis in NLRP7 variant-associated recurrent hydatidiform mole.
    DOI:  https://doi.org/10.1038/s41467-026-69744-y
  2. Nat Commun. 2026 Mar 03.
    GPR146 in adipose tissue drives adipose-liver crosstalk and promotes hepatic steatosis in mice.
    Yu Shi, Kai Yan Cheng, Thi Tun Thi, Yifan Wang, Yang Yang, Xiaoyun Cao, Vanna Chhay, Yujia Shen, Yuchen He, Tianyun Zhao, Yan Ting Lim, Amy Deik, Courtney Dennis, Kerry Pierce, Kevin Bullock, Martin Wabitsch, Clary B Clish, Alexander S Banks, Radoslaw M Sobota, Chad A Cowan, Haojie Yu.
      The limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD) underscore the need for deeper mechanistic insight and new treatment strategies. Here, we identify the orphan G protein-coupled receptor GPR146 as a regulator of hepatic steatosis through adipose-liver crosstalk. Human genetic analyses link the GPR146 locus to circulating markers of liver injury and inflammation. In mice, both constitutive and acute GPR146 depletion protect against diet-induced obesity and hepatic steatosis. Notably, adipose-specific, but not liver-specific, GPR146 deletion reduces hepatic lipid accumulation by limiting free fatty acid (FFA) influx. Mechanistically, GPR146 promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating FFA. Together, these coordinated actions increase FFA delivery to the liver, promoting triglyceride accumulation. Our findings establish GPR146 as a pleiotropic regulator of adipose tissue biology and a potential therapeutic target for MASLD.
    DOI:  https://doi.org/10.1038/s41467-026-70136-5
  3. Nat Commun. 2026 Mar 06.
    The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.
    Qixia Xu, Gaoxiang Li, Hongwei Zhang, Zhirui Jiang, Xiuxia Gao, Zi Li, Larissa G P Langhi Prata, James L Kirkland, Guilong Zhang, Yu Sun.
      Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics suggests that dihydromyricetin promotes nuclear translocation of peroxiredoxin 2 (PRDX2) to facilitate DNA repair in senescent cells. In prematurely aged mice, dihydromyricetin administration mitigates tissue aging and age-related physiological decline. In anticancer regimens, dihydromyricetin improves outcomes of chemotherapy. However, dihydromyricetin demonstrates senolytic activity against senescent microglial cells, whose basal PRDX2 expression remains low, by impairing mitochondrial function to promote apoptosis. In mice developing Alzheimer's disease, dihydromyricetin eliminates senescent microglial cells from amyloid β-protein plaques and alleviates neurodegenerative symptoms. Together, our study proposes dihydromyricetin as a natural senotherapeutic agent for mitigating age-related morbidities, including but not limited to cancers and Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41467-026-70302-9
  4. Nat Commun. 2026 Feb 28.
    Dynamic subcellular proteomics identifies regulators of adipocyte insulin action.
    Olivia J Conway, Josie A Christopher, Lisa M Breckels, Hanqi Li, Dilip Menon, Meghna Birla, Bethan L Hawkins, Lu Liang, Satish Patel, Francoise Koumanov, David C Gershlick, David B Savage, Michael P Weekes, Kathryn S Lilley, Daniel J Fazakerley.
      Insulin acts on adipocytes to suppress lipolysis and increase glucose uptake to control whole-body glucose and lipid metabolism. Regulation of these processes by insulin signalling depends on changes in protein localisation. However, the extent of insulin-stimulated changes to the adipocyte spatial proteome, and the importance of these in the cellular insulin response, is unknown. Here, we use subcellular proteomics approaches to map acute insulin-stimulated protein relocalisation in adipocytes on a cell-wide scale. These data reveal extensive insulin-regulated protein redistribution, with hundreds of insulin-responsive proteins. These include the uncharacterised protein C3ORF18, which redistributes to the plasma membrane in response to insulin. Studies in C3ORF18-depleted adipocytes suggest this protein is required to maintain adipocyte insulin sensitivity. Overall, our data highlight the scale of protein relocalisation in the adipocyte insulin response, and provide an accessible resource to inform further studies into how changes in protein localisation contribute to cellular insulin responses.
    DOI:  https://doi.org/10.1038/s41467-026-70116-9
  5. J Immunol. 2026 Feb 09. pii: vkag010. [Epub ahead of print]215(2):
    Context-dependent roles of sex hormone signaling in controlling visceral adipose tissue Treg heterogeneity and clonal expansion.
    Cody Elkins, Jianliang Zhang, Chengyu Ye, Samara Moll, M Neale Weitzmann, Chaoran Li.
      Sex hormones are important for maintaining metabolic health. Females with low estrogen or high androgen levels exhibit an elevated risk for developing obesity-associated metabolic syndromes. Chronic low-grade inflammation in the visceral adipose tissue (VAT) is a major contributor to metabolic dysfunction during obesity. However, how sex hormones impact the VAT inflammatory environment to curtail obesity-associated pathology remain incompletely understood. Regulatory T cells (Tregs) expressing a clonally expanded T cell receptor (TCR) repertoire and high levels of the IL-33 receptor ST2 are highly enriched in male epididymal VAT (eVAT), in which they suppress tissue inflammation and protect against metabolic diseases. While TCR specificity and activation are critical for the accumulation of ST2+ eVAT Tregs in males, the factors governing Treg clonality in female ovarian VAT (oVAT) and their relevance to obesity-associated metabolic diseases remain largely unexplored. In this study, we used estrogen receptor α (ERα)-deficient mice, which exhibit impaired estrogen signaling and elevated androgen levels, to investigate the impact of sex hormone disruption on oVAT Tregs in lean and obese female mice. At steady state, ERα deficiency promoted age-dependent clonal expansion of specific ST2+ oVAT Treg subsets indirectly through modulating antigen presentation. However, combinations of obesity and ERα deficiency induced IFNγ production to deplete ST2+ oVAT Tregs, exacerbating oVAT inflammation and insulin resistance. Together, these findings reveal distinct, diet-dependent roles for sex hormones in regulating oVAT Tregs and suggest that loss of ST2+ oVAT Treg subsets during obesity may contribute to increased metabolic risk in females with disrupted sex hormone signaling.
    Keywords:  metabolism; regulatory T cells; sex hormones
    DOI:  https://doi.org/10.1093/jimmun/vkag010
  6. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00049-5. [Epub ahead of print]38(3): 445-446
    Why timing matters in MASLD: Late-day metabolic control.
    Amalia Gastaldelli.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is traditionally viewed as a static consequence of chronic caloric excess and insulin resistance. In the work previewed here, MASLD instead emerges as a disorder of time-of-day-dependent metabolic vulnerability, characterized by reduced insulin availability and worsening multisystem insulin resistance in the evening compared with the morning.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.006
  7. Nature. 2026 Mar 04.
    Microbiota-mediated induction of beige adipocytes in response to dietary cues.
    Takeshi Tanoue, Manabu Nagayama, Ayumi J A Roochana, Samuel Zimmerman, Orr Ashenberg, Tanvi Jain, Ryo Igarashi, Satoshi Sasajima, Kozue Takeshita, Nicola Hetherington, Nobuyuki Okahashi, Masahiro Ueda, Morichika Konishi, Yoshiaki Nakayama, Aki Minoda, Ashwin N Skelly, Yasuhiko Minokoshi, Nicholas Pucci, Daniel R Mende, Makoto Arita, Hironori Yamamoto, Shunji Watanabe, Kouichi Miura, Scott W Behie, Wataru Suda, Toshiro Sato, Koji Atarashi, Mami Matsushita, Shingo Kajimura, Damian R Plichta, Masayuki Saito, Ramnik J Xavier, Kenya Honda.
      Interactions between diet and the gut microbiota are fundamental to metabolic health, shaping energy balance and disease susceptibility1-5. However, the underlying mechanisms by which dietary and microbial factors converge to regulate host physiology remain unclear. Here we show that protein availability profoundly modulates the functional landscape of the gut microbiota and promotes remodelling of white adipose tissue (WAT). Specifically, low-protein diets (LPDs) robustly induce signature genes of browning in WAT to a similar extent to that seen in response to classical stimuli, such as cold exposure or β-adrenergic receptor activation6-8. LPD-mediated browning was markedly diminished in germ-free mice, and this defect was rescued by colonization with defined bacterial consortia made up of strains that were isolated and down-selected from the faeces of either LPD-fed mice or healthy human volunteers with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)-confirmed brown- or beige-fat activity9-12. Microbiota-induced browning was mediated both by bile acids driving the activation of the farnesoid X receptor (FXR) in adipose progenitor cells, and by nrfA-encoding commensal-derived ammonia driving the expression of fibroblast growth factor 21 (FGF21) in hepatocytes. The bile acid-FXR and ammonia-FGF21 axes both have non-redundant, essential roles in promoting WAT browning. These findings highlight a mechanistic link between diet, gut microbial metabolism and adipose tissue remodelling, uncovering microbiota-dependent pathways by which the host responds to dietary cues.
    DOI:  https://doi.org/10.1038/s41586-026-10205-3
  8. Sci Rep. 2026 Mar 03.
    Adipocyte-specific NR5A2 deficiency ameliorates diet-induced metabolic syndrome by suppressing adipose tissue inflammation.
    Weiwei Yuan, Shengqing He, Yuan Zang, Liping Deng.
      Obesity is a global epidemic characterized by adipose tissue dysfunction, chronic inflammation, and metabolic syndrome. The orphan nuclear receptor NR5A2 has been implicated in metabolic regulation, but its role in adipocytes remains unclear. Here, we demonstrate that NR5A2 expression is upregulated in adipose tissue of high-fat diet (HFD)-fed and genetically obese (ob/ob) mice. Adipocyte-specific NR5A2 knockout (AKO) mice exhibited resistance to HFD-induced obesity, with reduced fat mass, smaller adipocytes, and improved glucose tolerance and insulin sensitivity. Mechanistically, NR5A2 ablation attenuated adipose tissue inflammation, evidenced by decreased pro-inflammatory cytokines (IL-6, TNF-α) and macrophage infiltration, while enhancing energy expenditure and thermogenesis. Additionally, AKO mice showed reduced hepatic steatosis and improved lipid profiles. In vitro, NR5A2 deficiency impaired adipocyte differentiation and lipid accumulation. These findings identify NR5A2 as a key regulator of adipocyte hypertrophy, inflammation, and systemic metabolism, suggesting its inhibition as a potential therapeutic strategy for obesity-related metabolic disorders.
    Keywords:  Adipocyte; Inflammation; NRF5A2; Obesity
    DOI:  https://doi.org/10.1038/s41598-026-40395-9
  9. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  10. J Lipid Res. 2026 Mar 03. pii: S0022-2275(26)00039-8. [Epub ahead of print] 101013
    LYPLAL1 Rare Loss-of-Function Variants in Humans and Deletion in Human Hepatoma Cells Protect Against MASLD.
    Rawdat Hussain, Chinmay Raut, Ponnandy Prabhu, Akram Irshaid, Yash Hegde, Yue Chen, Asmita Pant, Antonino Oliveri, Xiaochao Wei, Lishi Yin, Tiffany L Russell, Brian Halligan, Clay F Semenkovich, Elizabeth K Speliotes.
      Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells.
    Keywords:  LYPLAL1; MASLD; UK BioBank; liver; steatosis; β-oxidation
    DOI:  https://doi.org/10.1016/j.jlr.2026.101013
  11. Nat Cell Biol. 2026 Mar 06.
    Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
    Alexis Betrancourt, M Talha Cinko, Ana Beatriz Varanda, Maykel Arias, Iratxe Uranga-Murillo, Natacha Peña, Lucia-Maria Kaps, Long Fung Chau, Bianca Buratti, Johannes Brägelmann, Diego de Miguel, Kerstin Becker, Ramona Casper, Rocio Martin, Antonio Alcami, Brian J Ferguson, Julian Pardo, Eva Rieser, Henning Walczak.
      Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS-STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS-STING, TLR3 and TLR4.
    DOI:  https://doi.org/10.1038/s41556-026-01886-z
  12. Nat Commun. 2026 Mar 06.
    STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
    Isshin Shiiba, Yuto Ishikawa, Hijiri Oshio, Naoki Ito, Fuya Yamaguchi, Shun Nagashima, Hideya Ando, Keitaro Umezawa, Yuri Miura, Yuhei Araiso, Koki Nakamura, Yusuke Hirabayashi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondria form contact sites with multiple organelles to coordinate diverse cellular processes. Melanosomes, lysosome-related organelles, undergo stepwise maturation to synthesize and store melanin, but how they interact with mitochondria remains unclear. Here we show that mitochondria-melanosome contacts dynamically increase during melanosome maturation and are mediated by STIM1-MFN2 interactions. Using a NanoBiT-based reporter system, MiMSBiT (Mitochondria-Melanosome contact reporter applying NanoBiT), to monitor reversible mitochondria-melanosome contacts in living cells, we demonstrate that STIM1 localizes to melanosomes and promotes their contact with mitochondrial MFN2. A transient decrease in melanosomal lumen calcium induces STIM1 clustering and enhances its association with MFN2. These contacts locally increase mitochondrial ATP availability, leading to melanosome lumen acidification via proton channel activation. This acidification facilitates PMEL fibrillation, a key step in melanosome maturation. Together, our findings reveal a mechanism by which mitochondria-melanosome contacts regulate melanosome maturation.
    DOI:  https://doi.org/10.1038/s41467-026-70282-w
  13. Cell Rep. 2026 Mar 03. pii: S2211-1247(26)00119-1. [Epub ahead of print]45(3): 117041
    Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants.
    Monica L Gonzalez Ramirez, Lennis B Orduña-Castillo, Carolyne Bardeleben, Huaping Qin, Ying Lin, Cierra A Birch, Irina Kufareva, JoAnn Trejo.
      G protein-coupled receptors (GPCRs) exhibit signaling bias or preferential activation of heterotrimeric G proteins versus GPCR kinase (GRK)-mediated β-arrestin signaling. The protease-activated receptor-1 (PAR1) activates both G protein and β-arrestin in response to thrombin but only β-arrestin in response to activated protein C (APC). Thrombin-activated PAR1-G protein signaling is desensitized by β-arrestin-1, whereas APC-activated PAR1 signaling is propagated by β-arrestin-2. The mechanisms underlying PAR1 biased signaling are not known. Here, using computational modeling combined with cellular and biochemical studies, we reveal the molecular basis of signaling by thrombin- and APC-activated PAR1. Although both thrombin- and APC-induced PAR1 signaling are regulated by the same GRK, GRK5, the two types of signaling are differentially dependent on GRK5 membrane anchoring, PAR1 C-terminal phosphorylation sites, and the binding mode of β-arrestin-2. These differences translate into distinct β-arrestin-2 conformations and define the APC cytoprotective signaling signature, which contrasts with thrombin inflammatory signaling.
    Keywords:  APC; CP: molecular biology; G protein; G protein-coupled receptor; G protein-coupled receptor kinase; GPCR; GRK; PAR1; activated protein C; biased agonists; biased signaling; phosphorylation; thrombin
    DOI:  https://doi.org/10.1016/j.celrep.2026.117041
  14. Mol Metab. 2026 Mar 03. pii: S2212-8778(26)00028-1. [Epub ahead of print] 102344
    Nutrient-driven histone acetylation underlies energy storage and mobilization.
    Linyun Chen, Lingyan Zhu, Huabing Xiao, Xiaotao Wang, Fan Xia, Zhichao Wang, Long Wu, Dayu Wu, Qi Liu, Junyun Cheng, Jun Qi, Qiong Duan.
      In natural settings, energy storage and mobilization maintain a dynamic balance in response to recurrent overfeeding and fasting. Imbalanced energy storage and mobilization lead to a variety of metabolic dysfunctions. However, whether the metabolic status directly couples with epigenetic modifications and transcriptional outputs remains unclear. Here, we aimed to investigate the epigenetic mechanism underlying this adaptive balance and observed that, in an overfeeding state, increased glucose availability is associated with enhanced histone acetylation coinciding with acetyl-CoA production in an acyl-CoA short-chain synthetase 2 (ACSS2)-dependent manner, contributing to energy storage (e.g., lipogenesis); in contrast, in the fasting state, elevated D-β-hydroxybutyrate levels are associated with altered histone acetylation distribution and transcriptional programs, supporting a metabolic shift from anabolism to catabolism, such as fatty acid oxidation. In both overfeeding and fasting states, acetylated lysines in the histone require BRD4 to recognize and initiate transcriptional regulation. Inhibition of BRD4 leads to context-dependent phenotypic effects: it ameliorates non-alcoholic fatty liver disease (NAFLD) pathology induced by a high-fat diet, while it exacerbates hepatic steatosis in fasted mice or mice fed a ketogenic diet. Thus, these findings highlights that epigenetic regulation of energy storage and mobilization is closely linked to the availability of glucose, and ketone bodies. Moreover, our study revealed that modulation of ACSS2-associated pathway may represent a potential strategy for treatment of metabolic diseases, such as NAFLD.
    Keywords:  ACSS2; BRD4; Fatty acid oxidation; Histone acetylation; lipogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2026.102344
  15. J Clin Invest. 2026 Mar 02. pii: e172380. [Epub ahead of print]136(5):
    α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models.
    Shuaijun Li, Jiefeng Huang, Ting Shang, Laiya Lu, Orion R Fan, Peisheng Jin, Xin Zou, Zixin Cai, Wuyan Lu, Shuangmeng Jia, Linxiao Li, Ke Fang, Fengting Niu, Jiaojiao Li, Cheng Zhao, Qian Wang, Ruizhu Sun, Si Shi, Feng Yin, Yun Zhang, Yi Eve Sun, Lei Cui.
      The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle- and HIF-1α-independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and oxidative phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.
    Keywords:  Cartilage; Inflammation; Metabolism
    DOI:  https://doi.org/10.1172/JCI172380
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒08 at 15:21.