bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–04–19
sixteen papers selected by
Xiong Weng, University of Edinburgh
  1. POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.
  2. Caspase-6 Controls Lipid and Energy Metabolism in Diet-Induced Obesity.
  3. Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
  4. TOX3 in hypothalamic POMC-lineage cells regulates energy balance via the PTEN-AKT signaling axis.
  5. Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits.
  6. Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
  7. Adipocyte small extracellular vesicle-derived microRNA-30a-3p exacerbates hepatic steatosis in high fat diet-fed male mice.
  8. Longitudinal multimorbidity trajectories shape personalized glycaemic patterns.
  9. Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
  10. The genetic basis for DNA methylation variation across tissues and development.
  11. Exercise ameliorates adipose tissue insulin resistance by activating the lactate/GPR81 signaling pathway in DIO-IR mice.
  12. 5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
  13. Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.
  14. Hepatic Sirt2-PARP1-HMGB1 axis promotes exercise-mediated amelioration of MASH in mice.
  15. Loss of cardiomyocyte AKT signaling causes deterioration of lipid metabolism and cellular atrophy.
  16. SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
  1. Nat Commun. 2026 Apr 15.
    POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.
    Yuan Li, Min-Hyun Kim, Decheng Ren, Liangyou Rui.
      METTL14 mediates N6-methyladenosine (m6A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m6A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m6A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ΔPOMC mice are resistant to obesity, revealing an m6A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14ΔPOMC and Ythdc1ΔPOMC mice, defining an anti-obesity METTL14/m6A/YTHDC1/POMC axis. These findings identify METTL14 as the m6A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m6A epitranscriptomic regulation in melanocortin circuit development and maintenance.
    DOI:  https://doi.org/10.1038/s41467-026-71672-w
  2. Adv Sci (Weinh). 2026 Apr;13(21): e14784
    Caspase-6 Controls Lipid and Energy Metabolism in Diet-Induced Obesity.
    Abhishek Gupta, Wenjing You, Linmeng Han, Jianfei Ji, Meixia Pan, Xianlin Han, Xiaoli Sun, Peng Zhao.
      Caspases are cysteine proteases that regulate programmed cell death. While caspase-6, an executioner caspase, is known for its role in neurodegeneration and cell death, its broader physiological functions remain poorly understood. Our previous study revealed that caspase-6 drives liver injury and fibrosis in metabolic dysfunction-associate steatohepatitis. Here, we report that caspase-6 deficiency protects against high fat diet-induced obesity. Both global and adipocyte-specific caspase-6 knockout mice exhibit increased energy expenditure, reduced adiposity and inflammation, and improved glucose metabolism. Mechanistically, caspase-6 directly cleaves peroxisome proliferator-activated receptor gamma (PPARγ) and its cofactor specificity protein 1 (SP1), thereby suppressing adipose triglyceride lipase (ATGL) expression. Caspase-6 deficiency restores ATGL, enhancing lipolysis and elevating fatty acyl esters of hydroxy fatty acids (FAHFAs), which alleviate inflammation and enhance insulin sensitivity. These findings uncover a novel Casp6-PPARγ/SP1-ATGL axis in adipose tissue and establish caspase-6 as a potential therapeutic target for obesity and insulin resistance.
    Keywords:  ATGL; adipose tissue; caspase‐6; lipid metabolism; obesity
    DOI:  https://doi.org/10.1002/advs.202514784
  3. Nat Aging. 2026 Apr 13.
    Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
    Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.
      Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Furthermore, circulating C3a is elevated during aging in humans and in mice; we identified a non-senescent age-associated macrophage subset that expands in visceral fat as the predominant source. In macrophages, C3a-C3AR1 autocrine signaling via extracellular signal-regulated kinase (ERK) regulates age-related inflammation. Intra-adipose administration of a C3a-specific neutralizing antibody reduced inflammaging in mice. In addition, fibroblast growth factor 21 (FGF21) overexpression and deficiency of phospholipase A2 group VII (PLA2G7/lp-PLA2), which enhance lifespan and healthspan in mice, lowered C3a in aging. Thus, complement C3a reduction is a metabolically regulated inflammatory checkpoint that can be harnessed to attenuate inflammaging.
    DOI:  https://doi.org/10.1038/s43587-026-01107-0
  4. Nat Commun. 2026 Apr 13.
    TOX3 in hypothalamic POMC-lineage cells regulates energy balance via the PTEN-AKT signaling axis.
    Qin Tang, Juan Pang, Jinhang Zhang, Qinhui Liu, Jiahui Li, Ailin Zhang, Ying Xu, Haiying Song, Haifeng Zeng, Xiandan Jing, Na Yang, Yimin Xiong, Zijing Zhang, Yining Xu, Yanping Li, Li Mo, Jinhan He.
      Obesity and its associated metabolic disorders, including type 2 diabetes and fatty liver disease, represent a growing global health burden. Although the hypothalamus is well-established as the central regulator of energy homeostasis through specialized neuronal circuits, the molecular mechanisms governing these pathways remain incompletely elucidated. In this study, we identify thymocyte selection-associated high mobility group box 3 (TOX3) as a critical metabolic regulator in hypothalamic pro-opiomelanocortin (POMC)-lineage cells in mice. By employing cell-type-specific genetic manipulation in murine models, we establish that conditional TOX3 ablation in POMC-lineage cells exacerbates diet-induced obesity and metabolic dysfunction, while its overexpression in these neurons confers robust metabolic benefits. Mechanistically, TOX3 enhances the function of POMC-lineage cells through a post-translational regulatory mechanism involving PTEN proteasomal degradation, leading to potentiated AKT signaling. This central modulation drives sympathetic activation of brown adipose tissues, resulting in enhanced thermogenesis and energy expenditure. Notably, TOX3 exhibits striking neuronal specificity, as both loss- and gain-of-function manipulation in agouti-related peptide (AgRP) neurons produce negligible metabolic consequences. Our work identifies previously unrecognized physiological roles of TOX3 in POMC-lineage cells that are essential for maintaining energy homeostasis in mice, thereby revealing therapeutic opportunities for metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-71575-w
  5. Nat Commun. 2026 Apr 11.
    Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits.
    Clair Crewe, Christy M Gliniak, Toshiharu Onodera, Shiuhwei Chen, Jan-Bernd Funcke, May-Yun Wang, Snigdha Tiash, Yun-Ling Pai, Marjori Russo, Saket Awadhesbhai Patel, Ze Yu, Yi-Cian Zheng, Alex Larkin, Chao Xing, Laurent Gautron, Chun-Kan Chen, Chen Liu, Philipp E Scherer.
      Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discover that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.
    DOI:  https://doi.org/10.1038/s41467-026-71740-1
  6. Nat Rev Immunol. 2026 Apr 15.
    Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
    Neil T Sprenkle, Evanna L Mills.
      Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s41577-026-01292-4
  7. Nat Commun. 2026 Apr 11.
    Adipocyte small extracellular vesicle-derived microRNA-30a-3p exacerbates hepatic steatosis in high fat diet-fed male mice.
    Tian Zhang, Longkun Hu, Diao Chen, Yongxin Chen, Fei Zhou, Ruohan Lou, Yuxia Zhou, Yuanyuan Wang, Mingjun Shi, Ke-Gang Linghu, Ligen Lin, Bing Guo.
      Adipose tissue dysfunction drives hepatic lipid overload in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the involvement of adipose tissue-derived small extracellular vesicles (sEVs) remains unclear. Herein, we showed that transplanting adipose tissue from high‑fat diet (HFD)-fed male mice exacerbated insulin resistance and hepatic steatosis in lean recipients. Adipose‑specific Sirt3 overexpression (Sirt3AKI) alleviated insulin resistance and liver steatosis in HFD-fed male mice, whereas adipose‑specific Sirt3 knockdown aggravated these phenotypes. Moreover, adipose sEV miRNAs regulated hepatic lipid metabolism in Sirt3AKI male mice. MicroRNA sequencing identified miR-30a-3p was increased in the circulating sEVs from HFD-fed male mice, while decreased in sEVs from Sirt3OE adipocytes and Sirt3AKI male mice. Mechanistically, miR‑30a‑3p promoted hepatic steatosis by targeting Becn1; this process was suppressed when Sirt3 downregulated miR‑30a‑3p transcription via deacetylation of H3K56. These findings highlight the critical role of adipose sEV microRNAs in driving hepatocyte lipotoxicity, and suggest miR-30a-3p inhibition as a promising MASLD therapy.
    DOI:  https://doi.org/10.1038/s41467-026-71731-2
  8. Nat Metab. 2026 Apr 16.
    Longitudinal multimorbidity trajectories shape personalized glycaemic patterns.
    Ke Zhang, Jieteng Chen, Yan Yan, Huijun Wang, Zelei Miao, Wanglong Gou, Congmei Xiao, Ruiqi Shi, Xiaofang Jia, Wenwen Du, Yujing Huang, Tiannan Guo, Chang Su, Yuanqing Fu, Yu-Ming Chen, Ju-Sheng Zheng.
      Older individuals often live with diverse combinations of chronic diseases. However, whether multimorbidity contributes to glycaemic dysregulation remains unclear. Here we show that cumulative disease trajectories shape interindividual glycaemic variability throughout the ageing process. Tracking 1,398 participants in the Guangzhou Nutrition and Health Study cohort over 12 years, we develop a systemic multimorbidity index (MMI-system) that reflects the cumulative burden of chronic disorders. We also measure individual glycaemic dynamics and responses to dietary challenges using continuous glucose monitoring at the latest follow-up visit (mean age, 69.2 years). MMI-system exhibits dose-dependent associations with glycaemic variability and sensitivity to dietary challenges, independent of diabetes status. Longitudinal proteome mapping reveals that lipid homeostasis proteins explain 12.9% of the association between MMI-system and personalized dietary responses. These findings are independently validated in the China Health and Nutrition Survey cohort. Overall, our study suggests that integrating longitudinal multimorbidity profiling with circulating proteomics may enhance precision glycaemic management, offering actionable insights for dietary interventions in the older population.
    DOI:  https://doi.org/10.1038/s42255-026-01512-0
  9. Nat Commun. 2026 Apr 14.
    Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2.
    Yingfan Zhang, Hailey A Parry, Laura Reyes, Alex Shamoun, Junhui Sun, Chengyu Liu, Danielle Springer, Audrey Noguchi, Sachiko Nakamori, Angel M Aponte, Jeeva Munasinghe, Raul Covian, Elizabeth Murphy, Brian Glancy.
      Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na+/Ca2+ exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65 as indispensable for neuronal function. Additionally, skeletal muscle-specific knockout produced adult-onset myopathy preceded by elevated mitochondrial Ca2+. Consistently, TMEM65 ablation caused loss of Na+-dependent mitochondrial Ca2+ export. Notably, blocking mitochondrial Ca2+ entry by mitochondrial calcium uniporter (MCU) knockout rescued the early lethality of whole-body Tmem65 ablation, extending lifespan from ~3 weeks to >1 year. These data reveal an essential physiological role for TMEM65 and suggest that modulating mitochondrial Ca2+ may offer therapeutic value for TMEM65 misexpression and other mitochondrial diseases associated with Ca2+ overload.
    DOI:  https://doi.org/10.1038/s41467-026-71761-w
  10. Nat Commun. 2026 Apr 15.
    The genetic basis for DNA methylation variation across tissues and development.
    Jonathan Rosenski, Ofra Sabag, Eitan Marcus, Netanel Loyfer, Yuval Dor, Howard Cedar, Tommy Kaplan.
      The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.
    DOI:  https://doi.org/10.1038/s41467-026-71693-5
  11. Am J Physiol Endocrinol Metab. 2026 Apr 16.
    Exercise ameliorates adipose tissue insulin resistance by activating the lactate/GPR81 signaling pathway in DIO-IR mice.
    Yihsuan Lin, Ge Song, Yue Chen, Chunyu Liang, Zhen Ni, Lijing Gong, Yi Yan.
      Growing evidence indicates that both exogenous lactate administration and physical exercise improve insulin resistance (IR). This study investigates, from a novel perspective, whether exercise-induced lactate serves as a signaling molecule to ameliorate adipose tissue IR and explores the underlying mechanisms. Using diet-induced obese and insulin-resistant (DIO-IR) mice subjected to high-lactate exercise training, insulin-resistant 3T3-L1 (IR-3T3-L1) adipocytes treated with lactate, and a GPR81-overexpressing cell line, we demonstrate three key findings: First, high-lactate exercise training markedly alleviated adipose tissue and systemic IR in DIO-IR mice. Second, acute high-lactate exercise mirrored the effects of L-lactate injection by elevating circulating and epididymal white adipose tissue (eWAT) lactate concentrations, concomitantly upregulating GPR81 and glucose uptake signaling expression while modulating adipokine secretion. Mechanistically, lactate/GPR81 signaling potentiated glucose uptake in IR-3T3-L1 adipocytes via the IRS1-AKT-GLUT4 pathway. Collectively, these results demonstrate that exercise-induced lactate enhances glucose uptake signaling and rebalances adipokine secretion. It may act as a signaling molecule that upregulates the specific receptor GPR81, thereby alleviating adipose tissue and systemic insulin resistance in diet-induced obese insulin-resistant (DIO-IR) mice. Our findings uncover a previously unrecognized link between exercise metabolism and adipose tissue homeostasis, highlighting lactate as a potential therapeutic target for IR-related metabolic disorders.
    Keywords:  GPR81; adipose tissue; exercise; insulin resistance; lactate
    DOI:  https://doi.org/10.1152/ajpendo.00321.2025
  12. EMBO Rep. 2026 Apr 13.
    5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
    Jimmy Ly, Eric M Smith, Matteo Di Bernardo, Yi Fei Tao, Elizabeth M Black, Ekaterina Khalizeva, Iain M Cheeseman.
      The 5' untranslated region (5' UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5' UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5' UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that endogenous changes in 5' UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5' UTR length, including a deletion in the VHL 5' UTR in von Hippel-Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5' UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding changes can reshape the proteome.
    DOI:  https://doi.org/10.1038/s44319-026-00776-7
  13. Sci Adv. 2026 Apr 17. 12(16): eady9895
    Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.
    Robert Wang, Feng Wang, Nicole DeBruyne, Xinjun Ji, Nicole M Engelhardt, Joseph Jee-Hwan Park, Amber Notaro, Samantha Gaerlan, Ryan Park, Matthew J Schultz, Sheila Clever, Elizabeth M McCormick, Kelsey Keith, Bobby G Ng, Kathryn E Kadash-Edmondson, Hudson H Freeze, Christina T Lam, Eva Morava, Ingo Helbig, Marni J Falk, Rebecca D Ganetzky, Andrew C Edmondson, Lan Lin, Yi Xing.
      Diagnosing rare genetic diseases remains a major challenge despite widespread clinical testing. Long-read RNA sequencing (RNA-seq) offers a powerful approach to capturing the effects of genetic variants on the transcriptome, yet challenges with sequencing coverage, cost, tissue selection, and scalability have limited its clinical adoption. To address this, we developed STRIPE (Sequencing Targeted RNAs Identifies Pathogenic Events), a targeted long-read RNA-seq-based strategy for rare disease diagnosis and variant interpretation. STRIPE enables deep sequencing of full-length transcripts for any customized disease-specific gene panel such that a wide range of clinically informative readouts, including transcript aberrations and sequence variants, can be detected at haplotype-level resolution. Applying STRIPE to 88 individuals spanning two major rare disease groups, we accurately reidentified known pathogenic variants and revealed their transcript consequences, including many unexpected ones. For 8 of 15 splice site region variants, we observed more complex RNA processing defects beyond single exon skipping or cryptic splice site activation. Notably, we find that donor splice site variants frequently activate cryptic intronic polyadenylation sites, leading to premature transcript termination. Leveraging unique strengths of long-read RNA-seq, STRIPE also resolved variants of uncertain significance and uncovered disease-causing variants in five previously undiagnosed individuals. Overall, STRIPE is a powerful, adaptable, and scalable strategy with broad potential to improve clinical variant interpretation and advance genetic diagnosis of rare diseases.
    DOI:  https://doi.org/10.1126/sciadv.ady9895
  14. Sci China Life Sci. 2026 Apr 10.
    Hepatic Sirt2-PARP1-HMGB1 axis promotes exercise-mediated amelioration of MASH in mice.
    Shan Li, Wang-Jing Mu, Zi-Ang Zhao, Wan-Qiu Peng, Jie-Ying Zhu, Ruo-Ying Li, Lin-Jing Yan, Yang Li, Hong-Yang Luo, Min Chen, Meng-Ting Yin, Xin Li, Hu-Min Chen, Ya-Lan Yang, Quan Liu, Le Li, Liang Guo.
      Exercise is an effective non-pharmacological strategy for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanism needs further investigation. Sirtuin 2 (Sirt2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that is expressed in multiple tissues, including the liver, whose role in MASH is not well defined. In our study, exercise induces hepatic Sirt2 expression through the DNA demethylation on the Sirt2 gene promoter mediated by α-ketoglutaric acid (α-KG)/ten-eleven translocation (TET) enzymes axis. Hepatocyte-specific knockout of Sirt2 (Sirt2LKO) increases hepatic lipid accumulation, cell death, inflammation, and fibrosis in MASH diet-fed mice and reduces the protective effects of exercise against MASH, while hepatocyte-specific overexpression of Sirt2 works in concert with exercise to alleviate MASH. Mechanistically, Sirt2 promotes deacetylation and proteasomal degradation of poly (ADP-ribose) polymerase 1 (PARP1) in hepatocytes. This decreases polyADP-ribosylation (PAR) and acetylation of high mobility group box 1 (HMGB1), which inhibits HMGB1 nuclei-to-cytosol translocation and secretion from hepatocytes to attenuate free fatty acids (FFAs)-induced hepatocyte injury and blunts dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells (HSCs). Therefore, by regulating the hepatic PARP1/HMGB1 pathway, Sirt2 acts as a downstream effector of exercise to alleviate MASH.
    Keywords:  HMGB1; MASH; PARP1; Sirtuins 2; exercise
    DOI:  https://doi.org/10.1007/s11427-025-3241-0
  15. Metabolism. 2026 Apr 11. pii: S0026-0495(26)00129-0. [Epub ahead of print]180 156619
    Loss of cardiomyocyte AKT signaling causes deterioration of lipid metabolism and cellular atrophy.
    Stefanie Gödecke, André Heinen, Tim Appel, Phil-Torben Müller, Tim Stemmer, Daniela Müller, Uli Flögel, Diran Herebian, Fiorella A Solari, Rene Deenen, Karl Köhrer, Albert Sickmann, Axel Gödecke.
      The mammalian heart critically depends on oxidative metabolism of fatty acids, glucose, ketones, and amino acids to meet its extensive ATP demands. AKT/protein kinase B plays a central role in regulating cell growth and metabolism by coordinating an anabolic metabolism in response to insulin or IGF1, particularly by elevating glucose uptake and mTOR activity. Here, we investigated the effect of simultaneous deletion of the two major cardiac isoforms AKT1 and AKT2 on the function and metabolism of the adult mouse heart. Inducible cardiomyocyte specific AKT1 AKT2 double knockout mice developed a rapidly progressing and lethal heart failure with extensive cardiomyocyte atrophy. Metabolic analyses of substrate-specific respiration of mitochondria (respirometry) and of isolated cardiac tissue (Seahorse flux analysis) demonstrated that fatty acid metabolism was severely compromised, whereas glucose metabolism was less affected. Volume-specific in vivo NMR spectroscopy and CrCEST (Creatine chemical exchange saturation transfer) imaging revealed a drop of the cardiac phosphocreatine/ATP ratios from 2 to 1.5, indicating severe energetic depletion. Transcriptomic and proteomic studies showed that genes of the TCA cycle, β-oxidation, and oxidative phosphorylation were coordinately down-regulated. Moreover, AKT1/AKT2 deficient cardiomyocytes lost the ability to store fatty acids in lipid droplets (LDs) due to an early loss of perilipins and other proteins involved in LD generation and function. In conclusion, our data show that general, isoform-independent AKT signaling in cardiac myocytes is indispensable for preservation of cardiac fatty acid metabolism and energy supply.
    Keywords:  AKT signaling; Cardiac atrophy; Cardiac lipid metabolism; Heart failure; Perilipins
    DOI:  https://doi.org/10.1016/j.metabol.2026.156619
  16. Nat Cell Biol. 2026 Apr 17.
    SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
    Shanshan Liu, Mark Gad, Caifan Li, Kevin Cho, Yuyang Liu, Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J Patti, Ekaterina V Vinogradova, Richard K Hite, Kıvanç Birsoy.
      The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.
    DOI:  https://doi.org/10.1038/s41556-026-01922-y
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