bims-obesme Biomed News
on Obesity metabolism
Issue of 2024‒05‒05
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to promote insulin sensitivity and metabolic homeostasis.
  2. Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity.
  3. Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.
  4. Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.
  5. TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes.
  6. The Essential Role of Architectural Noncoding RNA Neat1 in Cold-Induced Beige Adipocyte Differentiation in Mice.
  7. Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.
  8. The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
  9. Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.
  10. Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
  11. Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.
  1. Immunity. 2024 Apr 25. pii: S1074-7613(24)00207-3. [Epub ahead of print]
    Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to promote insulin sensitivity and metabolic homeostasis.
    Gang Wang, Andrés R Muñoz-Rojas, Raul German Spallanzani, Ruth A Franklin, Christophe Benoist, Diane Mathis.
      Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect. Transcriptional comparison of adipocyte precursors, matured in the presence or absence of the eVAT-Treg-conditioned medium, identified the oncostatin-M (OSM) signaling pathway as a key distinction. Addition of OSM to in vitro cultures blocked the differentiation of adipocyte precursors, while co-addition of anti-OSM antibodies reversed the ability of the eVAT-Treg-conditioned medium to inhibit in vitro adipogenesis. Genetic depletion of OSM (specifically in Treg) cells or of the OSM receptor (specifically on stromal cells) strongly impaired insulin sensitivity and related metabolic indices. Thus, Treg-cell-mediated control of local progenitor cells maintains adipose tissue and metabolic homeostasis, a regulatory axis seemingly conserved in humans.
    Keywords:  adipose tissue; oncostatin M; progenitor cells; regulatory T cells; stromal cells
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.002
  2. J Biol Chem. 2024 Apr 26. pii: S0021-9258(24)01829-5. [Epub ahead of print] 107328
    Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity.
    Debarun Patra, Palla Ramprasad, Shivam Sharma, Upalabdha Dey, Vinod Kumar, Satpal Singh, Suman Dasgupta, Aditya Kumar, Kulbhushan Tikoo, Durba Pal.
      Management of chronic obesity-associated metabolic disorders is a key challenge for biomedical researchers. During chronic obesity, visceral adipose tissue (VAT) undergoes substantial transformation characterized by a unique lipid-rich hypoxic AT microenvironment (ATenv) which plays a crucial role in VAT dysfunction, leading to insulin resistance (IR) and type 2 diabetes(T2D). Here, we demonstrate that obese ATenv triggers the release of miR-210-3p microRNA-loaded extracellular vesicles (EVs) from adipose tissue macrophages (ATMs), which disseminate miR-210-3p to neighboring adipocytes, skeletal muscle cells, and hepatocytes through paracrine and endocrine actions, thereby influencing insulin sensitivity. Moreover, EVs collected from Dicer-silenced miR-210-3p-overexpressed bone marrow-derived macrophages (BMDMs), induce glucose intolerance and IR in lean mice. Mechanistically, miR-210-3p interacts with the 3'-UTR of GLUT4 mRNA and silences its expression, compromising cellular glucose uptake and insulin sensitivity. Therapeutic inhibition of miR-210-3p in VAT notably rescues high-fat diet (HFD)-fed mice from obesity-induced systemic glucose intolerance. Thus, targeting ATM-specific miR-210-3p during obesity could be a promising strategy for managing IR and T2D.
    Keywords:  Adipose tissue microenvironment; Extracellular vesicles; GLUT4; Insulin resistance; Obesity; miR-210-3p
    DOI:  https://doi.org/10.1016/j.jbc.2024.107328
  3. Nat Metab. 2024 May 01.
    Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.
    MoTrPAC Study Group
      Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.
    DOI:  https://doi.org/10.1038/s42255-023-00959-9
  4. Cell Rep. 2024 Apr 27. pii: S2211-1247(24)00497-2. [Epub ahead of print]43(5): 114169
    Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.
    Derek Lee, Abigail M Benvie, Benjamin M Steiner, Nikolai J Kolba, Josie G Ford, Sean M McCabe, Yuwei Jiang, Daniel C Berry.
      Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.
    Keywords:  CP: Immunology; CP: Metabolism; Cxcl2; brown adipocytes; macrophage; smooth muscle cells; sympathetic innervation; thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114169
  5. Autophagy. 2024 Apr 30. 1-21
    TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes.
    Tian Zhang, Ke-Gang Linghu, Jia Tan, Mingming Wang, Diao Chen, Yan Shen, Junchao Wu, Mingjun Shi, Yuxia Zhou, Lei Tang, Lirong Liu, Zheng-Hong Qin, Bing Guo.
      Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.
    Keywords:  Chaperone-mediated autophagy; TIGAR; lipid metabolism; macroautophagy; obesity
    DOI:  https://doi.org/10.1080/15548627.2024.2338576
  6. RNA. 2024 May 01. pii: rna.079972.124. [Epub ahead of print]
    The Essential Role of Architectural Noncoding RNA Neat1 in Cold-Induced Beige Adipocyte Differentiation in Mice.
    Hikaru Toya, Yuko Okamatsu-Ogura, Saori Yokoi, Misuzu Kurihara, Mari Mito, Shintaro Iwasaki, Tetsuro Hirose, Shinichi Nakagawa.
      Neat1 is an architectural RNA that provides the structural basis for nuclear bodies known as paraspeckles. Although the assembly processes by which Neat1 organizes paraspeckle components are well-documented, the physiological functions of Neat1 remain less defined. This is partly because Neat1 knockout (KO) mice, lacking paraspeckles, do not exhibit overt phenotypes under normal laboratory conditions. During our search for conditions that elicit clear phenotypes in Neat1 KO mice, we discovered that the differentiation of beige adipocytes-inducible thermogenic cells that emerge upon cold exposure-is severely impaired in these mutant mice. Neat1_2, the architectural isoform of Neat1, is transiently upregulated during the early stages of beige adipocyte differentiation, coinciding with increased paraspeckle formation. Genes with altered expression during beige adipocyte differentiation typically cluster at specific chromosomal locations, some of which move closer to paraspeckles upon cold exposure. These observations suggest that paraspeckles might coordinate the regulation of these gene clusters by controlling the activity of certain transcriptional condensates that co-regulate multiple genes. We propose that our findings highlight a potential role for Neat1 and paraspeckles in modulating chromosomal organization and gene expression, potentially crucial processes for the differentiation of beige adipocytes.
    DOI:  https://doi.org/10.1261/rna.079972.124
  7. Cell Rep. 2024 Apr 30. pii: S2211-1247(24)00470-4. [Epub ahead of print]43(5): 114142
    Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.
    Zihan Yu, Xianju Li, Yanni Quan, Jiawen Chen, Jiarui Liu, Nairen Zheng, Shuwen Liu, Yini Wang, Wanlin Liu, Chen Qiu, Yi Wang, Ruimao Zheng, Jun Qin.
      Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.
    Keywords:  CP: Metabolism; brown adipocyte; itaconate; obesity; proteomics; thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114142
  8. Immunol Rev. 2024 Apr 29.
    The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
    Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu.
      White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.
    Keywords:  immunity; macrophage; metabolism; obesity; white adipose tissue
    DOI:  https://doi.org/10.1111/imr.13338
  9. Nat Metab. 2024 Apr 29.
    Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.
    Sajjad Khani, Hande Topel, Ronja Kardinal, Ana Rita Tavanez, Ajeetha Josephrajan, Bjørk Ditlev Marcher Larsen, Michael James Gaudry, Philipp Leyendecker, Nadia Meincke Egedal, Aylin Seren Güller, Natasa Stanic, Phillip M M Ruppert, Isabella Gaziano, Nils Rouven Hansmeier, Elena Schmidt, Paul Klemm, Lara-Marie Vagliano, Rainer Stahl, Fraser Duthie, Jens-Henning Krause, Ana Bici, Christoph Andreas Engelhard, Sabrina Gohlke, Peter Frommolt, Thorsten Gnad, Alvaro Rada-Iglesias, Marta Pradas-Juni, Tim Julius Schulz, Frank Thomas Wunderlich, Alexander Pfeifer, Alexander Bartelt, Martin Jastroch, Dagmar Wachten, Jan-Wilhelm Kornfeld.
      Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.
    DOI:  https://doi.org/10.1038/s42255-024-01033-8
  10. Nat Metab. 2024 Apr 30.
    Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
    Shan Jiang, Taolin Yuan, Florian A Rosenberger, Arnaud Mourier, Nathalia R V Dragano, Laura S Kremer, Diana Rubalcava-Gracia, Fynn M Hansen, Melissa Borg, Mara Mennuni, Roberta Filograna, David Alsina, Jelena Misic, Camilla Koolmeister, Polyxeni Papadea, Martin Hrabe de Angelis, Lipeng Ren, Olov Andersson, Anke Unger, Tim Bergbrede, Raffaella Di Lucrezia, Rolf Wibom, Juleen R Zierath, Anna Krook, Patrick Giavalisco, Matthias Mann, Nils-Göran Larsson.
      The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3-5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.
    DOI:  https://doi.org/10.1038/s42255-024-01038-3
  11. Epigenetics Chromatin. 2024 Apr 27. 17(1): 12
    Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.
    Bethany C Taylor, Loic H Steinthal, Michelle Dias, Hari Krishna Yalamanchili, Scott A Ochsner, Gladys E Zapata, Nitesh R Mehta, Neil J McKenna, Nicolas L Young, Alli M Nuotio-Antar.
      BACKGROUND: Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT.RESULTS: Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression datasets suggest a role for epigenetic modification of DNA in regulation of gene expression in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT.
    CONCLUSIONS: Our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.
    Keywords:  Brown adipose tissue; DNA methylation; Epigenetics; Gene expression; Histone; Thermogenesis
    DOI:  https://doi.org/10.1186/s13072-024-00536-8
This page is being maintained by Thomas Krichel. It was last updated on 2024‒05‒05 at 9:50.