bims-obesme 2024-06-30 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024‒06‒30
twelve papers selected by
Xiong Weng, University of Edinburgh

Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
Macrophage-derived chemokine CCL22 establishes local LN-mediated adaptive thermogenesis and energy expenditure.
Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.
Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.
Comprehensive Role of GDF15 in Inhibiting Adipogenesis and Hyperlipidemia, Enhancing Cardiovascular Health and Alleviating Inflammation in Metabolic Disorders.
E3 ubiquitin ligase TRIM31 alleviates dopaminergic neurodegeneration by promoting proteasomal degradation of VDAC1 in Parkinson's Disease model.
Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.
HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.
Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress.
MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling.
TERT activation targets DNA methylation and multiple aging hallmarks.
METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.

Nat Commun. 2024 Jun 25. 15(1): 5394

Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.

Bam D Paneru, Julia Chini, Sam J McCright, Nicole DeMarco, Jessica Miller, Leonel D Joannas, Jorge Henao-Mejia, Paul M Titchenell, David M Merrick, Hee-Woong Lim, Mitchell A Lazar, David A Hill.

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.

DOI: https://doi.org/10.1038/s41467-024-49632-z
Sci Adv. 2024 Jun 28. 10(26): eadn5229

Macrophage-derived chemokine CCL22 establishes local LN-mediated adaptive thermogenesis and energy expenditure.

Yexian Yuan, Ruoci Hu, Jooman Park, Shaolei Xiong, Zilai Wang, Yanyu Qian, Zuoxiao Shi, Ruifan Wu, Zhenbo Han, Sang-Ging Ong, Shuhao Lin, Krista A Varady, Pingwen Xu, Daniel C Berry, Gang Shu, Yuwei Jiang.

There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.

DOI: https://doi.org/10.1126/sciadv.adn5229
Sci Adv. 2024 Jun 28. 10(26): eadn4508

Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.

Lingling Zhang, Chenhao Xin, Shuo Wang, Shixuan Zhuo, Jing Zhu, Zi Li, Yuyi Liu, Lifeng Yang, Yan Chen.

Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD+ level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.

DOI: https://doi.org/10.1126/sciadv.adn4508
Nat Commun. 2024 Jun 25. 15(1): 5364

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.

Aslihan Shenol, Ricardo Tenente, Michael Lückmann, Thomas M Frimurer, Thue W Schwartz.

A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding-and back - is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.

DOI: https://doi.org/10.1038/s41467-024-49536-y
Curr Pharm Des. 2024 Jun 26.

Comprehensive Role of GDF15 in Inhibiting Adipogenesis and Hyperlipidemia, Enhancing Cardiovascular Health and Alleviating Inflammation in Metabolic Disorders.

Nikita Nayak, Tuhin Mukherjee, Ashok Pattnaik.

  Growth Differentiation Factor 15 (GDF15) has emerged as a pivotal signaling molecule implicated in diverse physiological processes, spanning metabolic regulation, inflammation, and cardiovascular health. This studyprovides a comprehensive exploration of GDF15's multifaceted role, primarily focusing on its association with obesity-related complications and therapeutic potential. GDF15's involvement in energy homeostasis, specifically its regulation of body weight and appetite through hindbrain neuron activation and the GFRAL-RET signaling pathway, underscores its significance as an appetite-regulating hormone. GDF15's intricate modulation within adipose tissue dynamics in response to dietary changes and obesity, coupled with its influence on insulin sensitivity, highlights its critical role in metabolic health. The manuscript delves into the intricate crosstalk between GDF15 and pathways related to insulin sensitivity, macrophage polarization, and adipose tissue function, elucidating its potential as a therapeutic target for metabolic disorders associated with obesity. GDF15's association with chronic low-grade inflammation and its impact on cardiovascular health, particularly during hyperlipidemia and ischemic events, are explored. The intricate relationship between GDF15 and cardiovascular diseases, including its effects on endothelial function, cardiac hypertrophy, and heart failure, emphasizes its multifaceted nature in maintaining overall cardiovascular well-being. Challenges regarding the therapeutic application of GDF15, such as long-term safety concerns and ongoing clinical investigations, are discussed. Lastly, future research directions exploring GDF15's potential in addressing obesity-related complications and cardiovascular risks are proposed, highlighting its promising role as a therapeutic target in reshaping treatment strategies for obesity and associated health conditions.

Keywords:  GDF15; GFRAL-RET; cardiovascular disease; hyperlipidaemia; insulin sensitivity.; obesity

DOI:  https://doi.org/10.2174/0113816128318741240611114448
Cell Death Differ. 2024 Jun 25.

E3 ubiquitin ligase TRIM31 alleviates dopaminergic neurodegeneration by promoting proteasomal degradation of VDAC1 in Parkinson's Disease model.

Ze Zhao, Xiaomeng Song, Yimeng Wang, Lu Yu, Gan Huang, Yiquan Li, Runzhe Zong, Tengfei Liu, Qiuran Ji, Yi Zheng, Bingyu Liu, Qingfen Zhu, Lin Chen, Chengjiang Gao, Huiqing Liu.

Mitochondrial dysfunction plays a pivotal role in the pathogenesis of Parkinson's disease (PD). As a mitochondrial governor, voltage-dependent anion channel 1 (VDAC1) is critical for cell survival and death signals and implicated in neurodegenerative diseases. However, the mechanisms of VDAC1 regulation are poorly understood and the role of tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase which is enriched in mitochondria, in PD remains unclear. In this study, we found that TRIM31-/- mice developed age associated motor defects and dopaminergic (DA) neurodegeneration spontaneously. In addition, TRIM31 was markedly reduced both in nigrostriatal region of PD mice induced by MPTP and in SH-SY5Y cells stimulated by MPP+. TRIM31 deficiency significantly aggravated DA neurotoxicity induced by MPTP. Mechanistically, TRIM31 interacted with VDAC1 and catalyzed the K48-linked polyubiquitination to degrade it through its E3 ubiquitin ligase activity. In conclusion, we demonstrated for the first time that TRIM31 served as an important regulator in DA neuronal homeostasis by facilitating VDAC1 degradation through the ubiquitin-proteasome pathway. Our study identified TRIM31 as a novel potential therapeutic target and pharmaceutical intervention to the interaction between TRIM31 and VDAC1 may provide a promising strategy for PD.

DOI: https://doi.org/10.1038/s41418-024-01334-1
Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00728-9. [Epub ahead of print]43(7): 114400

Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.

Wei Liang Gan, Xi Ren, Vanessa Hui En Ng, Larry Ng, Yangyang Song, Vincent Tano, Jian Han, Omer An, Jinghe Xie, Bryan Y L Ng, Daryl Jin Tai Tay, Sze Jing Tang, Haoqing Shen, Shruti Khare, Kelvin Han Chung Chong, Dan Yock Young, Bin Wu, Ramanuj DasGupta, Leilei Chen.

  ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.

Keywords:  ADAR1; CP: Cell biology; CP: Immunology; EGFR; HCC; PGRN; RNA editing; immunosuppression; innate immunity; liver inflammation; macrophage infiltration

DOI:  https://doi.org/10.1016/j.celrep.2024.114400
J Clin Invest. 2024 Jun 17. pii: e164249. [Epub ahead of print]134(12):

HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.

Zachary A Bacigalupa, Emily N Arner, Logan M Vlach, Melissa M Wolf, Whitney A Brown, Evan S Krystofiak, Xiang Ye, Rachel A Hongo, Madelyn Landis, Edith K Amason, Kathryn E Beckermann, W Kimryn Rathmell, Jeffrey C Rathmell.

  Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.

Keywords:  Cancer; Cell biology; Hypoxia; Metabolism; Molecular biology

DOI:  https://doi.org/10.1172/JCI164249
Nat Aging. 2024 Jun 25.

Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress.

Kuo Du, Liuyang Wang, Ji Hye Jun, Rajesh K Dutta, Raquel Maeso-Díaz, Seh Hoon Oh, Dennis C Ko, Anna Mae Diehl.

Susceptibility to the biological consequences of aging varies among organs and individuals. We analyzed hepatocyte transcriptomes of healthy young and aged male mice to generate an aging hepatocyte gene signature, used it to deconvolute transcriptomic data from humans and mice with metabolic dysfunction-associated liver disease, validated findings with functional studies in mice and applied the signature to transcriptomic data from other organs to determine whether aging-sensitive degenerative mechanisms are conserved. We discovered that the signature enriches in diseased livers in parallel with degeneration. It is also enriched in failing human hearts, diseased kidneys and pancreatic islets from individuals with diabetes. The signature includes genes that control ferroptosis. Aged mice develop more hepatocyte ferroptosis and liver degeneration than young mice when fed diets that induce metabolic stress. Inhibiting ferroptosis shifts the liver transcriptome of old mice toward that of young mice and reverses aging-exacerbated liver damage, identifying ferroptosis as a tractable, conserved mechanism for aging-related tissue degeneration.

DOI: https://doi.org/10.1038/s43587-024-00652-w
Nat Commun. 2024 Jun 26. 15(1): 5423

MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling.

Hervé Técher, Diyavarshini Gopaul, Jonathan Heuzé, Nail Bouzalmad, Baptiste Leray, Audrey Vernet, Clément Mettling, Jérôme Moreaux, Philippe Pasero, Yea-Lih Lin.

Oncogene-induced senescence (OIS) arrests cell proliferation in response to replication stress (RS) induced by oncogenes. OIS depends on the DNA damage response (DDR), but also on the cGAS-STING pathway, which detects cytosolic DNA and induces type I interferons (IFNs). Whether and how RS and IFN responses cooperate to promote OIS remains unknown. Here, we show that the induction of OIS by the H-RASV12 oncogene in immortalized human fibroblasts depends on the MRE11 nuclease. Indeed, treatment with the MRE11 inhibitor Mirin prevented RS, micronuclei formation and IFN response induced by RASV12. Overexpression of the cytosolic nuclease TREX1 also prevented OIS. Conversely, overexpression of a dominant negative mutant of TREX1 or treatment with IFN-β was sufficient to induce RS and DNA damage, independent of RASV12 induction. These data suggest that the IFN response acts as a positive feedback loop to amplify DDR in OIS through a process regulated by MRE11 and TREX1.

DOI: https://doi.org/10.1038/s41467-024-49740-w
Cell. 2024 Jun 21. pii: S0092-8674(24)00592-0. [Epub ahead of print]

TERT activation targets DNA methylation and multiple aging hallmarks.

Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D Lan, Shan Jiang, Kayla Nutsch, Brittney A Beyer, Luke L Lairson, Adam T Boutin, Michael J Bollong, Peter G Schultz, Ronald A DePinho.

  Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

Keywords:  adult neurogenesis; cognition; epigenetics; inflammation; p16(INK4a); senescence; telomerase; telomere

DOI:  https://doi.org/10.1016/j.cell.2024.05.048
Nat Commun. 2024 Jun 26. 15(1): 5410

METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.

Chen Wang, Hideki Tanizawa, Connor Hill, Aaron Havas, Qiang Zhang, Liping Liao, Xue Hao, Xue Lei, Lu Wang, Hao Nie, Yuan Qi, Bin Tian, Alessandro Gardini, Andrew V Kossenkov, Aaron Goldman, Shelley L Berger, Ken-Ichi Noma, Peter D Adams, Rugang Zhang.

METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.

DOI: https://doi.org/10.1038/s41467-024-49745-5