bims-endanx Biomed News
on Endocrine Anxiety
Issue of 2025–03–02
eleven papers selected by
Logan K. Townsend, McMaster University
  1. Stress exposure in the mdx mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response.
  2. Enhanced Metabolic Adaptations Following Late Dark Phase Wheel Running in High-Fat Diet-Fed Mice.
  3. LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity.
  4. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
  5. Opioid-induced neuroanatomical, microglial and behavioral changes are blocked by suvorexant without diminishing opioid analgesia.
  6. Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo.
  7. Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model.
  8. Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.
  9. Endocannabinoid protection of the brain vasculature leads to stress resilience.
  10. Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood-brain barrier alterations.
  11. Dulling the sweet tooth.
  1. FEBS J. 2025 Feb 22.
    Stress exposure in the mdx mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response.
    Erynn E Johnson, James M Ervasti.
      Duchenne muscular dystrophy is a severe neuromuscular wasting disease that is caused by a primary defect in dystrophin protein and involves organism-wide comorbidities such as cardiomyopathy, metabolic and mitochondrial dysfunction, and nonprogressive cognitive impairments. Physiological stress exposure in the mdx mouse model of Duchenne muscular dystrophy results in phenotypic abnormalities that include locomotor inactivity, hypotension, and increased morbidity. Severe and lethal stress susceptibility in mdx mice corresponds to metabolic dysfunction in several coordinated metabolic pathways within dystrophin-deficient skeletal muscle, as well as prolonged elevation in mdx plasma corticosterone levels that extends beyond the wild-type (WT) stress response. Here, we performed a targeted mass spectrometry-based plasma metabolomics screen focused on biological stress pathways in healthy and dystrophin-deficient mdx mice exposed to mild scruff stress. One-third of the stress-relevant metabolites interrogated displayed significant elevation or depletion in mdx plasma after scruff stress and were restored to WT levels by skeletal muscle-specific dystrophin expression. The metabolic pathways of mdx mice altered by scruff stress are associated with regulation of the hypothalamic-pituitary-adrenal axis, locomotor tone, neurocognitive function, redox metabolism, cellular bioenergetics, and protein catabolism. Our data suggest that a mild stress triggers an exaggerated, multi-system metabolic response in mdx mice.
    Keywords:  Duchenne muscular dystrophy; biological stress; metabolism; metabolomics; skeletal muscle
    DOI:  https://doi.org/10.1111/febs.70029
  2. Mol Metab. 2025 Feb 22. pii: S2212-8778(25)00023-7. [Epub ahead of print] 102116
    Enhanced Metabolic Adaptations Following Late Dark Phase Wheel Running in High-Fat Diet-Fed Mice.
    Stephen P Ashcroft, Amy M Ehrlich, Krzysztof Burek, Logan A Pendergrast, Caio Y Yonamine, Jonas T Treebak, Juleen R Zierath.
      Exercise interventions represent an effective strategy to prevent and treat metabolic diseases and the time-of-day-dependent effects of exercise on metabolic outcomes are becoming increasingly apparent. We aimed to study the influence of time-restricted wheel running on whole-body energy and glucose homeostasis. Male, 8-week-old, C57BL/6NTac mice were fed either a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 4 weeks. Following this, mice were given access to a running wheel between zeitgeber time (ZT) 12-16 (early dark phase) or ZT 20-0 (late dark phase). Sedentary mice had access to a permanently locked wheel. Mice were housed under these conditions in metabolic chambers for 4 weeks in which LFD and HFD conditions were maintained. Following the exercise intervention, body composition and glucose tolerance were assessed. Wheel running during either the early or late dark phase resulted in metabolic improvements such as attenuation in body weight gain, enhanced glucose tolerance and reduced ectopic lipid deposition. However, late dark phase exercise resulted in a greater reduction in body weight gain, as well as enhanced metabolic flexibility and insulin sensitivity. Our data suggest that late dark phase versus early dark phase exercise confers greater metabolic adaptations in HFD-fed mice.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102116
  3. Commun Med (Lond). 2025 Feb 25. 5(1): 51
    LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity.
    Nellie Y Loh, Senthil K Vasan, Daniel B Rosoff, Emile Roberts, Andrea D van Dam, Manu Verma, Daniel Phillips, Agata Wesolowska-Andersen, Matt J Neville, Raymond Noordam, David W Ray, Jonathan H Tobias, Celia L Gregson, Fredrik Karpe, Constantinos Christodoulides.
       BACKGROUND: WNT signaling plays a key role in postnatal bone formation. Individuals with gain-of-function mutations in the WNT co-receptor LRP5 exhibit increased lower-body fat mass and potentially enhanced glucose metabolism, alongside high bone mass. However, the mechanisms by which LRP5 regulates fat distribution and its effects on systemic metabolism remain unclear. This study aims to explore the role of LRP5 in adipose tissue biology and its impact on metabolism.
    METHODS: Metabolic assessments and imaging were conducted on individuals with gain- and loss-of-function LRP5 mutations, along with age- and BMI-matched controls. Mendelian randomization analyses were used to investigate the relationship between bone, fat distribution, and systemic metabolism. Functional studies and RNA sequencing were performed on abdominal and gluteal adipose cells with LRP5 knockdown.
    RESULTS: Here we show that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity through cell-autonomous mechanisms, independent of its bone-related functions. LRP5 supports adipose progenitor cell function by activating WNT/β-catenin signaling and preserving valosin-containing protein (VCP)-mediated proteostasis. LRP5 expression in adipose progenitors declines with age, but gain-of-function LRP5 variants protect against age-related fat loss in the lower body.
    CONCLUSIONS: Our findings underscore the critical role of LRP5 in regulating lower-body fat distribution and insulin sensitivity, independent of its effects on bone. Pharmacological activation of LRP5 in adipose tissue may offer a promising strategy to prevent age-related fat redistribution and metabolic disorders.
    DOI:  https://doi.org/10.1038/s43856-025-00774-1
  4. Cell Rep. 2025 Feb 25. pii: S2211-1247(25)00121-4. [Epub ahead of print]44(3): 115350
    Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.
    Jinyang Li, Xiancheng Chen, Shiyu Song, Wangjie Jiang, Tianjiao Geng, Tiantian Wang, Yan Xu, Yongqiang Zhu, Jun Lu, Yongxiang Xia, Rong Wang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by metabolic dysfunction and inflammation burden, involving a significant enhancement of cellular glycolytic activity. Here, we elucidate how a positive feedback loop in liver macrophages drives MASLD pathogenesis and demonstrate that disrupting this cycle mitigates metabolic stress and macrophage M1 activation during MASLD. We detect elevated expression of hexokinase 2 (HK2) and H3K18la in liver macrophages from patients with MASLD and MASLD mice. This lactate-dependent histone lactylation promotes glycolysis and liver macrophage M1 polarization by enriching the promoters of glycolytic genes and activating transcription. Ultimately, the HK2/glycolysis/H3K18la positive feedback loop exacerbates the vicious cycle of enhancing metabolic dysregulation and histone lactylation and the inflammatory phenotype of liver macrophages. Myeloid-specific deletion of Hk2 or pharmacological inhibition of the transcription factor HIF-1α significantly disrupts this deleterious cycle. Therefore, our study illustrates that targeting this amplified pathogenic loop may offer a promising therapeutic strategy for MASLD.
    Keywords:  CP: Immunology; CP: Metabolism; MASLD; hexokinase 2; histone lactylation; liver macrophages; positive feedback loop
    DOI:  https://doi.org/10.1016/j.celrep.2025.115350
  5. Nat Ment Health. 2024 Sep;2(9): 1018-1031
    Opioid-induced neuroanatomical, microglial and behavioral changes are blocked by suvorexant without diminishing opioid analgesia.
    Ronald McGregor, Ming-Fung Wu, Thomas C Thannickal, Songlin Li, Jerome M Siegel.
      Heroin use disorder in humans and chronic opioid administration to mice result in an increase in the number and a decrease in the size of detected hypocretin (Hcrt, or orexin) neurons. Chronic morphine administration to mice increases Hcrt axonal projections to the ventral tegmental area (VTA), the level of tyrosine hydroxylase (TH) in VTA and the number of detected TH+ cells in VTA, and activates VTA and hypothalamic microglia. Co-administration of morphine with the dual Hcrt receptor antagonist suvorexant prevents morphine-induced changes in the number and size of Hcrt neurons, the increase in Hcrt projections to the VTA and microglial activation in the VTA and hypothalamus. Co-administration of suvorexant with morphine also prevents morphine anticipatory behavior and reduces opioid withdrawal symptoms. However, suvorexant does not diminish morphine analgesia. Here we show that combined administration of opioids and suvorexant may reduce the addiction potential of opioid use for pain relief in humans while maintaining the analgesic effects of opioids.
    DOI:  https://doi.org/10.1038/s44220-024-00278-2
  6. iScience. 2025 Feb 21. 28(2): 111838
    Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo.
    Juan A Garcia-Sanchez, Estelle Bonnet, Céline Loubatier, Anne Doye, Guillaume Paillier, Fabien Segui, Frédéric Larbret, Paul Chaintreuil, Ludovic Batistic, Cédric Torre, Marcel Deckert, Jolanta Polanowska, Patrick Munro, Laurent Boyer, Orane Visvikis.
      Transcription factor EB (TFEB) is a key transcription factor that orchestrates the cellular response to stress. Dysregulation of TFEB is associated with a range of human diseases, and understanding the regulatory mechanisms of TFEB is crucial for identifying potential drug targets. In this study, we used Caenorhabditis elegans to screen for E3 ubiquitin ligases regulating the activity of TFEB's homolog, HLH-30, upon pathogenic infection. We identified WWP-1 as a regulator of HLH-30-dependent immune response controlling HLH-30 stability to mediate host defense in vivo. We found that HLH-30 interacts with WWP-1, supporting a model of WWP-1 directly regulating HLH-30. Furthermore, we found that WWP-1's human homolog WWP2 binds TFEB, directly induces TFEB ubiquitination and stabilizes TFEB. Finally, we found that WWP2 is required for TFEB-dependent host response in human monocytes-derived macrophages upon infection. Overall, our work has identified an evolutionarily conserved regulation of TFEB by WWP2 and highlighted its role in modulating stress response.
    Keywords:  Cell biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.111838
  7. FEBS J. 2025 Feb 25.
    Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model.
    Andria Theodoulou, Thilo Speckmann, Louiza Potamiti, Otto Baba, Tsuyoshi Morita, Anthi Drousiotou, Mihalis I Panayiotidis, Annette Schürmann, Petros P Petrou.
      Starch-binding domain-containing protein 1 (Stbd1) is a glycogen-binding protein which localizes to the endoplasmic reticulum (ER) membrane and ER-mitochondria contact sites (ERMCs). The protein undergoes N-myristoylation, which is a major determinant of its subcellular targeting. Stbd1 has been implicated in the control of glucose homeostasis, as evidenced by the finding that mice with targeted inactivation of Stbd1 display insulin resistance associated with increased ERMCs in the liver. In the present study, we addressed the effects of increased Stbd1 expression levels on insulin signaling. We show that Stbd1 overexpression enhances cellular sensitivity to insulin and improves insulin resistance in an in vitro hepatocyte cell model. We further demonstrate that increased Stbd1 expression levels are associated with enhanced activation of the AMP-activated protein kinase (AMPK), which is a central regulator of metabolism and an attractive therapeutic target for metabolic disorders related to insulin resistance, such as type 2 diabetes (T2D). The activation of AMPK signaling and the improved cellular response to insulin induced by Stbd1 overexpression occurred independently of N-myristoylation and associated changes in the number of ERMCs, glycogen levels, mitochondrial calcium, mitochondrial morphology, and respiratory function. Collectively, our findings uncover a new level of interaction between Stbd1 and AMPK, with Stbd1 acting as an upstream activator of AMPK signaling. Given that first-line drug treatments for insulin resistance and T2D are known activators of the AMPK pathway, these findings may provide a new perspective for the development of more effective therapeutic strategies.
    Keywords:  AMPK; N‐myristoylation; Stbd1; glycogen; insulin resistance
    DOI:  https://doi.org/10.1111/febs.70040
  8. medRxiv. 2025 Feb 12. pii: 2025.02.11.25322053. [Epub ahead of print]
    Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.
    Emil Jørsboe, Phil Kubitz, Julius Honecker, Andrea Flaccus, Dagmar Mvondo, Matthias Raggi, Torben Hansen, Hans Hauner, Matthias Blüher, Philip D Charles, Cecilia M Lindgren, Christoffer Nellåker, Melina Claussnitzer.
      Fat distribution and macro structure of white adipose tissue are important factors in predicting obesity-associated diseases, but cellular microstructure of white adipose tissue has been less explored. To investigate the relationship between adipocyte size and obesity-related traits, and their underlying disease-driving genetic associations, we performed the largest study of automatic adipocyte phenotyping linking histological measurements and genetics to date. We introduce deep learning based methods for scalable and accurate semantic segmentation of subcutaneous and visceral adipose tissue histology samples (N=2,667) across 5 independent cohorts, including data from 9,000 whole slide images, with over 27 million adipocytes. Estimates of mean size of adipocytes were validated against Glastonbury et al. 2020. We show that adipocyte hypertrophy correlates with an adverse metabolic profile with increased levels of leptin, fasting plasma glucose, glycated hemoglobin and triglycerides, and decreased levels of adiponectin and HDL cholesterol. We performed the largest GWAS (N Subcutaneous = 2066, N Visceral = 1878) and subsequent meta-analysis of mean adipocyte area, and find two genome-wide significant loci (rs73184721, rs200047724) associated with increased 95%-quantile adipocyte size in respectively visceral and subcutaneous adipose tissue. Stratifying by sex, in females we find two genome-wide significant loci, with one variant (rs140503338) associated with increased mean adipocyte size in subcutaneous adipose tissue, and the other (rs11656704) is associated with decreased 95%-quantile adipocyte size in visceral adipose tissue.
    DOI:  https://doi.org/10.1101/2025.02.11.25322053
  9. Nat Neurosci. 2025 Feb 26.
    Endocannabinoid protection of the brain vasculature leads to stress resilience.
      
    DOI:  https://doi.org/10.1038/s41593-025-01892-8
  10. Nat Neurosci. 2025 Feb 27.
    Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood-brain barrier alterations.
    Katarzyna A Dudek, Sam E J Paton, Luisa Bandeira Binder, Adeline Collignon, Laurence Dion-Albert, Alice Cadoret, Manon Lebel, Olivier Lavoie, Jonathan Bouchard, Fernanda Neutzling Kaufmann, Valerie Clavet-Fournier, Claudia Manca, Manuel Guzmán, Matthew Campbell, Gustavo Turecki, Naguib Mechawar, Nicolas Flamand, Flavie Lavoie-Cardinal, Cristoforo Silvestri, Vincenzo Di Marzo, Caroline Menard.
      Blood-brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.
    DOI:  https://doi.org/10.1038/s41593-025-01891-9
  11. Sci Signal. 2025 Feb 25. 18(875): eadw8586
    Dulling the sweet tooth.
    Annalisa M VanHook.
      A gut microbe that is reduced in diabetes produces a metabolite that dulls the appetite for sugar.
    DOI:  https://doi.org/10.1126/scisignal.adw8586
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