Molecular Metabolism最新文献

{"title":"High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice","authors":"Eya Sellami ,&nbsp;Paulo Henrique Evangelista-Silva ,&nbsp;Caio Jordão Teixeira ,&nbsp;Khoudia Diop ,&nbsp;Patricia Mitchell ,&nbsp;Fernando Forato Anhê","doi":"10.1016/j.molmet.2025.102101","DOIUrl":"10.1016/j.molmet.2025.102101","url":null,"abstract":"<div><h3>Objective</h3><div>Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis.</div></div><div><h3>Methods</h3><div>Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively.</div></div><div><h3>Results</h3><div>High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling.</div></div><div><h3>Conclusion</h3><div>Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102101"},"PeriodicalIF":7.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040260","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":"Novel translational mouse models of metabolic dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity","authors":"Katharina L. Hupa-Breier ,&nbsp;Heiko Schenk ,&nbsp;Alejandro Campos-Murguia ,&nbsp;Freya Wellhöner ,&nbsp;Benjamin Heidrich ,&nbsp;Janine Dywicki ,&nbsp;Björn Hartleben ,&nbsp;Clara Böker ,&nbsp;Julian Mall ,&nbsp;Christoph Terkamp ,&nbsp;Ludwig Wilkens ,&nbsp;Friedrich Becker ,&nbsp;Karl Lenhard Rudolph ,&nbsp;Michael Peter Manns ,&nbsp;Young-Seon Mederacke ,&nbsp;Silke Marhenke ,&nbsp;Hanna Redeker ,&nbsp;Maren Lieber ,&nbsp;Konstantinos Iordanidis ,&nbsp;Richard Taubert ,&nbsp;Elmar Jaeckel","doi":"10.1016/j.molmet.2025.102104","DOIUrl":"10.1016/j.molmet.2025.102104","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome.</div></div><div><h3>Methods</h3><div>TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin.</div></div><div><h3>Results</h3><div>After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8⁺cells, CD4⁺cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH.</div></div><div><h3>Conclusions</h3><div>Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102104"},"PeriodicalIF":7.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040291","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":"Transcriptomic signatures of cold acclimated adipocytes reveal CXCL12 as a Brown autocrine and paracrine chemokine","authors":"Marina Agueda-Oyarzabal ,&nbsp;Marie S. Isidor ,&nbsp;Kaja Plucińska ,&nbsp;Lars R. Ingerslev ,&nbsp;Oksana Dmytriyeva ,&nbsp;Patricia S.S. Petersen ,&nbsp;Sara Laftih ,&nbsp;Axel B. Pontoppidan ,&nbsp;Jo B. Henningsen ,&nbsp;Kaja Rupar ,&nbsp;Erin L. Brown ,&nbsp;Thue W. Schwartz ,&nbsp;Romain Barrès ,&nbsp;Zachary Gerhart-Hines ,&nbsp;Camilla C. Schéele ,&nbsp;Brice Emanuelli","doi":"10.1016/j.molmet.2025.102102","DOIUrl":"10.1016/j.molmet.2025.102102","url":null,"abstract":"<div><div>Besides its thermogenic capacity, brown adipose tissue (BAT) performs important secretory functions that regulate metabolism. However, the BAT microenvironment and factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study brown adipocyte-derived secreted factors that may be involved in adipocyte function and/or may orchestrate intercellular communications. For this, mRNA levels in mature adipocytes from mouse adipose depots were assessed using RNA sequencing upon chronic cold acclimation, and bioinformatic analysis was used to identify secreted factors. Among 858 cold-sensitive transcripts in BAT adipocytes were 210 secreted factor-encoding genes, and <em>Cxcl12</em> was the top brown adipocyte-enriched cytokine. <em>Cxcl1</em>2 mRNA expression analysis by RT-qPCR and fluorescence in situ hybridization specified <em>Cxcl12</em> distribution in various cell types, and indicated its enrichment in cold-acclimated brown adipocytes. We found that CXCL12 secretion from BAT was increased after chronic cold, yet its level in plasma remained unchanged, suggesting a local/paracrine function. <em>Cxcl12</em> knockdown in mature brown adipocytes impaired thermogenesis, as assessed by norepinephrine (NE)-induced glycerol release and mitochondrial respiration. However, knockdown of <em>Cxcl12</em> did not impact β-adrenergic signaling, suggesting that CXCL12 regulates adipocyte function downstream of the β-adrenergic pathway. Moreover, we provide evidence for CXCL12 to exert intercellular cross-talk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Collectively, our results indicate that CXCL12 is a brown adipocyte-enriched, cold-induced secreted factor involved in adipocyte function and the BAT microenvironment communication network.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102102"},"PeriodicalIF":7.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028889","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":"Timing of exercise differentially impacts adipose tissue gain in male adolescent rats","authors":"Y. Kutsenko ,&nbsp;L.P. Iñiguez ,&nbsp;A. Barreda ,&nbsp;L. Pardo-Marín ,&nbsp;A. Toval ,&nbsp;D. Garrigos ,&nbsp;M. Martínez-Morga ,&nbsp;S. Pujante ,&nbsp;B. Ribeiro Do-Couto ,&nbsp;K.Y. Tseng ,&nbsp;J.J. Cerón ,&nbsp;M. Garaulet ,&nbsp;M.B. Wisniewska ,&nbsp;M. Irimia ,&nbsp;J.L. Ferran","doi":"10.1016/j.molmet.2025.102100","DOIUrl":"10.1016/j.molmet.2025.102100","url":null,"abstract":"<div><h3>Objective</h3><div>Circadian rhythms of metabolic, hormonal, and behavioral fluctuations and their alterations can impact health. An important gap in knowledge in the field is whether the time of the day of exercise and the age of onset of exercise exert distinct effects at the level of whole-body adipose tissue and body composition. The goal of the present study was to determine how exercise at different times of the day during adolescence impacts the adipose tissue transcriptome and content in a rodent model.</div></div><div><h3>Methods</h3><div>Rats were subjected to one of four conditions during their adolescence: early active phase control or exercise (EAC or EAE; ZT13), and late active phase control or exercise (LAC or LAE; ZT23). The effects of exercise timing were assessed at the level of subcutaneous and visceral adipose tissue transcriptome, body composition, hypothalamic expression of orexigenic and anorexigenic genes, blood serum markers and 24-hour core body temperature patterns.</div></div><div><h3>Results</h3><div>We found that late active phase exercise (ZT23) greatly upregulated pathways of lipid synthesis, glycolysis and NADH shuttles in LAE rats, compared to LAC or EAE. Conversely, LAE rats showed notably lower content of adipose tissue. In addition, LAE rats showed signs of impaired FGF21-adiponectin axis compared to other groups.</div></div><div><h3>Conclusions</h3><div>Finally, LAE rats showed higher post-exercise core body temperature compared to other groups. Our results thus indicate that our exercise protocol induced an unusual effect characterized by enhanced lipid synthesis but reduced adipose tissue content in late active phase but not early active phase exercise during adolescence.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102100"},"PeriodicalIF":7.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008438","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":"Endothelial autophagy-related gene 7 contributes to high fat diet-induced obesity","authors":"Guang Ren ,&nbsp;Sushant Bhatnagar ,&nbsp;Martin E. Young ,&nbsp;Timmy Lee ,&nbsp;Jeong-a Kim","doi":"10.1016/j.molmet.2025.102099","DOIUrl":"10.1016/j.molmet.2025.102099","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity-associated metabolic dysfunction is a major public health concern worldwide. Endothelial dysfunction is a hallmark of metabolic dysfunction, and endothelial cells affect metabolic functions. Because autophagy-related gene 7 (ATG7) is involved in various cellular physiology, we investigated the roles of endothelial cell-ATG7 (EC-ATG7) on high-fat diet-induced obesity and its related metabolic dysfunction.</div></div><div><h3>Methods</h3><div>We generated an endothelial-specific <em>Atg7</em> knock-out mouse by breeding <em>Atg7</em>^flox/flox mouse with the <em>Chd5-Cre</em> mouse, and investigated the metabolic phenotypes associated with high-fat diet (HFD)-induced obesity. Body weight, food intake, glucose tolerance, insulin sensitivity, and liver fat accumulation were measured in endothelial <em>Atg7</em> deficient (<em>Atg7</em>^ΔEnd) and control mice (<em>Atg7</em>^f/f). Adipose tissue inflammation was assessed by measuring the expression of pro-inflammatory genes. Furthermore, we performed indirect calorimetry and examined the insulin signaling pathway molecules.</div></div><div><h3>Results</h3><div>We found that deletion of EC-<em>Atg7</em> ameliorated HFD-induced weight gain, fatty liver, and adipocyte hypertrophy and inflammatory response in adipose tissue, and improved insulin sensitivity without changing glucose tolerance. These metabolic effects seem to be due to the reduced food intake because there were no differences in energy expenditure, energy excretion to feces, and physical activity. Interestingly, the deletion of EC-<em>Atg7</em> protected from HFD-induced vascular rarefaction, and the knock-down of <em>Atg7</em> in endothelial cells protected from fatty acid-induced cell death.</div></div><div><h3>Conclusions</h3><div>Our results suggest that EC-<em>Atg7</em> deletion ameliorates HFD-induced obesity and its related metabolic dysfunction, such as insulin resistance and fatty liver by attenuating appetite and vascular rarefaction. The EC-<em>Atg7</em> deletion may protect the endothelial cells from lipotoxicity and impaired angiogenesis, which preserves the endothelial function in metabolic tissues. These findings may have implications for developing new therapeutic strategies for preventing and treating obesity and its associated health risks.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102099"},"PeriodicalIF":7.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008437","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":"Regulation of energy balance by leptin as an adiposity signal and modulator of the reward system","authors":"Roshanak Asgari ,&nbsp;Maria Caceres-Valdiviezo ,&nbsp;Sally Wu ,&nbsp;Laurie Hamel ,&nbsp;Bailey E. Humber ,&nbsp;Sri Mahavir Agarwal ,&nbsp;Paul J. Fletcher ,&nbsp;Stephanie Fulton ,&nbsp;Margaret K. Hahn ,&nbsp;Sandra Pereira","doi":"10.1016/j.molmet.2024.102078","DOIUrl":"10.1016/j.molmet.2024.102078","url":null,"abstract":"<div><h3>Background</h3><div>Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose–response window.</div></div><div><h3>Scope of Review</h3><div>This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions.</div></div><div><h3>Major Conclusions</h3><div>Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102078"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770159","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":"Chemogenetic engagement of different GPCR signaling pathways segregates the orexigenic activity from the control of whole-body glucose metabolism by AGRP neurons","authors":"Valerie Espinal Abreu ,&nbsp;Rachel Barnes ,&nbsp;Vishnupriya Borra,&nbsp;Jennifer Schurdak,&nbsp;Diego Perez-Tilve","doi":"10.1016/j.molmet.2024.102079","DOIUrl":"10.1016/j.molmet.2024.102079","url":null,"abstract":"<div><h3>Objective</h3><div>The control of energy balance involves neural circuits in the central nervous system, including AGRP neurons in the arcuate nucleus of the hypothalamus (ARC). AGRP neurons are crucial for energy balance and their increased activity during fasting is critical to promote feeding behavior. The activity of these neurons is influenced by multiple signals including those acting on G-protein coupled receptors (GPCR) activating different intracellular signaling pathways. We sought to determine whether discrete G-protein mediated signaling in AGRP neurons, promotes differential regulation of feeding and whole-body glucose homeostasis.</div></div><div><h3>Methods</h3><div>To test the contribution of Gαq/11 or Gαs signaling, we developed congenital mouse lines expressing the different DREADD receptors (i.e., hM3q and rM3s), in AGRP neurons. Then we elicited chemogenetic activation of AGRP neurons in these mice during the postprandial state to determine the impact on feeding and glucose homeostasis.</div></div><div><h3>Results</h3><div>Activation of AGRP neurons via hM3q and rM3s promoted hyperphagia. In contrast, only hM3q activation of AGRP neurons of the hypothalamic arcuate nucleus during the postprandial state enhanced whole-body glucose disposal by reducing sympathetic nervous system activity to the pancreas and liver, promoting glucose-stimulated insulin secretion, glycogen deposition and improving glucose tolerance.</div></div><div><h3>Conclusions</h3><div>These data indicate that AGRP neurons regulate food intake and glucose homeostasis through distinct GPCR-dependent signaling pathways and suggest that the transient increase in AGRP neuron activity may contribute to the beneficial effects of fasting on glycemic control.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102079"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792084","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":"Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK","authors":"Renata T. Da Costa ,&nbsp;Anna Nichenko ,&nbsp;Matheus M. Perez ,&nbsp;Malgorzata Tokarska-Schlattner ,&nbsp;Sheida Kavehmoghaddam ,&nbsp;Vedangi Hambardikar ,&nbsp;Ernest R. Scoma ,&nbsp;Erin L. Seifert ,&nbsp;Uwe Schlattner ,&nbsp;Joshua C. Drake ,&nbsp;Maria E. Solesio","doi":"10.1016/j.molmet.2024.102077","DOIUrl":"10.1016/j.molmet.2024.102077","url":null,"abstract":"<div><div>Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged.</div></div><div><h3>Objective</h3><div>In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics.</div></div><div><h3>Methods</h3><div>To conduct our studies, we used a combination of cellular and animal models.</div></div><div><h3>Results</h3><div>Our findings demonstrate for the first time the intimate crosstalk between the levels of polyP and the activation status of the AMPK signaling pathway, via a mechanism involving free phosphate homeostasis. AMPK is a key player in mammalian cell signaling, and a crucial regulator of cellular and mitochondrial homeostasis. Our results show that the depletion of mitochondrial polyP in mammalian cells downregulates the activity of AMPK. Moreover, increased levels of polyP activate AMPK. Accordingly, the genetic downregulation of AMPKF0611 impairs polyP levels in both SH-SY5Y cells and in the brains of female mice.</div></div><div><h3>Conclusions</h3><div>This manuscript sheds new light on the regulation of AMPK and positions polyP as a potent regulator of mammalian cell physiology beyond mere bioenergetics, paving the road for using its metabolism as an innovative pharmacological target in pathologies characterized by dysregulated bioenergetics.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102077"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769991","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":"Modulation of stress-related behaviour by preproglucagon neurons and hypothalamic projections to the nucleus of the solitary tract","authors":"Marie K. Holt ,&nbsp;Natalia Valderrama ,&nbsp;Maria J. Polanco ,&nbsp;Imogen Hayter ,&nbsp;Ellena G. Badenoch ,&nbsp;Stefan Trapp ,&nbsp;Linda Rinaman","doi":"10.1016/j.molmet.2024.102076","DOIUrl":"10.1016/j.molmet.2024.102076","url":null,"abstract":"<div><div>Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP-1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute restraint stress, but that while this input is rich in corticotropin-releasing hormone (CRH), PPG neurons do not express significant levels of receptors for CRH and are not activated following lateral ventricle delivery of CRH. Finally, we demonstrate that cNTS-projecting PVN neurons are necessary for the ability of restraint stress to suppress food intake in male mice. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102076"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739913","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":"Intestinal butyric acid-mediated disruption of gut hormone secretion and lipid metabolism in vasopressin receptor-deficient mice","authors":"Kazuki Harada ,&nbsp;Eiji Wada ,&nbsp;Yuri Osuga ,&nbsp;Kie Shimizu ,&nbsp;Reiko Uenoyama ,&nbsp;Masami Yokota Hirai ,&nbsp;Fumihiko Maekawa ,&nbsp;Masao Miyazaki ,&nbsp;Yukiko K. Hayashi ,&nbsp;Kazuaki Nakamura ,&nbsp;Takashi Tsuboi","doi":"10.1016/j.molmet.2024.102072","DOIUrl":"10.1016/j.molmet.2024.102072","url":null,"abstract":"<div><h3>Objectives</h3><div>Arginine vasopressin (AVP), known as an antidiuretic hormone, is also crucial in metabolic homeostasis. Although AVP receptor-deficient mice exhibit various abnormalities in glucose and lipid metabolism, the mechanism underlying these symptoms remains unclear. This study aimed to explore the involvement of the gut hormones including glucagon-like peptide-1 (GLP-1) and microbiota as essential mediators.</div></div><div><h3>Methods</h3><div>We used the mouse GLP-1-secreting cell line, GLUTag, and performed live cell imaging to examine the contribution of V1a and V1b vasopressin receptors (V1aR and V1bR, respectively) to GLP-1 secretion. We next investigated the hormone dynamics of <em>V1aR</em>-deficient mice (<em>V1aR</em>^{<em>−/−</em>} mice), <em>V1bR</em>-deficient mice (<em>V1bR</em>^{<em>−/−</em>} mice), and <em>V1aR</em>/<em>V1bR</em>-double deficient mice (<em>V1aR</em>^{<em>−/−</em>} <em>V1bR</em>^{<em>−/−</em>}mice).</div></div><div><h3>Results</h3><div>AVP induced the increase in intracellular Ca²⁺ levels and GLP-1 secretion from GLUTag cells in a V1aR and V1bR-dependent manner. AVP receptor-deficient mice, particularly <em>V1aR</em>^{<em>−/−</em>}<em>V1bR</em>^{<em>−/−</em>} mice, demonstrated impaired secretion of GLP-1 and peptide YY secreted by enteroendocrine L cells. <em>V1aR</em>^{<em>−/−</em>}<em>V1bR</em>^{<em>−/−</em>}mice also exhibited abnormal lipid accumulation in the brown adipose tissue and skeletal muscle. We discovered that <em>V1aR</em>^{<em>−/−</em>} <em>V1bR</em>^{<em>−/−</em>} mice showed increased Paneth cell-related gene expression in the small intestine, which was attributed to increased fecal butyric acid levels. Exposure to butyric acid reduced GLP-1 secretion in L cell line. Additionally, human Paneth cell-related gene expressions negatively correlated with that of V1 receptor genes.</div></div><div><h3>Conclusions</h3><div>The deficiency in V1 receptor genes may increase gut butyric acid levels and impair the function of L cells, thus dysregulating lipid homeostasis in the brown adipose tissue and skeletal muscle. This study highlights the importance of appropriate control of the gut microbiota and its metabolites, including butyric acid, for the optimum functioning of enteroendocrine cells.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"91 ","pages":"Article 102072"},"PeriodicalIF":7.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11728074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818469","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}