Acta Physiologica最新文献

{"title":"Pax8-rtTA/LC1-Driven Inducible Ketohexokinase Deletion Protects Against High Fructose-Induced Metabolic Syndrome in Mice","authors":"Xiaoli Yi,&nbsp;Ying Zhu,&nbsp;Mulan Wang,&nbsp;Shanshan Song,&nbsp;Huiru Yang,&nbsp;Wenting Tan,&nbsp;Mengzhi Zhu,&nbsp;Lixiang Zheng,&nbsp;Jun Yu,&nbsp;Chuanming Xu","doi":"10.1111/apha.70187","DOIUrl":"10.1111/apha.70187","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Excessive fructose consumption is strongly linked to metabolic syndrome. Dietary fructose is predominantly transported into cells through the solute carrier family 2 member 5 and/or member 2, and then metabolized by fructokinase (also known as ketohexokinase, KHK), which is primarily expressed in the intestine, liver, and kidney. The significant contribution of KHK-mediated fructose metabolism in the intestine or liver to sugar-induced metabolic syndrome has been well documented. This study aimed to elucidate the pathophysiological significance of renal KHK-mediated fructose metabolism in the pathogenesis of fructose-induced metabolic syndrome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A mouse model with inducible deletion of both KHK isoforms (KHK-A and KHK-C) in renal tubules was generated using the <i>Cre-LoxP</i> recombination system. We then systematically evaluated parameters associated with fructose-induced metabolic syndrome in these mice fed a 20% fructose solution (w/v).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In mice receiving excess fructose solutions, the inducible deletion of KHK via the Pax8-rtTA/LC1 system entirely blocks fructose metabolism and is sufficient to prevent the development of metabolic syndrome. The latter is evidenced by improved glucose and insulin resistance, alleviated hepatic steatosis and liver injury, mitigated adipose tissue remodeling, and strengthened colonic epithelial barrier integrity in fructose-fed <i>Khk</i>-deficient mice. These protections are likely attributed to the reduced uric acid generation resulting from the blockade of fructose metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings suggest that KHK-mediated fructose metabolism in the kidneys may be crucial for the development of fructose-induced metabolic syndrome.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kisspeptin Restores Placental mTOR Signaling and Improves Glucose Homeostasis Mediators Disrupted by Maternal Hypothyroidism in Rats","authors":"Bianca Reis Santos,&nbsp;Jeane Martinha dos Anjos Cordeiro,&nbsp;Luciano Cardoso Santos,&nbsp;Cleisla Souza Oliveira,&nbsp;Maria Clara Pascoal Santos Alvarez,&nbsp;Natália Panhoca Rodrigues,&nbsp;Jorge Lopez-Tello,&nbsp;Amanda N. Sferruzzi-Perri,&nbsp;Rogéria Serakides,&nbsp;Juneo Freitas Silva","doi":"10.1111/apha.70188","DOIUrl":"10.1111/apha.70188","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Reduced placental mTOR signaling is associated with intrauterine growth restriction and impaired maternal and placental metabolism. Since maternal hypothyroidism induces intrauterine growth restriction, and maternal treatment with kisspeptin-10 (Kp10) has been shown to improve feto-placental development in hypothyroid rats, this study aimed to evaluate the effects of maternal hypothyroidism, with and without kisspeptin-10 treatment, on maternal energy homeostasis and placental expression of mTOR and glucose metabolism mediators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Maternal hypothyroidism was induced by administration of propylthiouracil, and kisspeptin-10 treatment began on gestational day 8.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Maternal hypothyroidism caused glucose intolerance, decreased insulin and HDL levels, reduced fetal and placental weights, and thinned the placental interhaemal barrier. It also increased INSRβ and AKT, while downregulating placental p-mTOR/mTOR and Glut1. Although kisspeptin-10 treatment did not improve maternal glucose homeostasis or prevent feto-placental growth restriction, it attenuated maternal hypothyroidism-induced placental Glut1 dysregulation, upregulated the IGF1/IGF1R axis, and restored placental AKT/mTOR expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that kisspeptin-10 treatment in hypothyroid pregnant rats improves placental mTOR signaling and glucose metabolism mediators, highlighting novel pathways through which kisspeptin may modulate placental physiology.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12960837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147352932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Brake on Disinhibition: Non-Hebbian Learning at VIP Interneuron Outputs","authors":"Alexey Semyanov,&nbsp;Karri Lamsa","doi":"10.1111/apha.70185","DOIUrl":"10.1111/apha.70185","url":null,"abstract":"&lt;p&gt;In the February issue of Acta Physiologica, Jabłońska and colleagues report a previously undocumented form of inhibitory synaptic plasticity that operates within hippocampal disinhibitory circuits [&lt;span&gt;1&lt;/span&gt;]. Inhibitory plasticity is increasingly recognized as a central mechanism shaping neuronal computation, yet most studies have focused on inhibitory synapses onto excitatory neurons. In contrast, how inhibitory synapses between interneurons adapt and how such plasticity regulates disinhibitory circuits has remained largely unexplored.&lt;/p&gt;&lt;p&gt;Jabłońska and colleagues address this knowledge gap by showing that inhibitory synapses formed by vasoactive intestinal peptide (VIP)-expressing interneurons onto &lt;i&gt;stratum oriens&lt;/i&gt; interneurons undergo a long-lasting depression triggered solely by postsynaptic burst firing. This plasticity is non-Hebbian, independent of presynaptic activity, and selectively expressed at interneuron—interneuron (I→ I) connections. The study, therefore, reveals that disinhibitory circuits are not static relays but adaptive elements whose gain is dynamically tuned by the circuit's activity (Figure 1).&lt;/p&gt;&lt;p&gt;Disinhibition mediated by VIP interneurons has emerged as a canonical circuit motif contributing to learning and memory [&lt;span&gt;2&lt;/span&gt;]. By preferentially targeting other interneurons, often dendrite-targeting somatostatin-positive cells, VIP interneurons can transiently relieve pyramidal neurons from inhibition and thereby facilitate context-dependent computation. In the hippocampus, VIP interneurons contribute to goal-directed spatial learning and the reorganization of CA1 population dynamics [&lt;span&gt;3&lt;/span&gt;]. This framework has largely portrayed VIP signaling as a fast, state-dependent gate. Jabłońska et al. now add a crucial new dimension by showing that the gate itself can be reshaped by experience [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The key finding is that burst firing of &lt;i&gt;stratum oriens&lt;/i&gt; interneurons induces a persistent weakening of VIP interneuron-mediated inhibition, even in the complete absence of presynaptic activity of VIP interneurons [&lt;span&gt;1&lt;/span&gt;]. Pairing presynaptic activation with postsynaptic bursts does not modify the magnitude of depression, confirming that classical spike-timing-dependent rules do not apply. Mechanistically, such inhibitory long-term depression (LTD) requires postsynaptic calcium influx through L- and T-type voltage-gated calcium channels but is independent of endocannabinoid signaling and presynaptic release probability, pointing to a postsynaptic locus of expression [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In fact, hippocampal inhibitory circuits express a diversity of learning rules that are distinct from classical Hebbian excitatory plasticity. Whereas correlated pre- and postsynaptic activity drives Hebbian long-term potentiation (LTP) and LTD at excitatory synapses, inhibitory synapses can develop anti-Hebbian or nonassociative forms of plasticity. Notably, many inhibitory neurons in hip","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147352947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH-Dependent Microenvironmental Ionic Signaling in Pancreatic Ductal Adenocarcinoma","authors":"Albrecht Schwab,&nbsp;Micol Rugi,&nbsp;Pawel Swietach,&nbsp;Wiktoria Błaszczak,&nbsp;Ivana Novak,&nbsp;Ganga Deshar,&nbsp;Stine Falsig Pedersen,&nbsp;Renata Ialchina,&nbsp;Albin Sandelin,&nbsp;Jiayi Yao,&nbsp;Stephan J. Reshkin,&nbsp;Rosa A. Cardone,&nbsp;Tiago M. A. Carvalho,&nbsp;Annarosa Arcangeli,&nbsp;Rayhana Bouazzi,&nbsp;Franco N. D'Alessandro,&nbsp;Natalia Prevarskaya,&nbsp;Madelaine M. Audero,&nbsp;Halima Ouadid-Ahidouch,&nbsp;Julie Schnipper,&nbsp;Luis A. Pardo,&nbsp;Xiaoyi Shi,&nbsp;Frauke Alves,&nbsp;Jakub Mitręga,&nbsp;Anna Trauzold,&nbsp;Sofie E. Hagelund,&nbsp;György Panyi,&nbsp;Marco Cozzolino,&nbsp;Clemens M. W. G. Löwik,&nbsp;Laura Mezzanotte,&nbsp;Roisin McMorrow,&nbsp;Andreas Pahl,&nbsp;Torsten Hechler,&nbsp;Elena Papacharisi,&nbsp;Alessandra Fiorio Pla,&nbsp;Ildiko Szabo,&nbsp;Verena Hofschröer,&nbsp;Zoltán Pethő","doi":"10.1111/apha.70183","DOIUrl":"10.1111/apha.70183","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) develops within a uniquely dynamic pH landscape shaped by substantial acid–base fluxes produced by the exocrine pancreas. Secretion of alkaline pancreatic juice, normally linked to digestion, produces intermittent acidifications of the pancreatic interstitium, which challenges epithelial and stromal cells. It was postulated that these unique pancreatic pH dynamics can facilitate PDAC initiation and progression through selection of a more aggressive phenotype emerging with PDAC driver mutations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we summarize evidence that pH-regulatory transport proteins have an important role in shaping the PDAC microenvironment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>pH-regulatory transport proteins generate and sense their microenvironment and act as signaling hubs to regulate proliferation, migration, and metabolism, and immune evasion. In this way, transport proteins that are crucial for the normal physiology of the exocrine pancreas are misused and become coerced into playing a pro-cancer role in pancreatic tumor cells, pancreatic stellate cells, or infiltrating immune cells. Experiments with PDAC mouse models revealed a therapeutic potential of targeting pH dynamics, notably by inhibition or genetic ablation of pH-regulatory proteins. It is a consistent finding that these maneuvers have a marked impact on the tumor immune defense and the communication between cancer and immune cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, we present a case for considering pH-regulating proteins as a therapeutic avenue.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conspiring Against Inspiration—Fentanyl Administration Increases Vagal Activity and Elicits Lower Airway Obstruction","authors":"Nimat A. Ajeigbe,&nbsp;Trevor A. Day","doi":"10.1111/apha.70170","DOIUrl":"10.1111/apha.70170","url":null,"abstract":"&lt;p&gt;Endogenous opioid peptides (e.g., endorphins, enkephalins, dynorphins, endomorphins) bind to opioid receptor subsets (e.g., mu, delta, kappa), distributed throughout the central, peripheral and enteric nervous systems. Opioid administration has been utilized since the early 1800s to exploit convenient and desirable symptoms, such as pain tolerance and relief, and the sedation effects of opioid-based medicines, such as morphine. Particularly, the effect of euphoria can lead to recreational use of opioid-based drugs (e.g., heroine, oxycodone, hydromorphone, fentanyl), and ultimately addiction and opioid use disorder in susceptible individuals. Unfortunately, respiratory depression is a well-described effect of opioid-based poisoning in recreational contexts, sometimes leading to respiratory arrest and death.&lt;/p&gt;&lt;p&gt;Deaths from opioid poisoning in non-clinical settings increased over the last decade, particularly in North America. Estimates put the number of global accidental deaths from non-medical opioid poisonings at ~56 000 in 2001, increasing to ~100 000 globally between 2022 and 2023, with over 80 000 deaths occurring in the US alone, the majority in males [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Previous work on respiratory rhythm generation in mammals elucidated the role of mu-opioid receptors (MOR) on the pre-Bötzinger complex (PreBötC) in the ventrolateral medulla (e.g., [&lt;span&gt;2&lt;/span&gt;]). Following an intense period of investigation elucidating the important role of the PreBötC in respiratory rhythm generation (e.g., [&lt;span&gt;3&lt;/span&gt;]), the role of the pre-inspiratory/parafacial respiratory group (PI/PFRG; [&lt;span&gt;4&lt;/span&gt;]) was integrated into the respiratory rhythm generator model (e.g., [&lt;span&gt;5, 6&lt;/span&gt;]). A more unified view of respiratory rhythm generation emerged, whereby a cascade of hierarchical neuronal signals arising from upstream signals from the PI/PFRG are normally transmitted through the PreBötC to phrenic pre-motoneurons, and on to elicit diaphragmatic contraction (e.g., [&lt;span&gt;2, 6&lt;/span&gt;]). Application of mu-opioid agonists to the brainstem causes quantal slowing, whereby transmission through the PreBötC is blocked, eliciting “skipped beats”, slowing of respiratory rhythm, reducing respiratory rate and minute ventilation, and eventually causing apnea at higher doses [&lt;span&gt;2&lt;/span&gt;]. This integrated view of the effects of opioid administration on respiratory rhythm generation contributed to a mechanistic understanding of respiratory depression in clinical contexts, and ultimately respiratory failure associated with opioid poisoning with recreational use. However, there are also increases in airway resistance and reductions in airflow (i.e., “wooden chest syndrome”; e.g., [&lt;span&gt;7&lt;/span&gt;]) associated with the use of the synthetic opioid fentanyl, but the mechanisms underlying this phenomenon are unclear.&lt;/p&gt;&lt;p&gt;With this background in mind, in a recent issue of Acta Physiologica, Parks and colleagues [&lt;span&gt;8&lt;/span&gt;] assessed the mechani","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Preservation of Muscle Mitochondrial Machinery During Hypometabolic Hibernation in Scandinavian Brown Bears (Ursus arctos)","authors":"Audrey Bergouignan,&nbsp;John Noone,&nbsp;Charlotte Brun,&nbsp;Laura Cussonneau,&nbsp;Alexandre Geffroy,&nbsp;Cecile Coudy-Gandilhon,&nbsp;Isabelle Chery,&nbsp;Alina Lynn Evans,&nbsp;Jon Martin Arnemo,&nbsp;Jonas Kindberg,&nbsp;Guillemette Gauquelin-Koch,&nbsp;Donal O'Gorman,&nbsp;Etienne Lefai,&nbsp;Fabrice Bertile","doi":"10.1111/apha.70177","DOIUrl":"10.1111/apha.70177","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Unlike humans, brown bears (<i>Ursus arctos</i>) uniquely preserve skeletal muscle mass and function during months of hibernation despite prolonged fasting and inactivity. We investigated how mitochondrial energetics respond in skeletal muscle to support this remarkable resilience.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Muscle biopsies from eight wild brown bears were collected during hibernation and again in the active summer season. We assessed mitochondrial respiration using high-resolution respirometry and evaluated changes in protein expression, enzyme activity, and mitochondrial content through proteomics, Western blotting, enzymatic assays, and DNA quantification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Hibernation was associated with lower mitochondrial respiratory capacity, largely due to a reduction in mitochondrial density rather than damage or dysfunction. Despite reduced SDH subunit expression in the whole skeletal muscle, SDH activity remained stable. This likely reflects post-translational regulation and increased, or at least maintained, functional efficiency of the remaining Complex II, allowing mitochondrial respiration to shift toward Complex II-mediated electron entry during hibernation. Proteomic analyses revealed targeted adjustments that maintained energy efficiency, supported both fat and carbohydrate oxidation at low temperatures, and minimized energy loss. Additionally, selective downregulation of mitochondrial dynamic proteins may help protect against muscle degradation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight a temperature-sensitive, multifaceted strategy that preserves mitochondrial energetics during prolonged inactivity, despite reduced mitochondrial density. The selective maintenance of electron flow and fuel flexibility offers novel insights for mitigating muscle wasting in sedentary or immobilized humans.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12926787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Surprising Molecule Not Required for Fatty Acid Handling by Adipocytes","authors":"Caroline M. Alexander","doi":"10.1111/apha.70178","DOIUrl":"10.1111/apha.70178","url":null,"abstract":"&lt;p&gt;The aqueous intracellular environment is subdivided into functional domains (organelles) by hydrophobic lipid membranes. Assembly of these lipid barriers requires shuttling of precursor lipids from their sites of synthesis or uptake to sites of oxidation or membrane assembly. Free fatty acids and their coenzyme A (CoA) esters are potent emulsifiers and can damage the cellular environment through generation of reactive oxygen species. Accordingly, the free intracellular concentrations of reactive oxygen species are tightly controlled by binding to carrier proteins, which traffic fatty acids to sites of utilization or storage reservoirs such as lipid droplets.&lt;/p&gt;&lt;p&gt;Against this backdrop, the recent report by Faergeman and colleagues in &lt;i&gt;Acta Physiologica&lt;/i&gt; is surprising [&lt;span&gt;1&lt;/span&gt;]. The authors show that adipocyte function and homeostasis in mice in vivo are unaffected by the knockout of acyl-CoA binding protein (ACBP) specifically in adipocytes. ACBP binds medium-, long-, and very-long-chain fatty acyl-CoA esters, and its deletion might therefore have been expected to disrupt lipid handling. Indeed, global knockout of ACBP has dramatic effects on systemic metabolism, including the adaptation of liver function to weaning and pronounced alterations in skin-associated epithelial cells—keratinocytes and sebocytes—leading to marked changes in skin function and energetics [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Given these findings, it would have been reasonable to predict that adipocytes—the ultimate specialists in lipid storage and mobilization—would also depend on ACBP. To test this, Faergeman and colleagues employed two distinct Cre drivers to delete &lt;i&gt;Acbp&lt;/i&gt; either selectively in brown adipose tissue, or across all adipose depots. These depots differ profoundly in morphology, regulation, and function (Figure 1). Yet, neither knock-out model displayed changes in systemic energy expenditure, food intake, adipose mass, lipid composition, mitochondrial respiration, or gene expression in white or brown adipose tissue.&lt;/p&gt;&lt;p&gt;This lack of phenotype is particularly striking in brown adipose tissue (BAT), a highly dynamic depot that repeatedly assembles and dismantles multilocular lipid droplets to fuel mitochondrial heat production. Defects in lipid metabolism often manifest prominently in BAT [&lt;span&gt;3&lt;/span&gt;], whether due to impaired endothelial or adipocyte lipid handling [&lt;span&gt;4, 5&lt;/span&gt;], or defects in the peripheral tissues that supply substrates for thermogenesis [&lt;span&gt;6&lt;/span&gt;]. Such perturbations commonly result in impaired maintenance of body temperature during acute cold exposure. Nevertheless, even under cold stress—when acyl-CoA flux and oxidation rates are maximal—ACBP-deficient adipose tissue showed little evidence of dysfunction.&lt;/p&gt;&lt;p&gt;Why, then, is ACBP essential for lipid handling in skin but dispensable in adipose tissue? One key distinction lies in lipid storage capacity. The epithelial compartment of skin produces two lipid pools wit","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosome pH Dynamics in Physiology and Disease: Molecular Mechanisms and Therapeutic Insights","authors":"Sonia Infante-Tadeo,&nbsp;Diane L. Barber","doi":"10.1111/apha.70160","DOIUrl":"10.1111/apha.70160","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>An acidic lysosomal lumen (pH ~4.5) is essential for the degradative and signaling functions of this organelle, which serves as a central hub for cellular homeostasis. Lysosome pH (pHlys), however, is not static but dynamically regulated by the coordinated action of the V-ATPase, counterion fluxes, membrane composition, and nutrient-sensitive signaling networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>This review integrates recent advances in the molecular mechanisms regulating pHlys with emerging insights on how dysregulated pHlys contributes to pathologies in neurodegenerative disorders, lysosomal storage diseases, and cancers with changes in lumenal proteolytic activity and macromolecular degradation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Findings</h3>\u0000 \u0000 <p>We discuss how pHlys acts as both a sensor and effector in lysosome biology, shaping transcriptional responses, membrane trafficking, and stress adaptation. We also review tools to measure pHlys, ranging from fluorescent dyes to genetically encoded biosensors and nanomaterial-based probes, and evaluate their use in disease-modeling applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>By highlighting pHlys as a nodal point in cellular functions, this review underscores the relevance of pHlys as a diagnostic marker and therapeutic target. Restoring pHlys in diseases offers translational potential to re-establish proteostasis and limit associated pathologies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal Excess Adiposity and Decidual Dyshomeostasis—A New Temporal Target for Intervention","authors":"Caroline Dunk","doi":"10.1111/apha.70180","DOIUrl":"10.1111/apha.70180","url":null,"abstract":"&lt;p&gt;The mechanisms linking maternal metabolic health to adverse pregnancy outcomes are important to understand. The December issue of Acta Physiologica contains an excellent study with an insightful analysis that changes prevailing hypotheses [&lt;span&gt;1&lt;/span&gt;]. Bellissimo and colleagues question the long-standing paradigm that structural failure of spiral artery remodeling is the initial pathology that links maternal metabolic dysfunction to adverse outcomes like preeclampsia [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Bellissimo and colleagues found that diet-induced obesity in prepregnant mice induces profound decidual immune and vascular dyshomeostasis at gestational Day 10.5, which is the end of decidualization in the mouse. Yet, the process of spiral artery remodeling was not impaired [&lt;span&gt;1&lt;/span&gt;]. The study offers a powerful and nuanced perspective on this critical maternal-fetal interface, and their findings are illuminating when contrasted with the bulk of research on placental insufficiency. Preeclampsia models, for instance, often focus on the ultimate failure of trophoblast-mediated spiral artery remodeling as the central pathology, a structural defect that prevents adequate blood flow and nutrient delivery to the placenta.&lt;/p&gt;&lt;p&gt;While prior work has established that maternal obesity influences the overall uterine immune environment and compromises endometrial stromal cell decidualization [&lt;span&gt;3&lt;/span&gt;], this study delineates the defect in detail. The demonstration that maternal obesity induces significant decidual immune and vascular dyshomeostasis at GD 10.5 &lt;i&gt;before&lt;/i&gt; any impairment in spiral artery remodeling provides a vital temporal shift [&lt;span&gt;1&lt;/span&gt;]. This refinement redirects attention from late-stage structural failure and supports the contention that an early inflammatory-metabolic imbalance in decidual development is the key initiating event in maternal obesity-driven placental dysfunction.&lt;/p&gt;&lt;p&gt;By focusing on the decidua, the interface where maternal and fetal tissues first interact, the authors pinpoint a state of early immunological imbalance. While some research observed a net decrease in total decidual immune cells under maternal obesity [&lt;span&gt;4&lt;/span&gt;], Bellissimo et al. demonstrate that the key pathology lies in the quality and proportion of the populations. They first observed an increase in total decidual immune cell populations in the High Fat High Sucrose treated mothers compared to controls, which allowed them to control for and recognize the critical increase in Natural Killer (NK) cells of both tissue resident NK and conventional like NK phenotypes and MHCII&lt;sup&gt;+&lt;/sup&gt; macrophages essential for immune tolerance and vascular support. The concurrent demonstration of decidual and vascular dyshomeostasis including elevated inflammation, activation, coagulation markers, and angiogenic growth factor levels, distinct from structural remodeling failure, suggests that even subtle shifts in the decidual milieu can compromise t","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Acetylglucosamine Selectively Attenuates Neuroinflammation in a Mouse Model of Mitochondrial Dysfunction","authors":"Laura Jiménez-Sánchez,&nbsp;Paula Ruiz-López,&nbsp;Pilar González-García,&nbsp;Janne Purhonen,&nbsp;Juan Manuel Martínez-Gálvez,&nbsp;Sergio López-Herrador,&nbsp;Julia Corral-Sarasa,&nbsp;María Elena Díaz-Casado,&nbsp;Carmen Venegas,&nbsp;Isaac Santos-Pérez,&nbsp;Enrica Olivieri,&nbsp;Adriana L. Rojas,&nbsp;Luis Carlos López","doi":"10.1111/apha.70179","DOIUrl":"10.1111/apha.70179","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characterize the progression of neurodegeneration in a mouse model of fatal mitochondrial encephalopathy and to evaluate the therapeutic potential of oral N-acetylglucosamine supplementation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A mouse model of primary coenzyme Q deficiency was used to examine neurodegeneration at presymptomatic, symptomatic and terminal stages. Neuronal integrity, glial activation, myelination and inflammatory responses were assessed using histological, molecular and ultrastructural approaches, together with behavioral analysis of motor coordination. N acetylglucosamine was administered orally from 1 month of age, and its effects on neuroinflammation, myelin integrity and motor performance were evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Astrocyte activation and neuronal loss were detected before the onset of clinical symptoms, whereas proinflammatory microglia appeared at later disease stages. Early myelin abnormalities were accompanied by an initial increase in oligodendrocyte precursor cells, suggesting a compensatory response to early myelin stress. Oral N-acetylglucosamine supplementation reduced glial activation and neuroinflammatory markers, likely through modulation of inflammatory signaling pathways. Although treatment did not fully reverse structural damage or restore myelin protein expression, it led to a significant improvement in motor coordination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings define a temporal sequence of early glial activation, neuronal loss, and myelin alterations in mitochondrial encephalopathy. Targeting glial responses and neuroinflammation at early disease stages may mitigate neurodegenerative progression and improve functional outcomes, highlighting a physiologically relevant therapeutic window for mitochondrial disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12913237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}