bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–01–12
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism.
  2. Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
  3. Advancing de novo lipogenesis: Genetic and metabolic insights.
  4. Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution.
  5. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  6. JMJD8 regulates adipocyte hypertrophy through the interaction with Perilipin 2.
  7. Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.
  8. Adipose ZFP36 protects against diet-induced obesity and insulin resistance.
  9. Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
  10. Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.
  11. Host metabolism balances microbial regulation of bile acid signalling.
  12. The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis.
  13. N6-methyladenosine RNA methylation, a new hallmark of metabolic reprogramming in the immune microenvironment.
  1. Nat Commun. 2025 Jan 09. 16(1): 533
    Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism.
    Ling Xiao, Dario F De Jesus, Cheng-Wei Ju, Jiang-Bo Wei, Jiang Hu, Ava DiStefano-Forti, Valeria Salerno Gonzales, Tadataka Tsuji, Siying Wei, Matthias Blüher, Yu-Hua Tseng, Chuan He, Rohit N Kulkarni.
      N6-methyladenosine (m6A) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. In humans and mice with insulin resistance, METTL14 expression differs significantly from BAT and WAT in the context of its correlation with insulin sensitivity. Mettl14-knockout in BAT promotes prostaglandin secretion, improving systemic insulin sensitivity. Conversely, Mettl14-knockout in WAT triggers adipocyte apoptosis and systemic insulin resistance. m6A-seq and RNA-seq integration revealed upregulated prostaglandin biosynthesis pathways in BAT and apoptotic pathways in WAT with Mettl14 deficiency. Stable METTL14-knockout hBAs/hWAs show METTL14-mediated m6A promotes mRNA decay of PTGES2 and CBR1 in hBAs and TRAIL and TNFR1 in hWAs. These data shed light on the ability of m6A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-55694-w
  2. Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01542-0. [Epub ahead of print]44(1): 115191
    Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
    Kylie R VanDerMolen, Martin A Newman, Peter C Breen, Yunjing Gao, Laura A Huff, Robert H Dowen.
      Organisms allocate energetic resources between essential cellular processes to maintain homeostasis and, in turn, maximize fitness. The nutritional regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in Caenorhabditis elegans. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor TRA-1/GLI, but rather via non-canonical signaling that engages mammalian target of rapamycin complex 2 (mTORC2). Hh mutants display impaired lipid homeostasis, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we find that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation to modulate lipid homeostasis. Our findings reveal a non-canonical role for Hh signaling in lipid metabolism via regulation of core homeostatic pathways.
    Keywords:  C. elegans; CP: Metabolism; Hedgehog; LIN-29; autophagy; growth; hepatocytes; lipid metabolism; mTORC2; p38; vitellogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2024.115191
  3. Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00483-2. [Epub ahead of print]37(1): 3-4
    Advancing de novo lipogenesis: Genetic and metabolic insights.
    Sean M Hartig, Mark A Herman.
      De novo lipogenesis (DNL) is the process whereby cells synthesize fatty acids from acetyl-CoA, contributing to steatosis in fatty liver disease. Two new studies, using genetic mouse models, metabolomics, and pharmacology, identified alternative pathways in DNL and unexpected physiological effects when targeting key enzymes in this pathway.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.001
  4. Aging (Albany NY). 2024 Dec 29. 16(22): 13452-13504
    Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution.
    Huige Tong, Xiaolong Guo, Macsue Jacques, Qi Luo, Nir Eynon, Andrew E Teschendorff.
      The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution. Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock's accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer's Disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge-clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally. In summary, this work highlights the importance of dissecting epigenetic clocks and quantifying biological age at cell-type resolution.
    Keywords:  Alzheimer’s disease; DNA methylation; biological aging; cell-type deconvolution; epigenetic clocks; obesity
    DOI:  https://doi.org/10.18632/aging.206184
  5. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  6. Diabetes. 2025 Jan 09. pii: db230883. [Epub ahead of print]
    JMJD8 regulates adipocyte hypertrophy through the interaction with Perilipin 2.
    Dongjoo You, Sona Kang.
      Adipocyte hypertrophy significantly contributes to insulin resistance and metabolic dysfunction. Our previous research established JMJD8 as a mediator of insulin resistance, noting its role in promoting adipocyte hypertrophy within an autonomous adipocyte context. Nevertheless, the precise mechanisms underlying this phenomenon remained elusive. In this study, we employed a proteomics approach to identify Perilipin 2 (PLIN2), a lipid-associated protein, as a binding partner of JMJD8. Our investigations unveiled a robust interaction between JMJD8 and PLIN2, demonstrating its pivotal role in driving adipocyte hypertrophy and promoting insulin resistance. Furthermore, we show that JMJD8 suppresses fasting-induced lipophagy and curtails energy production, which involves inhibition of PLIN2 phosphorylation. These findings underscore the critical roles played by JMJD8 and PLIN2 in governing lipid droplet homeostasis, while also shedding light on a potential regulatory mechanism governing fat store mobilization during energy deprivation.
    DOI:  https://doi.org/10.2337/db23-0883
  7. Sci Immunol. 2025 Jan 10. 10(103): eadl4909
    Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.
    Cody Elkins, Chengyu Ye, Pulavendran Sivasami, Roy Mulpur, Pamela P Diaz-Saldana, Amy Peng, Miaoer Xu, Yeun-Po Chiang, Samara Moll, Dormarie E Rivera-Rodriguez, Luisa Cervantes-Barragan, Tuoqi Wu, Byron B Au-Yeung, Christopher D Scharer, Mandy L Ford, Haydn Kissick, Chaoran Li.
      Regulatory T cells (Tregs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT Tregs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2hi VAT Treg subsets. Treg-specific deletion of Srebf2, the master regulator of cholesterol homeostasis, selectively reduced ST2hi VAT Tregs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2hi VAT Treg subsets after Srebf2 deletion. Srebf2-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2hi VAT Treg accumulation. However, long-term high-fat diet feeding disrupted VAT Treg cholesterol homeostasis and impaired clonal expansion of the ST2hi subset. Restoring Treg cholesterol homeostasis rescued VAT Treg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for Treg-targeted therapies in obesity-associated metabolic diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.adl4909
  8. Metabolism. 2025 Jan 04. pii: S0026-0495(24)00359-7. [Epub ahead of print]164 156131
    Adipose ZFP36 protects against diet-induced obesity and insulin resistance.
    Yang Hu, Jinghan Hai, Yun Ti, Binghui Kong, Guoqing Yao, Yuan Zhao, Chen Zhang, Xuehui Zheng, Chunmei Zhang, Xiangping Ma, Huaitao Yu, Xiaoning Qin, Pavel Kovarik, Cheng Zhang, Shaozhuang Liu, Wencheng Zhang, Jingyuan Li, Peili Bu.
       AIMS: Obesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear.
    METHODS: The expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36AKO) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo.
    RESULTS: Western blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36AKO mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36AKO mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of Sirt1 expression.
    CONCLUSIONS: This study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.
    Keywords:  Adipose; Hypoxia; Lipolysis; Obesity; RNF128; Sirt1; ZFP36
    DOI:  https://doi.org/10.1016/j.metabol.2024.156131
  9. Nature. 2025 Jan;637(8045): E11-E14
    Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
    Max L Valenstein, Pranav V Lalgudi, Jibril F Kedir, Kendall J Condon, Anna Platzek, Daniel G Freund, Martin S Taylor, Yunhan Xu, Raghu R Chivukula, David M Sabatini.
      
    DOI:  https://doi.org/10.1038/s41586-024-07974-0
  10. Nat Genet. 2025 Jan 08.
    Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.
    Tsion Abay, Robert R Stickels, Meril T Takizawa, Benan N Nalbant, Yu-Hsin Hsieh, Sidney Hwang, Catherine Snopkowski, Kenny Kwok Hei Yu, Zaki Abou-Mrad, Viviane Tabar, Brooke E Howitt, Leif S Ludwig, Ronan Chaligné, Ansuman T Satpathy, Caleb A Lareau.
      Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing identifies rare populations that express specific marker transcript combinations, traditional flow sorting requires cell surface markers with high-fidelity antibodies, limiting our ability to interrogate these populations. In addition, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. In the present report, we addressed these limitations by developing Programmable Enrichment via RNA FlowFISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations defined by the abundance of specific RNA transcripts. Across immune populations (n = 184,126 cells) and fresh-frozen and formalin-fixed, paraffin-embedded brain tissue (n = 33,145 nuclei), we demonstrated that programmable sorting logic via RNA-based cytometry can isolate rare cell populations and uncover phenotypic heterogeneity via downstream, high-throughput, single-cell genomics analyses.
    DOI:  https://doi.org/10.1038/s41588-024-02036-7
  11. Nature. 2025 Jan 08.
    Host metabolism balances microbial regulation of bile acid signalling.
    JRI Live Cell Bank
      Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2-4, immune responses5-7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.
    DOI:  https://doi.org/10.1038/s41586-024-08379-9
  12. Cell Rep. 2025 Jan 09. pii: S2211-1247(24)01516-X. [Epub ahead of print]44(1): 115165
    The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis.
    Shangang Zhao, Qingzhang Zhu, Wang-Hsin Lee, Jan-Bernd Funcke, Zhuzhen Zhang, May-Yun Wang, Qian Lin, Bianca Field, Xue-Nan Sun, Guannan Li, Mbolle Ekane, Toshiharu Onodera, Na Li, Yi Zhu, Christine M Kusminski, Terry D Hinds, Philipp E Scherer.
      Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated HSC-specific adiponectin overexpression and null models that demonstrate that HSC-specific adiponectin overexpression dramatically reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression. We identify a local adiponectin-peroxisome proliferator-activated receptor gamma (PPARγ) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.
    Keywords:  CP: Metabolism; PPARγ; adiponectin; liver fibrosis; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2024.115165
  13. Front Immunol. 2024 ;15 1464042
    N6-methyladenosine RNA methylation, a new hallmark of metabolic reprogramming in the immune microenvironment.
    Xiaoyue Li, Lin Peng, Xuelian Yang, Jing Luo, Jianmei Wang, Kelin Mou, Huan Zhou, Yuhao Luo, Li Xiang.
      N6-methyladenosine is one of the most common and reversible post-transcriptional modifications in eukaryotes, and it is involved in alternative splicing and RNA transcription, degradation, and translation. It is well known that cancer cells acquire energy through metabolic reprogramming to exhibit various biological behaviors. Moreover, numerous studies have demonstrated that m6A induces cancer metabolic reprogramming by regulating the expression of core metabolic genes or by activating metabolic signaling pathways. Meanwhile, m6A modifications and related regulators are key targets in the regulation of immune effects. We further summarize how m6A modifications contribute to tumor metabolism, and how these events affect the tumor immune microenvironment, with a specific focus on different cell types. Finally, we focus on the specific applications of this field to tumor immunotherapy. We review the potential role of m6A in metabolic reprogramming of tumor immune microenvironment and its regulatory mechanism, with the aim of providing new targets for tumor metabolic regulation and immunotherapy.
    Keywords:  N6-methyladenosine; immunotherapy; m6A modification; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1464042
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