bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–02–09
seventeen papers selected by
Xiong Weng, University of Edinburgh
  1. Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.
  2. Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes.
  3. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  4. Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.
  5. Lrtm1 - A Novel Sensor of Insulin Signaling and Regulator of Metabolism and Activity.
  6. The metabolic and cardiovascular effects of amphetamine are partially mediated by the central melanocortin system.
  7. Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk.
  8. METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7.
  9. SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.
  10. The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
  11. Adipose tissue-derived microRNA-450a-5p induces type 2 diabetes mellitus by downregulating DUSP10.
  12. Multiomics identify the gene expression signature of the spinal cord during aging process.
  13. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
  14. Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease.
  15. Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target.
  16. Exercise-induced adipokine Nrg4 alleviates MASLD by disrupting hepatic cGAS-STING signaling.
  17. A new gut-brain therapeutic target for hepatic encephalopathy.
  1. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00526-6. [Epub ahead of print]
    Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.
    Fabian S Passini, Bavat Bornstein, Sarah Rubin, Yael Kuperman, Sharon Krief, Evi Masschelein, Tevie Mehlman, Alexander Brandis, Yoseph Addadi, Shira Huri-Ohev Shalom, Erik A Richter, Tal Yardeni, Amir Tirosh, Katrien De Bock, Elazar Zelzer.
      Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.
    Keywords:  PIEZO2; Runx3/PV sensory neurons; body composition; brown and beige adipose tissues; glucose tolerance; insulin sensitivity; mechanosensing; metabolic diseases; norepinephrine; systemic metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.016
  2. Science. 2025 Feb 07. 387(6734): 674-682
    Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes.
    Haaglim Cho, Chien-Cheng Lai, Rémy Bonnavion, Mohamad Wessam Alnouri, ShengPeng Wang, Kenneth Anthony Roquid, Haruya Kawase, Diana Campos, Min Chen, Lee S Weinstein, Alfredo Martínez, Mario Looso, Miloslav Sanda, Stefan Offermanns.
      Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin's actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B-mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide-synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.
    DOI:  https://doi.org/10.1126/science.adr4731
  3. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  4. Nat Commun. 2025 Feb 04. 16(1): 1330
    Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.
    G V Naveen Kumar, Rui-Sheng Wang, Ankit X Sharma, Natalie L David, Tânia Amorim, Daniel S Sinden, Nandini K Doshi, Martin Wabitsch, Sebastien Gingras, Asim Ejaz, J Peter Rubin, Bradley A Maron, Pouneh K Fazeli, Matthew L Steinhauser.
      Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting.
    DOI:  https://doi.org/10.1038/s41467-025-56613-3
  5. Diabetes. 2025 Feb 07. pii: db241031. [Epub ahead of print]
    Lrtm1 - A Novel Sensor of Insulin Signaling and Regulator of Metabolism and Activity.
    Yingying Yu, Guoxiao Wang, Wenqiang Chen, Xiangyu Liu, Vitor Rosetto Munoz, Weikang Cai, Antonio S Gomes, C Ronald Kahn.
      Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here we show that Lrtm1 (Leucine Rich Repeats and Transmembrane Domains 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1 deficient mice exhibit a reduced the percentage of fat mass, increased percentage of lean mass, and enhanced glucose tolerance and insulin sensitivity compared to control mice, under both chow and high fat diet conditions. Lrtm1 whole-body deficiency also affects dopamine signaling in the brain leading to hyperactivity. The improvements in glucose and insulin tolerance, but not the behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. These effects occur with no change in classical insulin receptor-Akt signaling Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel post-receptor regulator of metabolic and behavioral activity.
    DOI:  https://doi.org/10.2337/db24-1031
  6. Cell Rep Med. 2025 Jan 31. pii: S2666-3791(25)00009-6. [Epub ahead of print] 101936
    The metabolic and cardiovascular effects of amphetamine are partially mediated by the central melanocortin system.
    Stephanie E Simonds, Jack T Pryor, Brian Y H Lam, Georgina K Dowsett, Tomris Mustafa, Astrid Munder, Kayla Elysee, Eglantine Balland, Lachlan O Cowley, Giles S H Yeo, Andrew Lawrence, David C Spanswick, Michael A Cowley.
      Amphetamine (AMPH) exerts metabolic and cardiovascular effects. The central melanocortin system is a key regulator of both metabolic and cardiovascular functions. Here, we show that the melanocortin system partially mediates AMPH-induced anorexia, energy expenditure, tachycardia, and hypertension. AMPH increased α-melanocyte stimulating hormone (αMSH) secretion from the hypothalamus, elevated blood pressure and heart rate (HR), increased brown adipose tissue (BAT) thermogenesis, and reduced both food intake (FI) and body weight (BW). In melanocortin 4 receptor-deficient (MC4R knockout [KO]) mice, metabolic and cardiovascular effects of AMPH were significantly attenuated. Antagonism of serotonergic and noradrenergic neurotransmitter systems attenuated AMPH-induced αMSH secretion as well as AMPH-induced metabolic and cardiovascular effects. We propose that AMPH increases serotonergic activation of proopiomelanocortin (POMC) neurons and reduces the noradrenergic inhibition of POMC neurons, thereby disinhibiting them. Together, these presynaptic mechanisms result in increased POMC activity, increased αMSH secretion, and increased activation of MC4R pathways that regulate both the metabolic and cardiovascular systems.
    Keywords:  BAT; MC4R; amphetamine; blood pressure; body weight; cardiovascular; energy expenditure; food intake; hypertension; melanocortin system; obesity; thermogenesis; weight loss
    DOI:  https://doi.org/10.1016/j.xcrm.2025.101936
  7. Cell Metab. 2025 Feb 03. pii: S1550-4131(24)00493-5. [Epub ahead of print]
    Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk.
    Thibaux Van der Stede, Alexia Van de Loock, Guillermo Turiel, Camilla Hansen, Andrea Tamariz-Ellemann, Max Ullrich, Eline Lievens, Jan Spaas, Nurten Yigit, Jasper Anckaert, Justine Nuytens, Siegrid De Baere, Ruud Van Thienen, Anneleen Weyns, Laurie De Wilde, Peter Van Eenoo, Siska Croubels, John R Halliwill, Pieter Mestdagh, Erik A Richter, Lasse Gliemann, Ylva Hellsten, Jo Vandesompele, Katrien De Bock, Wim Derave.
      Plasticity of skeletal muscle is induced by transcriptional and translational events in response to exercise, leading to multiple health and performance benefits. The skeletal muscle microenvironment harbors myofibers and mononuclear cells, but the rich cell diversity has been largely ignored in relation to exercise adaptations. Using our workflow of transcriptome profiling of individual myofibers, we observed that their exercise-induced transcriptional response was surprisingly modest compared with the bulk muscle tissue response. Through the integration of single-cell data, we identified a small mast cell population likely responsible for histamine secretion during exercise and for targeting myeloid and vascular cells rather than myofibers. We demonstrated through histamine H1 or H2 receptor blockade in humans that this paracrine histamine signaling cascade drives muscle glycogen resynthesis and coordinates the transcriptional exercise response. Altogether, our cellular deconstruction of the human skeletal muscle microenvironment uncovers a histamine-driven intercellular communication network steering muscle recovery and adaptation to exercise.
    Keywords:  crosstalk; exercise; glycogen; histamine; macrophages; mast cells; metabolism; muscle fibers; skeletal muscle; transcriptomics
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.011
  8. Cell Death Discov. 2025 Feb 01. 11(1): 37
    METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7.
    Linnan Li, Hao Cheng, Yufei Zhou, Di Zhao, Xiaoxue Zhang, Yajun Wang, Jianying Ma, Junbo Ge.
      N6-methyladenosine (m6A) mRNA modification is the most common mRNA internal modification in eukaryotes, which participates in a variety of biological processes. However, the role of m6A methylation in regulating autophagy induced by ischemia and hypoxia remains to be widely investigated. Here, we investigated the impact of METTL3, a key m6A methyltransferase, on the autophagy regulation in ischemic and hypoxic cardiomyocytes, as well as in mice following acute myocardial infarction (AMI). METTL3 negatively regulated autophagy in cardiomyocytes under ischemia and hypoxia conditions. Silencing METTL3 enhanced autophagy and mitigated cardiomyocyte injury, whereas overexpression of METTL3 exerted the opposite effect. Mechanistically, METTL3 methylated ATG7 mRNA, a crucial autophagy-related gene, leads to the recruitment of the m6A-binding protein YTHDF2. Subsequently, YTHDF2 facilitated the degradation of ATG7 mRNA, consequently inhibiting autophagy and exacerbating cellular damage. Our study shed light on the pivotal role of METTL3-mediated m6A modification in the regulation of autophagy during AMI, providing novel insights into the functional significance of m6A methylation and its regulatory mechanisms.
    DOI:  https://doi.org/10.1038/s41420-025-02320-3
  9. Genome Biol. 2025 Feb 05. 26(1): 22
    SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.
    Ryan T Wagner, Ryan A Hlady, Xiaoyu Pan, Liguo Wang, Sungho Kim, Xia Zhao, Louis Y El Khoury, Shafiq Shaikh, Jian Zhong, Jeong-Heon Lee, Jolanta Grembecka, Tomasz Cierpicki, Thai H Ho, Keith D Robertson.
       BACKGROUND: SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor function. SETD2 mutation promotes the epithelial-mesenchymal transition and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation.
    RESULTS: We employ an unbiased genome-wide synthetic lethal screen, which identifies another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction is performed in isogenic clear cell renal cell carcinoma and immortalized renal epithelial cell lines, in mouse and human backgrounds. Depletion of NSD1 using a CRISPRi targeting approach promotes the loss of SETD2-mutant cells coincident with elevated levels of DNA damage and apoptosis. Surprisingly, only suppression of NSD1, but not related H3K36-methyltransferases, promotes synthetic lethality in these models. Mapping of genomic H3K36me2 targeting by NSD1 and NSD2 individually highlights the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle, we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using BT5, a first-in-class pharmacologic inhibitor against NSD1.
    CONCLUSIONS: These findings unify genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach to individualize therapies against a challenging loss-of-function SETD2 mutation in cancer.
    Keywords:  CRISPRi; Clear cell renal cell carcinoma (ccRCC); Epithelial-mesenchymal transition (EMT); Histone 3, lysine 36, tri-methylation (H3K36me3); Homologous recombination (HR); Homology-directed repair (HDR); NSD1; SETD2; Synthetic lethality (SL)
    DOI:  https://doi.org/10.1186/s13059-025-03483-z
  10. Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00036-X. [Epub ahead of print]85(3): 638-651.e9
    The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
    Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen.
      Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.
    Keywords:  DNAJC; OGDH; TCAIM; charperon; metabolism; mitochondria; protein degradation; protein interaction; single-particle cryo-EM; α-ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.006
  11. Mol Biomed. 2025 Feb 06. 6(1): 7
    Adipose tissue-derived microRNA-450a-5p induces type 2 diabetes mellitus by downregulating DUSP10.
    Jiaojiao Zhu, Yanting Hou, Wei Yu, Jingzhou Wang, Xiaolong Chu, Xueting Zhang, Huai Pang, Dingling Ma, Yihan Tang, Menghuan Li, Chenggang Yuan, Jianxin Xie, Cuizhe Wang, Jun Zhang.
      Type 2 diabetes mellitus (T2DM) has rapidly increased worldwide, emerging as the fifth leading cause of death. The treatment of T2DM is challenging due to the side effects of oral hypoglycemic drugs and the limited efficacy of long-term insulin therapy, which can lead to insulin resistance (IR). Consequently, there is significant in discovering new drugs that have minimal side effects and a pronounced hypoglycemic effect. In obesity, microRNA levels have been implicated in glucose metabolism disorders and T2DM, although many aspects remain unresolved. Here, we confirmed that visceral adipose tissue and serum microRNA-450a-5p content increased under obesity and T2DM, and it was significantly positively associated with fasting blood glucose, triglycerides, cholesterol, low-density lipoproteins-cholesterol levels of the subjects. In high-fat diet (HFD)-induced obese mice, microRNA-450a-5p expression was increased in the serum, liver, and white adipose tissue. Moreover, the adipose Dicer-knockout mouse model was constructed to identify adipose tissue as the main source of microRNA-450a-5p. microRNA-450a-5p could inactivate the insulin signal pathway by targeting the inhibited Dual Specificity Phosphatase 10 (DUSP10) and inducing IR and glucose metabolism disorders in vitro cultured hepatocytes and adipocytes. Additionally, microRNA-450a-5p was found to regulate DUSP10 expression and insulin signaling activity, influencing glucose tolerance and insulin sensitivity across various models, including normal diet, HFD-induced obese, adipose tissue-specific microRNA-450a-5p-knockout, and db/db mice. Furthermore, gallic acid might play a potential role in inhibiting glucose levels by decreasing microRNA-450a-5p expression. Thus, microRNA-450a-5p emerges as an attractive therapeutic target for addressing obesity, IR, and T2DM.
    Keywords:  DUSP10; Obesity; T2DM; microRNA-450a-5p
    DOI:  https://doi.org/10.1186/s43556-025-00247-w
  12. Commun Biol. 2025 Feb 07. 8(1): 193
    Multiomics identify the gene expression signature of the spinal cord during aging process.
    Lintao Xu, Jingyu Wang, Jinjie Zhong, Weiwei Lin, Gerong Shen, Ning He, Xingjia Mao, Chunyan Fu, Zhaobo Huang, Fengdong Zhao, Xin Ye, Yongjian Zhu, Mingzhi Zheng, Hui Li, Lin-Lin Wang, Kai Zhong, Lijun Zhu, Ying-Ying Chen.
      Age-related long-term disability is attracting increasing attention due to the growing ageing population worldwide. However, the current understanding of the senescent spinal cord remains insufficient. Bulk RNA sequencing reveals that 526 genes are upregulated and 300 genes are downregulated in senescent spinal cords. Pathway enrichment analysis of differentially expressed genes shows that senescence in spinal cords is related to phagosome function, neuroinflammation, ferroptosis, and necroptosis. Prediction of upstream transcription factors and interactome analysis identify Spi1 as a transcription factor that potentially plays a core role in senescent spinal cords. Spatial transcriptomics illustrates the spatial distribution of the transcriptomic landscape in both young and senescent spinal cords and identifies distinct neuronal and glial subtypes. The ferroptosis-associated gene Fth1 is upregulated in aged spinal cords. Flow cytometry reveals increased accumulation of free Fe2+ and ROS in senescent mixed glial cells; however, CCK-8 assays reveal that these cells are resistant to ferroptosis. SiRNA and lentivirus experiments indicate that the overexpression of Fth1 in normal mixed glial cells reduces their sensitivity to ferroptosis, whereas Fth1 knockdown increases their sensitivity to ferroptosis. In summary, spatial and bulk transcriptomics elucidate the transcriptional characteristics of young versus senescent spinal cords, thus highlighting the role of Fth1 in mediating ferroptosis resistance in senescent mixed glial cells.
    DOI:  https://doi.org/10.1038/s42003-025-07475-4
  13. Science. 2025 Feb 06. eadf2034
    Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
    Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.
      Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
    DOI:  https://doi.org/10.1126/science.adf2034
  14. Cell Death Discov. 2025 Feb 05. 11(1): 49
    Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: driving forces in the progression of metabolic dysfunction-associated steatotic liver disease.
    Yihuai He, Jinlian Jiang, Lili Ou, Yunfen Chen, Aikedaimu Abudukeremu, Guimei Chen, Weiwei Zhong, Zhigang Jiang, Nuerbiye Nuermaimaiti, Yaqun Guan.
      RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study explored the relationship between impaired RelA signaling and lipid metabolism disorders in hepatocytes, and how they synergistically contribute to the advancement of MASLD. We assessed the changes, regulatory relationships, and impacts of RelA signaling and lipid metabolism remodeling on disease progression both in vitro and in vivo. During MASLD, there was a decrease in the expression of RelA and hepatocyte nuclear factor 1 alpha (HNF1α), with both factors showing mutual enhancement of each other's expression under normal conditions. This synergistic effect was absent during hepatocyte steatosis. RelA or HNF1α depletion in hepatocytes intensified MASLD symptoms, whereas overexpression of RELA or treatment with necrostatin-1 (a necroptosis inhibitor) or Z-VAD (a caspase inhibitor) significantly mitigated these effects. Mechanistically, during hepatic steatosis, altered lipid profiles exhibited lipotoxicity, inducing hepatocyte apoptosis and necroptosis, whereas endoplasmic reticulum (ER) stress triggered lipid remodeling processes similar to those observed in MASLD. RelA signaling upregulated the expression of activating transcription factor 4 and glucose-regulated protein 78, thereby alleviating ER stress. Impaired RelA signaling remodeled the ER stress response and lipid metabolism, and enhanced lipid accumulation and lipid toxicity. In conclusion, impaired RelA signaling and disrupted lipid metabolism form a detrimental feedback loop in hepatocytes that promotes MASLD progression. Lipid accumulation suppresses RelA signaling, remodeling the ER stress response and exacerbating lipid metabolism disorder, ultimately leading to hepatocyte apoptosis and necroptosis.
    DOI:  https://doi.org/10.1038/s41420-025-02312-3
  15. Nat Aging. 2025 Feb 05.
    Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target.
    Xinrong Zuo, Rui Zhao, Minming Wu, Yanyan Wang, Shisheng Wang, Kuo Tang, Yang Wang, Jie Chen, Xiaoxiang Yan, Yang Cao, Tao Li.
      Sarcopenia is a geriatric disorder characterized by a gradual loss of muscle mass and function. Despite its prevalence, the underlying mechanisms remain unclear, and there are currently no approved treatments. In this study, we conducted a comprehensive analysis of the molecular and metabolic signatures of skeletal muscle in patients with impaired muscle strength and sarcopenia using multi-omics approaches. Across discovery and replication cohorts, we found that disrupted branched-chain amino acid (BCAA) catabolism is a prominent pathway in sarcopenia, which leads to BCAA accumulation and decreased muscle health. Machine learning analysis further supported the causal role of BCAA catabolic dysfunction in sarcopenia. Using mouse models, we validated that defective BCAA catabolism impairs muscle mass and strength through dysregulated mTOR signaling, and enhancing BCAA catabolism by BT2 protects against sarcopenia in aged mice and in mice lacking Ppm1k, a positive regulator of BCAA catabolism in skeletal muscle. This study highlights improving BCAA catabolism as a potential treatment of sarcopenia.
    DOI:  https://doi.org/10.1038/s43587-024-00797-8
  16. Cell Rep. 2025 Jan 30. pii: S2211-1247(25)00022-1. [Epub ahead of print]44(2): 115251
    Exercise-induced adipokine Nrg4 alleviates MASLD by disrupting hepatic cGAS-STING signaling.
    Min Chen, Yang Li, Jie-Ying Zhu, Wang-Jing Mu, Hong-Yang Luo, Lin-Jing Yan, Shan Li, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo.
      Exercise is an effective non-pharmacological strategy for ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD). Neuregulin-4 (Nrg4) is an adipokine with a potential role in metabolic homeostasis. Previous findings have shown that Nrg4 is upregulated by exercise and that Nrg4 reduces hepatic steatosis, but the underlying mechanism is not fully understood. Here, we show that adipose Nrg4 is transactivated by Pparγ in response to exercise in mice. Adeno-associated virus (AAV)-mediated knockdown of adipose Nrg4 as well as hepatocyte-specific knockout of Erbb4 (Nrg4 receptor) impair exercise-mediated alleviation of MASLD in mice. Conversely, AAV-mediated overexpression of adipose Nrg4 mitigates MASLD in mice in synergy with exercise. Mechanistically, Nrg4/Erbb4/AKT signaling promotes cyclic guanosine monophosphate-AMP synthase (cGAS) phosphorylation to blunt its enzyme activity, thereby inhibiting cGAS-STING pathway-mediated inflammation and steatosis in hepatocytes. Thus, Nrg4 functions as an exercise-induced adipokine that participates in adipose-liver tissue communication to counteract MASLD.
    Keywords:  AKT; CP: Immunology; CP: Metabolism; Erbb4; MASLD; Nrg4; PPARγ; STING; cGAS; exercise; hepatic steatosis; inflammation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115251
  17. Nat Med. 2025 Feb 07.
    A new gut-brain therapeutic target for hepatic encephalopathy.
    Patricia P Bloom.
      
    DOI:  https://doi.org/10.1038/s41591-024-03467-9
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