bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–12–15
twelve papers selected by
Xiong Weng, University of Edinburgh
  1. Emerging debates and resolutions in brown adipose tissue research.
  2. ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools.
  3. The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice.
  4. Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings.
  5. Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions.
  6. Mitochondrial fission is required for thermogenesis in brown adipose tissue.
  7. Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis.
  8. GDF-15 as a proxy for epigenetic aging: associations with biological age markers, and physical function.
  9. Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease.
  10. Establishing Immortalized Brown and White Preadipocyte Cell Lines from Young and Aged Mice.
  11. HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via noncanonical phosphorylation.
  12. Editorial: Frailty- and age-associated diseases: possibilities for intervention.
  1. Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00448-0. [Epub ahead of print]
    Emerging debates and resolutions in brown adipose tissue research.
    Aaron M Cypess, Barbara Cannon, Jan Nedergaard, Lawrence Kazak, Douglas C Chang, Jonathan Krakoff, Yu-Hua Tseng, Camilla Schéele, Jeremie Boucher, Natasa Petrovic, Denis P Blondin, André C Carpentier, Kirsi A Virtanen, Sander Kooijman, Patrick C N Rensen, Cheryl Cero, Shingo Kajimura.
      Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential.
    Keywords:  brown adipose tissue; clinical trials; metabolism; pharmacology; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.002
  2. Sci Transl Med. 2024 Dec 11. 16(777): eadi6682
    ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools.
    Veronica D Dahik, Pukar Kc, Clément Materne, Canelle Reydellet, Marie Lhomme, Céline Cruciani-Guglielmacci, Jessica Denom, Eric Bun, Maharajah Ponnaiah, Florence Deknuydt, Eric Frisdal, Lise M Hardy, Hervé Durand, Isabelle Guillas, Philippe Lesnik, Ivan Gudelj, Gordan Lauc, Maryse Guérin, Anatol Kontush, Antoine Soprani, Christophe Magnan, Marc Diedisheim, Olivier Bluteau, Nicolas Venteclef, Wilfried Le Goff.
      The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.
    DOI:  https://doi.org/10.1126/scitranslmed.adi6682
  3. Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00449-2. [Epub ahead of print]
    The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice.
    Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Valentina Pirro, Margo P Emont, Brian A Droz, Kyla Ai Collins, Chanmin Joung, Mackenzie J Pearson, Corey M James, Gopal J Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A An, Evan D Rosen, Matthew P Coghlan, Ricardo J Samms, Philipp E Scherer, Christine M Kusminski.
      Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance.
    Keywords:  GIP receptor; SERCA pathway; adipose tissue; energy expenditure; obesity; weight loss
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.003
  4. Elife. 2024 Dec 13. pii: RP90419. [Epub ahead of print]12
    Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings.
    DiscovEHR collaboration
      Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.
    Keywords:  NAFLD; Type II diabetes; genetics; genomics; human; mouse; zinc transporter
    DOI:  https://doi.org/10.7554/eLife.90419
  5. Geroscience. 2024 Dec 12.
    Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions.
    Ahmed M Elmansi, Abraham Kassem, Rafael M Castilla, Richard A Miller.
      Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging mice. These included both sexes of GHRKO and Snell Dwarf mutant mice, and in females only of PAPPA KO mice. P65 is also lower in both sexes of mice treated with rapamycin, canagliflozin, meclizine, or acarbose, and in mice undergoing caloric restriction. Two drugs that extend lifespan of male mice, i.e. 17α-estradiol and astaxanthin, however, did not produce lower levels of p65. We also measured other canonical NF-κB signaling regulators, including the activators IKKα and IKKβ and the inhibitor IκB-α. We found that those regulators do not consistently change in a direction that would lead to of NF-κB inhibition. In contrast, we found that NCoR1, an HDAC3 cofactor and a transcription co-repressor that regulates p65 activity, was also downregulated in many of these mouse models. Finally, we report downregulation of three p65 target proteins that regulate the metabolic and inflammatory states of the liver (HNF4α, IL-1β, and CRP) in multiple slow-aging mouse models. Together, these data suggest that NF-κB signaling, might be inhibited in liver of multiple varieties of slow aging mice. This establishes p65 as a potential target for novel longevity interventions.
    Keywords:  Inflammation; Longevity; NCoR1; NF-kB; P65
    DOI:  https://doi.org/10.1007/s11357-024-01466-9
  6. PLoS One. 2024 ;19(12): e0312352
    Mitochondrial fission is required for thermogenesis in brown adipose tissue.
    Yuta Ibayashi, Nao Hasuzawa, Seiji Nomura, Masaharu Kabashima, Ayako Nagayama, Shimpei Iwata, Miyuki Kitamura, Kenji Ashida, Yoshinori Moriyama, Ken Yamamoto, Masatoshi Nomura, Lixiang Wang.
      Brown adipose tissue (BAT) thermogenesis is pivotal for maintaining body temperature and energy balance. Mitochondrial morphology is dynamically controlled by a balance between fusion and fission, which is crucial for cell differentiation, response to metabolic insults, and heat production. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. This study investigates the role of Drp1 in BAT development and thermogenesis by generating Drp1-deficient mice. These mice were created by crossing Drp1 floxed mice with fatty acid-binding protein 4-Cre (aP2-Cre) transgenic mice, resulting in aP2-Cre+/-Drp1flox/flox (aP2-Drp1f/f) mice. The aP2-Drp1f/f mice exhibited severe BAT and brain hypoplasia, with the majority dying within 48 hours postnatally, highlighting Drp1's crucial role in neonatal survival. Impaired thermogenic responses were observed in aP2-Drp1f/f mice, characterized by significantly decreased expression of thermogenic and lipogenic genes in BAT. Ultrastructural analysis revealed disrupted mitochondrial morphology and reduced lipid droplet content in BAT. The few surviving adult aP2-Drp1f/f mice also showed impaired BAT and brain development, along with BAT thermogenesis dysfunction during cold exposure. Our findings underscore the essential role of Drp1-mediated mitochondrial fission in BAT thermogenesis and neonatal survival, providing insights into potential therapeutic approaches for metabolic disorders.
    DOI:  https://doi.org/10.1371/journal.pone.0312352
  7. JHEP Rep. 2025 Jan;7(1): 101230
    Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis.
    Arantza Lamas-Paz, Alejandro Hionides-Gutiérrez, Feifei Guo, Gonzalo Jorquera, Laura Morán-Blanco, Raquel Benedé-Ubieto, Mariana Mesquita, Olga Estévez-Vázquez, Kang Zheng, Marina Mazariegos, Elena Vázquez-Ogando, Elena Blázquez-López, Iris Asensio, Beste Mutlu, Beatriz Gomez-Santos, María Isabel Peligros, Javier Vaquero, Rafael Bañares, Teresa C Delgado, María Luz Martínez-Chantar, Eduardo Martínez-Naves, Carlos Sanz-García, Mohamed Ramadan Mohamed, Sofía Tesolato, Pilar Iniesta, Rocío Gallego-Durán, Douglas Maya-Miles, Javier Ampuero, Manuel Romero-Gómez, Ana Martínez-Alcocer, David Sanfeliu-Redondo, Anabel Fernández-Iglesias, Jordi Gracia-Sancho, Mar Coll, Isabel Graupera, Pere Ginès, Andrea Ciudin, Jesús Rivera-Esteban, Juan M Pericàs, Matías A Ávila, Maria Dolores Frutos, Carlos Manuel Martínez-Cáceres, Bruno Ramos-Molina, Patricia Aspichueta, Pere Puigserver, Yulia A Nevzorova, Francisco Javier Cubero.
       Background & Aims: Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD.
    Methods: CDKN1A expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a -/- and Cdkn1a +/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH (ethanol) binges, or a DuAL diet (metabolic dysfunction-associated fatty liver disease and alcohol-related liver). Primary hepatocytes were isolated and functional assays performed.
    Results: A significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAFLD Activity Score and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a +/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a -/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in fatty acid oxidation and reduction in free fatty acid uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals.
    Conclusions: Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAFLD Activity Score and fibrosis in patients with SLD. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in patients with SLD, with and without alcohol consumption.
    Impact and implications: Expression of p21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD), but the molecular mechanisms remain elusive. Interestingly, in this study we found that Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis, via the AMPK-SIRT3 axis. Translationally, Cdkn1a expression was found to be directly correlated with increased severity of NAFLD Activity Score (NAS) and fibrosis in SLD patients, and therefore, CDKN1A might be used potential theragnostic target for the treatment of metabolically induced SLD, with and without alcohol consumption.
    Keywords:  CDKN1A; Hepatocyte; Metabolic dysregulation; Palbociclib; Senescence; Steatotic liver disease (SLD)
    DOI:  https://doi.org/10.1016/j.jhepr.2024.101230
  8. Biogerontology. 2024 Dec 07. 26(1): 22
    GDF-15 as a proxy for epigenetic aging: associations with biological age markers, and physical function.
    Margalida Torrens-Mas, Cayetano Navas-Enamorado, Aina Galmes-Panades, Luis Masmiquel, Andrés Sanchez-Polo, Xavier Capo, Marta Gonzalez-Freire.
      Growth differentiation factor 15 (GDF-15) has emerged as a significant biomarker of aging, linked to various physiological and pathological processes. This study investigates circulating GDF-15 levels in a cohort of healthy individuals from the Balearic Islands, exploring its associations with biological age markers, including multiple DNA methylation (DNAm) clocks, physical performance, and other age-related biomarkers. Seventy-two participants were assessed for general health, body composition, and physical function, with GDF-15 levels quantified using ELISA. Our results indicate that GDF-15 levels significantly increase with age, particularly in individuals over 60. Strong positive correlations were observed between GDF-15 levels and DNAm GrimAge, DNAm PhenoAge, Hannum, and Zhang clocks, suggesting that GDF-15 could serve as a proxy for epigenetic aging. Additionally, GDF-15 levels were linked to markers of impaired glycemic control, systemic inflammation, and physical decline, including decreased lung function and grip strength, especially in men. These findings highlight the use of GDF-15 as a biomarker for aging and age-related functional decline. Given that GDF-15 is easier to measure than DNA methylation, it has the potential to be more readily implemented in clinical settings for broader health assessment and management.
    Keywords:  Aging; Biological aging; Epigenetic clocks; GDF-15; Inflammation; Physical performance
    DOI:  https://doi.org/10.1007/s10522-024-10165-z
  9. Nat Med. 2024 Dec;30(12): 3624-3633
    Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease.
    Violeta Raverdy, Federica Tavaglione, Estelle Chatelain, Guillaume Lassailly, Antonio De Vincentis, Umberto Vespasiani-Gentilucci, Sami F Qadri, Robert Caiazzo, Helene Verkindt, Chiara Saponaro, Julie Kerr-Conte, Gregory Baud, Camille Marciniak, Mikael Chetboun, Naima Oukhouya-Daoud, Samuel Blanck, Jimmy Vandel, Lisa Olsson, Rima Chakaroun, Viviane Gnemmi, Emmanuelle Leteurtre, Philippe Lefebvre, Joel T Haas, Hannele Yki-Järvinen, Sven Francque, Bart Staels, Carel W Le Roux, Valentina Tremaroli, Philippe Mathurin, Guillemette Marot, Stefano Romeo, François Pattou.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits considerable variability in clinical outcomes. Identifying specific phenotypic profiles within MASLD is essential for developing targeted therapeutic strategies. Here we investigated the heterogeneity of MASLD using partitioning around medoids clustering based on six simple clinical variables in a cohort of 1,389 individuals living with obesity. The identified clusters were applied across three independent MASLD cohorts with liver biopsy (totaling 1,099 participants), and in the UK Biobank to assess the incidence of chronic liver disease, cardiovascular disease and type 2 diabetes. Results unveiled two distinct types of MASLD associated with steatohepatitis on histology and liver imaging. The first cluster, liver-specific, was genetically linked and showed rapid progression of chronic liver disease but limited risk of cardiovascular disease. The second cluster, cardiometabolic, was primarily associated with dysglycemia and high levels of triglycerides, leading to a similar incidence of chronic liver disease but a higher risk of cardiovascular disease and type 2 diabetes. Analyses of samples from 831 individuals with available liver transcriptomics and 1,322 with available plasma metabolomics highlighted that these two types of MASLD exhibited distinct liver transcriptomic profiles and plasma metabolomic signatures, respectively. In conclusion, these data provide preliminary evidence of the existence of two distinct types of clinically relevant MASLD with similar liver phenotypes at baseline, but each with specific underlying biological profiles and different clinical trajectories, suggesting the need for tailored therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41591-024-03283-1
  10. Curr Protoc. 2024 Dec;4(12): e70072
    Establishing Immortalized Brown and White Preadipocyte Cell Lines from Young and Aged Mice.
    Xiangdong Wu, Salaheldeen Elsaid, Florian Levet, Winson Li, Sui Seng Tee.
      Studying adipogenesis and adipocyte biology requires the isolation of primary preadipocytes from adipose tissues. However, primary preadipocytes have a limited lifespan, can only undergo a finite number of divisions, and often lose their original biological characteristics before becoming senescent. The repeated isolation of fresh preadipocytes, particularly from young pups or aged animals, is costly and time consuming. Immortalization of these cells offers a solution by overcoming cellular senescence and maintaining proliferative capacity, allowing for long-term studies without the continuous need to isolate new cells from animals. Immortalized cell lines thus provide a consistent and reproducible experimental model, significantly reducing variability across different animals. However, successfully establishing immortalized preadipocyte cell lines presents challenges, including selecting appropriate adipose tissue depots, isolating primary preadipocytes, and choosing an effective immortalization strategy. In this article, we present optimized protocols and share first-hand experiences establishing immortalized brown and white preadipocyte cell lines from young and aging mice. These protocols offer a valuable resource for researchers studying adipogenesis and metabolism. © 2024 Wiley Periodicals LLC. Support Protocol 1: Retrovirus production Basic Protocol 1: Isolation and culture of primary brown and white preadipocytes from mouse interscapular brown adipose tissue (iBAT) and subcutaneous white adipose tissue (sWAT) in the same region Basic Protocol 2: Immortalization of mouse brown and white preadipocytes Basic Protocol 3: Selection of immortalized preadipocytes Basic Protocol 4: Selection of single-cell clones of immortalized mouse preadipocytes Basic Protocol 5: Single-cell sorting in a 96-well plate using a flow cytometer for the selection of single-cell clones of immortalized preadipocytes Support Protocol 2: Cryopreservation of immortalized mouse preadipocytes Support Protocol 3: Thawing and culture of cryopreserved immortalized mouse preadipocytes Support Protocol 4: Subculture and expansion of immortalized mouse preadipocytes Basic Protocol 6: Differentiation of immortalized mouse brown and white preadipocytes Support Protocol 5: Identification of differentiated white and brown adipocytes.
    Keywords:  aging preadipocytes; brown preadipocytes; immortalized cell lines; white preadipocytes; young preadipocytes
    DOI:  https://doi.org/10.1002/cpz1.70072
  11. Hepatology. 2024 Nov 13.
    HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via noncanonical phosphorylation.
    Zhongqiu Pang, Hui Zhang, Shaoqin Zheng, Xueling Yang, Chang Liu, Qing Han, Yi Chen, Zexu Li, Xi Zhang, Liu Cao, Qiang Wang, Yanli Cao, Xun Sun, Pu Zhao, Xuexin Li, Qianqian Zheng, Ren Sheng.
       BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though mild in early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers, and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine.
    APPROACH AND RESULTS: Herein, we identified cyclin-dependent kinase-like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related hepatic inflammation, fibrosis, and diabetes. Mechanism-wise, CDKL3 directly phosphorylates forkhead box O (FoxO)1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic CDKL3 is a direct target gene of Hepatocyte nuclear factor 4α (HNF4α). HNF4α is inhibited during MASLD, which leads to diminished CDKL3 expression. The CDKL3-mediated cross talk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression.
    CONCLUSIONS: We unearthed an alternative but critical regulatory path of FoxO1 by the HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.
    DOI:  https://doi.org/10.1097/HEP.0000000000001147
  12. Front Aging. 2024 ;5 1522451
    Editorial: Frailty- and age-associated diseases: possibilities for intervention.
    Cristina Mas-Bargues, Jose Viña, Consuelo Borrás.
      
    Keywords:  cellular senescence; early detection; exercise intervention; frailty; polypharmacy
    DOI:  https://doi.org/10.3389/fragi.2024.1522451
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