bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–08–18
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. PAK4 phosphorylates and inhibits AMPKα to control glucose uptake.
  2. Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.
  3. Macrophages dig into the obesity paradox in cancer.
  4. Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.
  5. Gut-muscle communication links FGF19 levels to the loss of lean muscle mass following rapid weight loss.
  6. Chromatin Immunoprecipitation in Adipose Tissue and Adipocytes: How to Proceed and Optimize the Protocol for Transcription Factor DNA Binding.
  7. Remodeling p38 signaling in muscle controls locomotor activity via IL-15.
  8. GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
  9. OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
  10. SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans.
  11. Aging human abdominal subcutaneous white adipose tissue at single cell resolution.
  1. Nat Commun. 2024 Aug 10. 15(1): 6858
    PAK4 phosphorylates and inhibits AMPKα to control glucose uptake.
    Dandan Wu, Hwang Chan Yu, Hye-Na Cha, Soyoung Park, Yoonji Lee, Sun-Jung Yoon, So-Young Park, Byung-Hyun Park, Eun Ju Bae.
      Our recent studies have identified p21-activated kinase 4 (PAK4) as a key regulator of lipid catabolism in the liver and adipose tissue, but its role in glucose homeostasis in skeletal muscle remains to be explored. In this study, we find that PAK4 levels are highly upregulated in the skeletal muscles of diabetic humans and mice. Skeletal muscle-specific Pak4 ablation or administering the PAK4 inhibitor in diet-induced obese mice retains insulin sensitivity, accompanied by AMPK activation and GLUT4 upregulation. We demonstrate that PAK4 promotes insulin resistance by phosphorylating AMPKα2 at Ser491, thereby inhibiting AMPK activity. We additionally show that skeletal muscle-specific expression of a phospho-mimetic mutant AMPKα2S491D impairs glucose tolerance, while the phospho-inactive mutant AMPKα2S491A improves it. In summary, our findings suggest that targeting skeletal muscle PAK4 may offer a therapeutic avenue for type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-51240-w
  2. Am J Physiol Endocrinol Metab. 2024 Aug 14.
    Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.
    Daniel Gamu, Makenna S Cameron, William T Gibson.
      Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests chromatin modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and CREB-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using Ucp1-Cre mediated knockdown in mice to determine if their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via b3-agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, "browning" of white adipose tissue by the b3-adrenergic agonist CL-316,243remained largely intact in knockout mice. Although p300 and CBP have non-overlapping roles in other tissues, our results indicate they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another.
    Keywords:  brown adipose; histone acetyltransferases; metabolism; obesity; thermogenesis
    DOI:  https://doi.org/10.1152/ajpendo.00120.2024
  3. Immunity. 2024 Aug 13. pii: S1074-7613(24)00362-5. [Epub ahead of print]57(8): 1731-1733
    Macrophages dig into the obesity paradox in cancer.
    Christopher S Nabel, Florian Gourgue, Matthew G Vander Heiden.
      Response to immune checkpoint blockade is increased in obesity-related cancers, but the mechanisms remain unclear. In a recent issue of Nature, Bader et al. report that obesity in mice induces macrophage PD-1 upregulation to promote tumor growth while potentiating immunotherapy responses.
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.013
  4. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2319724121
    Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.
    Jorge C Correia, Paulo R Jannig, Maya L Gosztyla, Igor Cervenka, Serge Ducommun, Stine M Præstholm, José M Dias, Kyle D Dumont, Zhengye Liu, Qishan Liang, Daniel Edsgärd, Olof Emanuelsson, Paul Gregorevic, Håkan Westerblad, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Johanna T Lanner, Ana I Teixeira, Gene W Yeo, Jorge L Ruas.
      Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Notably, although Zfp697 is expressed in several cell types in skeletal muscle, myofiber-specific Zfp697 genetic ablation in mice is sufficient to hinder the inflammatory and regenerative response to muscle injury, compromising functional recovery. We show that Zfp697 is an essential mediator of the interferon gamma response in muscle cells and that it functions primarily as an RNA-interacting protein, with a very high number of miRNA targets. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue remodeling and regeneration.
    Keywords:  RNA-binding protein; Zfp697; inflammation; muscle atrophy; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2319724121
  5. Diabetes Metab. 2024 Aug 10. pii: S1262-3636(24)00062-4. [Epub ahead of print] 101570
    Gut-muscle communication links FGF19 levels to the loss of lean muscle mass following rapid weight loss.
    Jordan Wean, Salisha Baranwal, Nicole Miller, Jae Hoon Shin, Robert W O'Rourke, Charles F Burant, Randy J Seeley, Amy E Rothberg, Nadejda Bozadjieva-Kramer.
       OBJECTIVE: Optimal weight loss involves decreasing adipose tissue while preserving lean muscle mass. Identifying molecular mediators that preserve lean muscle mass is therefore a clinically important goal. We have shown that circulating, postprandial FGF19 levels are lower in patients with obesity and decrease further with comorbidities such as type 2 diabetes and MASLD. Preclinical studies have shown that FGF15 (mouse ortholog of human FGF19) is necessary to protect against lean muscle mass loss following metabolic surgery-induced weight loss in a mouse model of diet-induced obesity. We evaluated if non-surgical weight loss interventions also lead to increased systemic levels of FGF19 and whether FGF19 levels are predictive of lean muscle mass following rapid weight loss in human subjects with obesity.
    RESEARCH DESIGN AND METHODS: Weight loss was induced in 176 subjects with obesity via a very low-energy diet, VLED (800 kcal/d) in the form of total liquid meal replacement for 3-4 months. We measured plasma FGF19 levels at baseline and following VLED-induced weight loss. Multiple linear regression was performed to assess if FGF19 levels were predictive of lean mass at baseline (obesity) and following VLED.
    RESULTS: Postprandial levels of FGF19 increased significantly following VLED-weight loss. Multiple linear regression analysis showed that baseline (obesity) FGF19 levels, but not post VLED FGF19 levels, significantly predicted the percent of lean muscle mass after VLED-induced weight loss, while controlling for age, sex, and the baseline percent lean mass.
    CONCLUSION: These data identify gut-muscle communication and FGF19 as a potentially important mediator of the preservation of lean muscle mass during rapid weight loss.
    Keywords:  FGF19; Lean muscle mass; Obesity; VLED; Very low-energy diets; Weight loss
    DOI:  https://doi.org/10.1016/j.diabet.2024.101570
  6. Methods Mol Biol. 2024 ;2846 35-45
    Chromatin Immunoprecipitation in Adipose Tissue and Adipocytes: How to Proceed and Optimize the Protocol for Transcription Factor DNA Binding.
    Céline Jouffe, Kenneth A Dyar, Nina Henriette Uhlenhaut.
      Chromatin immunoprecipitation (ChIP) coupled to qPCR or sequencing is a crucial experiment to determine direct transcriptional regulation under the control of specific transcriptional factors or co-regulators at loci-specific or pan-genomic levels.Here we provide a reliable method for processing ChIP from adipocytes or frozen adipose tissue collection, isolation of nuclei, cross-linking of protein-DNA complexes, chromatin shearing, immunoprecipitation, and DNA purification. We also discuss critical steps for optimizing the experiment to perform a successful ChIP in lipid-rich cells/tissues.
    Keywords:  Adipocyte; Adipose tissue; ChIP; Chromatin immunoprecipitation
    DOI:  https://doi.org/10.1007/978-1-0716-4071-5_3
  7. Sci Adv. 2024 Aug 16. 10(33): eadn5993
    Remodeling p38 signaling in muscle controls locomotor activity via IL-15.
    Cintia Folgueira, Leticia Herrera-Melle, Juan Antonio López, Victor Galvan-Alvarez, Marcos Martin-Rincon, María Isabel Cuartero, Alicia García-Culebras, Phillip A Dumesic, Elena Rodríguez, Luis Leiva-Vega, Marta León, Begoña Porteiro, Cristina Iglesias, Jorge L Torres, Lourdes Hernández-Cosido, Clara Bonacasa, Miguel Marcos, María Ángeles Moro, Jesús Vázquez, Jose A L Calbet, Bruce M Spiegelman, Alfonso Mora, Guadalupe Sabio.
      Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.
    DOI:  https://doi.org/10.1126/sciadv.adn5993
  8. Dev Cell. 2024 Aug 02. pii: S1534-5807(24)00455-6. [Epub ahead of print]
    GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
    Inés Soro-Arnáiz, Gillian Fitzgerald, Sarah Cherkaoui, Jing Zhang, Paola Gilardoni, Adhideb Ghosh, Ori Bar-Nur, Evi Masschelein, Pierre Maechler, Nicola Zamboni, Martin Poms, Alessio Cremonesi, Juan Carlos Garcia-Cañaveras, Katrien De Bock, Raphael Johannes Morscher.
      Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation.
    Keywords:  GLUD1; glutamine metabolism; malate aspartate shuttle; metabolite compartmentalization; muscle stem cells; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.015
  9. Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]
    OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
    Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.
      Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.
    Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
  10. Nat Commun. 2024 Aug 12. 15(1): 6895
    SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans.
    Veronica L Li, Shuke Xiao, Pascal Schlosser, Nora Scherer, Amanda L Wiggenhorn, Jan Spaas, Alan Sheng-Hwa Tung, Edward D Karoly, Anna Köttgen, Jonathan Z Long.
      N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating SLC17A1/3-dependent de-coupling of urine and plasma Lac-Phe pools. Together, these data establish SLC17A1/3 family members as the physiologic urine Lac-Phe transporters and uncover a biochemical pathway for the renal excretion of this signaling metabolite.
    DOI:  https://doi.org/10.1038/s41467-024-51174-3
  11. Aging Cell. 2024 Aug 14. e14287
    Aging human abdominal subcutaneous white adipose tissue at single cell resolution.
    K L Whytock, A Divoux, Y Sun, M F Pino, G Yu, C A Jin, J J Robino, A Plekhanov, O Varlamov, S R Smith, M J Walsh, L M Sparks.
      White adipose tissue (WAT) is a robust energy storage and endocrine organ critical for maintaining metabolic health as we age. Our aim was to identify cell-specific transcriptional aberrations that occur in WAT with aging. We leveraged full-length snRNA-Seq and histology to characterize the cellular landscape of human abdominal subcutaneous WAT in a prospective cohort of 10 younger (≤30 years) and 10 older individuals (≥65 years) balanced for sex and body mass index (BMI). The older group had greater cholesterol, very-low-density lipoprotein, triglycerides, thyroid stimulating hormone, and aspartate transaminase compared to the younger group (p < 0.05). We highlight that aging WAT is associated with adipocyte hypertrophy, increased proportions of lipid-associated macrophages and mast cells, an upregulation of immune responses linked to fibrosis in pre-adipocyte, adipocyte, and vascular populations, and highlight CXCL14 as a biomarker of these processes. We show that older WAT has elevated levels of senescence marker p16 in adipocytes and identify the adipocyte subpopulation driving this senescence profile. We confirm that these transcriptional and phenotypical changes occur without overt fibrosis and in older individuals that have comparable WAT insulin sensitivity to the younger individuals.
    Keywords:  White adipose tissue; aging; senescence; single nuclei RNA‐Seq
    DOI:  https://doi.org/10.1111/acel.14287
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