bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–10–20
sixteen papers selected by
Xiong Weng, University of Edinburgh
  1. Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
  2. Glycerol Kinase Drives Hepatic de novo Lipogenesis and Triglyceride Synthesis in Nonalcoholic Fatty Liver by Activating SREBP-1c Transcription, Upregulating DGAT1/2 Expression, and Promoting Glycerol Metabolism.
  3. Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
  4. Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells.
  5. Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.
  6. Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology.
  7. YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.
  8. Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
  9. The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters.
  10. SOX4 facilitates brown fat development and maintenance through EBF2-mediated thermogenic gene program in mice.
  11. Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.
  12. Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation.
  13. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
  14. Temporal regulation of acetylation status determines PARP1 role in DNA damage response and metabolic homeostasis.
  15. Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
  16. The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity.
  1. J Clin Invest. 2024 Oct 15. pii: e169722. [Epub ahead of print]
    Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
    Andrew LaPoint, Jason M Singer, Daniel Ferguson, Trevor M Shew, M Katie Renkemeyer, Hector H Palacios, Rachael L Field, Sireeesha Yerrathota, Roshan Kumari, Mahalakshmi Shankaran, Gordon I Smith, Jun Yoshino, Mai He, Gary J Patti, Marc K Hellerstein, Samuel Klein, E Matthew Morris, Jonathan R Brestoff, Brian N Finck, Andrew Lutkewitte.
      Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.
    Keywords:  Diabetes; Hepatology; Insulin signaling; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169722
  2. Adv Sci (Weinh). 2024 Oct 17. e2401311
    Glycerol Kinase Drives Hepatic de novo Lipogenesis and Triglyceride Synthesis in Nonalcoholic Fatty Liver by Activating SREBP-1c Transcription, Upregulating DGAT1/2 Expression, and Promoting Glycerol Metabolism.
    Shuyu Ouyang, Shu Zhuo, Mengmei Yang, Tengfei Zhu, Shuting Yu, Yu Li, Hao Ying, Yingying Le.
      Glycerol kinase (GK) participates in triglyceride (TG) synthesis by catalyzing glycerol metabolism. Whether GK contributes to nonalcoholic fatty liver (NAFL) is unclear. The expression of hepatic Gk is found to be increased in diet-induced and genetic mouse models of NAFL and is positively associated with hepatic SREBP-1c expression and TG levels. Cholesterol and fatty acids stimulate GK expression in hepatocytes. In HFD-induced NAFL mice, knockdown of hepatic Gk decreases expression of SREBP-1c and its target lipogenic genes as well as DGAT1/2, increases serum glycerol levels, decreases serum TG levels, and attenuates hepatic TG accumulation. Overexpression of GK in hepatocytes in mice or in culture produces opposite results. Mechanistic studies reveal that GK stimulates SREBP-1c transcription directly by binding to its gene promoter and indirectly by binding to SREBP-1c protein, thereby increasing lipogenic gene expression and de novo lipogenesis. Studies with truncated GK and mutant GKs indicate that GK induces SREBP-1c transcription independently of its enzyme activity. GK contributes to lipid homeostasis under physiological conditions by catalyzing glycerol metabolism rather than by regulating SREBP-1c transcription. Collectively, these results demonstrate that increased hepatic GK promotes de novo lipogenesis and TG synthesis in NAFL by stimulating SREBP-1c transcription and DGAT1/2 expression and catalyzing glycerol metabolism.
    Keywords:  SREBP‐1c; de novo lipogenesis; glycerol kinase; nonalcoholic fatty liver disease; triglyceride
    DOI:  https://doi.org/10.1002/advs.202401311
  3. bioRxiv. 2024 Oct 13. pii: 2024.10.12.618004. [Epub ahead of print]
    Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
    Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Rihao Qu, Manish Mishra, Emily L Goldberg, Sviatoslav Sidorov, Stephen T Yeung, Camille Khairallah, David Gonzalez, Taverlyn M Shepard, Christina Camell, Maxim N Artyomov, Yuval Kluger, Kamal M Khanna, Vishwa Deep Dixit.
      Age-related inflammation or inflammaging is a key mechanism that increases disease burden and may control lifespan. How adipose tissue macrophages (ATMs) control inflammaging is not well understood in part because the molecular identities of niche-specific ATMs are incompletely known. Using intravascular labeling to exclude circulating myeloid cells and subsequent single-cell sequencing with orthogonal validation, we define the diversity and alterations in niche resident ATMs through lifespan. Aging led to depletion of vessel-associated macrophages (VAMs), expansion of lipid-associated macrophages (LAMs), and emergence of a unique subset of CD38+ age-associated macrophages (AAMs) in visceral white adipose tissue (VAT). Interestingly, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting that they are necessary for preventing catecholamine resistance in VAT. These findings reveal specialized ATMs control adipose homeostasis and link inflammation to tissue dysfunction during aging.
    DOI:  https://doi.org/10.1101/2024.10.12.618004
  4. Aging Cell. 2024 Oct 11. e14367
    Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells.
    T Blake Monroe, Ann V Hertzel, Deborah M Dickey, Thomas Hagen, Simon Vergara Santibanez, Islam A Berdaweel, Catherine Halley, Patrycja Puchalska, Ethan J Anderson, Christina D Camell, Paul D Robbins, David A Bernlohr.
      Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) or 4-oxo-2-nonenal (4-ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells. In such cells, lipid enals induced accumulation of γH2AX foci, increased p53 signaling, enhanced expression of p21Cip1, and upregulated the expression and secretion of numerous cytokines, chemokines, and regulatory factors independently from NF-κB activation. Concomitantly, lipid enal treatment resulted in covalent modification of mitochondrial proteins, reduced mitochondrial spare respiratory capacity, altered nucleotide pools, and increased the phosphorylation of AMP kinase. Lipid-induced senescent cells upregulated BCL2L1 (Bcl-xL) and BCL2L2 (Bcl-w). and were resistant to apoptosis while pharmacologic inhibition of BAX/BAK macropores attenuated lipid-induced senescence. In situ, the 4-HNE scavenger L-carnosine ameliorated the development of the cellular senescence, while in visceral fat of obese C57BL/6J mice, L-carnosine reduced the abundance of 4-HNE-modified proteins and blunted the expression of senescence biomarkers CDKN1A (p21Cip1), PLAUR, BCL2L1, and BCL2L2. Taken together, the results suggest that lipid enals are endogenous regulators of cellular senescence and that biogenic lipid-induced senescence (BLIS) may represent a mechanistic link between oxidative stress and age-dependent pathologies.
    Keywords:  4‐HNE; adipose; lipid peroxidation; mitochondrion; senescence
    DOI:  https://doi.org/10.1111/acel.14367
  5. Sci Adv. 2024 Oct 18. 10(42): eadp1115
    Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.
    Carlos G Ardanaz, Aida de la Cruz, Paras S Minhas, Nira Hernández-Martín, Miguel Ángel Pozo, M Pilar Valdecantos, Ángela M Valverde, Palmira Villa-Valverde, Marcos Elizalde-Horcada, Elena Puerta, María J Ramírez, Jorge E Ortega, Ainhoa Urbiola, Cristina Ederra, Mikel Ariz, Carlos Ortiz-de-Solórzano, Joaquín Fernández-Irigoyen, Enrique Santamaría, Gerard Karsenty, Jens C Brüning, Maite Solas.
      Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e., GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1ΔGFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Mechanistically, we observed that GLUT1-deficient astrocytes exhibited increased insulin receptor-dependent ATP release, and that both astrocyte insulin signaling and brain purinergic signaling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its depletion triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis, and cognitive function.
    DOI:  https://doi.org/10.1126/sciadv.adp1115
  6. Nat Metab. 2024 Oct 17.
    Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology.
    A L Madsen, S Bonàs-Guarch, S Gheibi, R Prasad, J Vangipurapu, V Ahuja, L R Cataldo, O Dwivedi, G Hatem, G Atla, M Guindo-Martínez, A M Jørgensen, A E Jonsson, I Miguel-Escalada, S Hassan, A Linneberg, Tarunveer S Ahluwalia, T Drivsholm, O Pedersen, T I A Sørensen, A Astrup, D Witte, P Damm, T D Clausen, E Mathiesen, T H Pers, R J F Loos, L Hakaste, M Fex, N Grarup, T Tuomi, M Laakso, H Mulder, J Ferrer, T Hansen.
      The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3-7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10-14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.
    DOI:  https://doi.org/10.1038/s42255-024-01140-6
  7. Cell Death Discov. 2024 Oct 16. 10(1): 439
    YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.
    Hongna Zuo, Jin Liu, Bin Shen, Yue Sheng, Zhenyu Ju, Hu Wang.
      YTHDC1, a reader of N6-methyladenosine (m6A) modifications on RNA, is posited to exert significant influence over RNA metabolism. Despite its recognized importance, the precise function and underlying mechanisms of YTHDC1 in the preservation of normal hematopoietic stem cell (HSCs) homeostasis remain elusive. Here, we investigated the role of YTHDC1 in normal hematopoiesis and HSCs maintenance in vivo. Utilizing conditional Ythdc1 knockout mice and Ythdc1/Mettl3 double knockout mice, we demonstrated that YTHDC1 is required for HSCs maintenance and self-renewal by regulating microRNA maturation. YTHDC1 deficiency resulted in HSCs apoptosis. Furthermore, we uncovered that YTHDC1 interacts with HP1BP3, a nuclear RNA binding protein involved in microRNA maturation. Deletion of YTHDC1 brought about significant alterations in microRNA levels. However, over-expression of mir-125b, mir-99b, and let-7e partially rescued the functional defect of YTHDC1-null HSCs. Taken together, these findings indicated that the nuclear protein YTHDC1-HP1BP3-microRNA maturation axis is essential for the long-term maintenance of HSCs.
    DOI:  https://doi.org/10.1038/s41420-024-02203-z
  8. Nat Metab. 2024 Oct 18.
    Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
    Xiaomin Zhang, Yali Chen, Geng Sun, Yankang Fei, Ha Zhu, Yanfang Liu, Junyan Dan, Chunzhen Li, Xuetao Cao, Juan Liu.
      Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA-MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01149-x
  9. Sci Signal. 2024 Oct 15. 17(858): eadn6324
    The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters.
    Alba de Juan, Darawan Tabtim-On, Alice Coillard, Burkhard Becher, Christel Goudot, Elodie Segura.
      Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4-induced transcriptional responses and inhibited the IL-4-induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.
    DOI:  https://doi.org/10.1126/scisignal.adn6324
  10. Cell Death Differ. 2024 Oct 15.
    SOX4 facilitates brown fat development and maintenance through EBF2-mediated thermogenic gene program in mice.
    Shuai Wang, Ting He, Ya Luo, Kexin Ren, Huanming Shen, Lingfeng Hou, Yixin Wei, Tong Fu, Wenlong Xie, Peng Wang, Jie Hu, Yu Zhu, Zhengrong Huang, Qiyuan Li, Weihua Li, Huiling Guo, Boan Li.
      Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.
    DOI:  https://doi.org/10.1038/s41418-024-01397-0
  11. Cell Death Dis. 2024 Oct 18. 15(10): 757
    Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity.
    Jean de Lima, Jefferson Antônio Leite, Paulo José Basso, Bruno Ghirotto, Eloisa Martins da Silva, Luisa Menezes-Silva, Meire Ioshie Hiyane, Carolina Purcell Goes, Luiz Lehmann Coutinho, Vinicius de Andrade Oliveira, Niels Olsen Saraiva Câmara.
      Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards pro-inflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-β was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPARγ-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice, which was challenged and confirmed using BMDCs from mice with conditional knockout of Sirt1 in dendritic cells (SIRT1∆). This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway, with significant implications for obesity-related inflammation.
    DOI:  https://doi.org/10.1038/s41419-024-07125-3
  12. Cells. 2024 Oct 05. pii: 1654. [Epub ahead of print]13(19):
    Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation.
    Hongyi Zhou, Vijay Patel, Robert Rice, Richard Lee, Ha Won Kim, Neal L Weintraub, Huabo Su, Weiqin Chen.
      The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis. However, much remains unknown about its role in adipogenesis. Here, we demonstrated that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Inhibition of neddylation by MLN4924 significantly reduced adipogenesis of 3T3-L1 and human stromal vascular cells. Deletion of NAE1, a subunit of the only NEDD8 E1 enzyme, suppressed neddylation and impaired adipogenesis. Neddylation deficiency did not affect mitotic cell expansion. Instead, it disrupted CREB/CEBPβ/PPARγ signaling, essential for adipogenesis. Interestingly, among the neddylation-targeted CUL family members, deletion of CUL3, but not CUL1, CUL2, or CUL4A, largely replicated the adipogenic defects observed with neddylation deficiency. A PPARγ agonist minimally rescued the adipogenic defects caused by the deletion of NAE1 and CUL3. In conclusion, our study demonstrates that neddylation and its targeted CUL3 are crucial for adipogenesis. These findings provide potential targets for therapeutic intervention in obesity and metabolic disorders.
    Keywords:  adipogenesis; metabolism; neddylation; obesity; post-translational modification
    DOI:  https://doi.org/10.3390/cells13191654
  13. Nat Metab. 2024 Oct 14.
    Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
    Ekaterina D Korobkina, Camila Martinez Calejman, John A Haley, Miranda E Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R Green, Paula Vo, Clay F Semenkovich, Jason R Pitarresi, Jessica B Spinelli, Ozkan Aydemir, Christian M Metallo, Matthew D Lynes, Cholsoon Jang, Nathaniel W Snyder, Kathryn E Wellen, David A Guertin.
      Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.
    DOI:  https://doi.org/10.1038/s42255-024-01143-3
  14. Sci Adv. 2024 Oct 18. 10(42): eado7720
    Temporal regulation of acetylation status determines PARP1 role in DNA damage response and metabolic homeostasis.
    Witty Tyagi, Sanjeev Das.
      Poly(ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear protein involved in DNA repair, chromatin structure, and transcription. However, the regulation of its different functions remains poorly understood. Here, we report the role of PARP1 acetylation status in modulating its DNA repair and transactivation functions. We demonstrate that histone deacetylase 5 (HDAC5) determines PARP1 acetylation at Lys498 and Lys521 sites. HDAC5-mediated deacetylation at Lys498 site regulates PARP1 DNA damage response and facilitates efficient recruitment of DNA repair factors at damaged sites, thereby promoting cell survival. Additionally, HDAC5-mediated deacetylation at Lys521 site promotes PARP1 coactivator function, resulting in induction of proliferative and metabolic genes in an activating transcription factor 4-dependent manner. Thus, PARP1 induces metabolic adaptation to spur malignant phenotype. Our studies in mouse tumor models suggest that pharmacological inhibition of PARP1 enzymatic activity does not block tumor progression robustly as transactivation function remains unperturbed. These findings provide key mechanistic insights into PARP1 regulation and expand its role in tumor development.
    DOI:  https://doi.org/10.1126/sciadv.ado7720
  15. Nat Metab. 2024 Oct 15.
    Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
      
    DOI:  https://doi.org/10.1038/s42255-024-01152-2
  16. Sci Immunol. 2024 Oct 18. 9(100): eadg6453
    The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity.
    Sreya Bagchi, Robert Yuan, Han-Li Huang, Weiruo Zhang, David Kung-Chun Chiu, Hyungjoo Kim, Sophia L Cha, Lorna Tolentino, Joshua Lowitz, Yilin Liu, Anna Moshnikova, Oleg Andreev, Sylvia Plevritis, Edgar G Engleman.
      Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell-derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.
    DOI:  https://doi.org/10.1126/sciimmunol.adg6453
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