Pub Date : 2026-01-01DOI: 10.1016/j.molmet.2025.102313
Irmak Gezginer , Giulia Mazzini , Christelle Le Foll , Diana Kindler , Thomas A. Lutz , Daniel Razansky
Obesity remains a major global health challenge, yet the brain-wide effects of hormones regulating appetite remain incompletely understood. Amylin, co-secreted with insulin by pancreatic β-cells, promotes satiation and is a promising therapeutic target for metabolic disorders. While its receptor distribution is well-characterized, its influence on large-scale neural dynamics is unknown. Here, resting-state fMRI was used to map time-resolved connectivity changes following peripheral amylin administration in wild-type (WT) and receptor activity-modifying protein 1/3 knockout (RAMP1/3 KO) mice. In WT animals, amylin triggered rapid and transient network reconfigurations, engaging canonical satiation hubs such as the area postrema and parabrachial nucleus, and extending to sensory-integrative areas including the inferior colliculus and insular cortex. Early hindbrain responses propagated to hypothalamic, thalamic, and mesolimbic circuits implicated in appetite and reward. These effects, along with amylin-driven modulation of large-scale networks and low-frequency oscillations, were absent in KO mice. The findings position amylin as a potent modulator of distributed brain circuits, offering a framework for targeted obesity treatments.
{"title":"Pancreatic amylin dynamically reconfigures distributed brain networks governing appetite regulation in mice","authors":"Irmak Gezginer , Giulia Mazzini , Christelle Le Foll , Diana Kindler , Thomas A. Lutz , Daniel Razansky","doi":"10.1016/j.molmet.2025.102313","DOIUrl":"10.1016/j.molmet.2025.102313","url":null,"abstract":"<div><div>Obesity remains a major global health challenge, yet the brain-wide effects of hormones regulating appetite remain incompletely understood. Amylin, co-secreted with insulin by pancreatic β-cells, promotes satiation and is a promising therapeutic target for metabolic disorders. While its receptor distribution is well-characterized, its influence on large-scale neural dynamics is unknown. Here, resting-state fMRI was used to map time-resolved connectivity changes following peripheral amylin administration in wild-type (WT) and receptor activity-modifying protein 1/3 knockout (RAMP1/3 KO) mice. In WT animals, amylin triggered rapid and transient network reconfigurations, engaging canonical satiation hubs such as the area postrema and parabrachial nucleus, and extending to sensory-integrative areas including the inferior colliculus and insular cortex. Early hindbrain responses propagated to hypothalamic, thalamic, and mesolimbic circuits implicated in appetite and reward. These effects, along with amylin-driven modulation of large-scale networks and low-frequency oscillations, were absent in KO mice. The findings position amylin as a potent modulator of distributed brain circuits, offering a framework for targeted obesity treatments.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102313"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827245","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}
Pub Date : 2025-12-26DOI: 10.1016/j.molmet.2025.102314
April E. Hartley , Katyayani Sukhavasi , Sile Hu , Matthew Traylor , Mar Gonzalez-Ramirez , Kristian Ebbesen Hanghøj , Husain Talukdar , Arno Ruusalepp , Ellen Björkegren , Johan LM. Björkegren , Joanna MM. Howson , Yalda Jamshidi
Understanding tissue-specific mechanisms of protein regulation gives crucial insights into cardiometabolic disease and informs drug discovery. Most proteomic studies have primarily concentrated on plasma, overlooking tissue-specific effects. Utilizing Olink technology, we assessed relative protein levels across plasma and tissue (aortic wall, mammary artery, liver, and skeletal muscle) from the STARNET cohort: 284 individuals with a high prevalence of coronary artery disease (CAD). We identified 608 cis protein quantitative trait loci (pQTLs), primarily in plasma, reflecting greater protein variability. Of 190 proteins with cis-pQTLs in non-plasma tissues, 50% also had plasma pQTLs, validating Olink technology in these tissues while reinforcing the relevance of plasma data for understanding protein regulation. To identify potential mechanistic pathways linking genetic variants to clinical traits, we performed Bayesian colocalization and Mendelian randomization. These analyses revealed shared genetic regulation between tissues at the gene expression and protein level, and key cardiometabolic traits including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Notably, analyses provide further support to SORT1 and PSRC1 gene and protein expression having liver-specific influences on CAD risk and lipid profiles. We also observed distinct genetic regulation of gene expression and protein within the same tissues, underscoring the value of tissue proteomics for therapeutic insights.
{"title":"Deciphering tissue-specific protein regulation for insights into cardiometabolic disease","authors":"April E. Hartley , Katyayani Sukhavasi , Sile Hu , Matthew Traylor , Mar Gonzalez-Ramirez , Kristian Ebbesen Hanghøj , Husain Talukdar , Arno Ruusalepp , Ellen Björkegren , Johan LM. Björkegren , Joanna MM. Howson , Yalda Jamshidi","doi":"10.1016/j.molmet.2025.102314","DOIUrl":"10.1016/j.molmet.2025.102314","url":null,"abstract":"<div><div>Understanding tissue-specific mechanisms of protein regulation gives crucial insights into cardiometabolic disease and informs drug discovery. Most proteomic studies have primarily concentrated on plasma, overlooking tissue-specific effects. Utilizing Olink technology, we assessed relative protein levels across plasma and tissue (aortic wall, mammary artery, liver, and skeletal muscle) from the STARNET cohort: 284 individuals with a high prevalence of coronary artery disease (CAD). We identified 608 <em>cis</em> protein quantitative trait loci (pQTLs), primarily in plasma, reflecting greater protein variability. Of 190 proteins with <em>cis</em>-pQTLs in non-plasma tissues, 50% also had plasma pQTLs, validating Olink technology in these tissues while reinforcing the relevance of plasma data for understanding protein regulation. To identify potential mechanistic pathways linking genetic variants to clinical traits, we performed Bayesian colocalization and Mendelian randomization. These analyses revealed shared genetic regulation between tissues at the gene expression and protein level, and key cardiometabolic traits including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Notably, analyses provide further support to SORT1 and PSRC1 gene and protein expression having liver-specific influences on CAD risk and lipid profiles. We also observed distinct genetic regulation of gene expression and protein within the same tissues, underscoring the value of tissue proteomics for therapeutic insights.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102314"},"PeriodicalIF":6.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850202","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}
Pub Date : 2025-12-19DOI: 10.1016/j.molmet.2025.102310
Melissa A. Fulham , John D. Griffin , Sylvie Perez , Zhongyuan Sun , Natalie A. Daurio , Gang Xing , Michelle F. Clasquin , Melissa R. Miller , Craig L. Hyde , Scott P. Kelly , Magalie Boucher , Rachel Poskanzer , Ramya Gamini , Evanthia Pashos , Ying Zhang , Elaine Kuang , Josh Fienman , Kendra K. Bence , Gregory J. Tesz
Objectives
Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.
Methods
Aldob was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.
Results
Deletion of Aldob caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.
Conclusions
Aldob deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.
{"title":"Impaired hepatic metabolism in Hereditary Fructose Intolerance confers fructose-independent risk for steatosis and hypertriglyceridemia","authors":"Melissa A. Fulham , John D. Griffin , Sylvie Perez , Zhongyuan Sun , Natalie A. Daurio , Gang Xing , Michelle F. Clasquin , Melissa R. Miller , Craig L. Hyde , Scott P. Kelly , Magalie Boucher , Rachel Poskanzer , Ramya Gamini , Evanthia Pashos , Ying Zhang , Elaine Kuang , Josh Fienman , Kendra K. Bence , Gregory J. Tesz","doi":"10.1016/j.molmet.2025.102310","DOIUrl":"10.1016/j.molmet.2025.102310","url":null,"abstract":"<div><h3>Objectives</h3><div>Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.</div></div><div><h3>Methods</h3><div><em>Aldob</em> was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.</div></div><div><h3>Results</h3><div>Deletion of <em>Aldob</em> caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.</div></div><div><h3>Conclusions</h3><div><em>Aldob</em> deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102310"},"PeriodicalIF":6.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805074","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}
Pub Date : 2025-12-17DOI: 10.1016/j.molmet.2025.102309
William De Nardo , Jacqueline Bayliss , Sheik Nadeem Elahee Doomun , Olivia Lee , Paula M. Miotto , Natasha D. Suriani , Shuai Nie , Michael Leeming , Diego A. Miranda , David P. De Souza , Matthew J. Watt
Abstract/objective
Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.
Methods
Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using 13C-glucose or 13C-palmitate. HSC activation was assessed by measuring ACTA2, TGFB1, and COL1A1 mRNA levels and collagen secretion by ELISA.
Results
TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by ACTA2, TGFB1, COL1A1 mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.
Conclusions
These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.
{"title":"Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells","authors":"William De Nardo , Jacqueline Bayliss , Sheik Nadeem Elahee Doomun , Olivia Lee , Paula M. Miotto , Natasha D. Suriani , Shuai Nie , Michael Leeming , Diego A. Miranda , David P. De Souza , Matthew J. Watt","doi":"10.1016/j.molmet.2025.102309","DOIUrl":"10.1016/j.molmet.2025.102309","url":null,"abstract":"<div><h3>Abstract/objective</h3><div>Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.</div></div><div><h3>Methods</h3><div>Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using <sup>13</sup>C-glucose or <sup>13</sup>C-palmitate. HSC activation was assessed by measuring <em>ACTA2, TGFB1, and COL1A1</em> mRNA levels and collagen secretion by ELISA.</div></div><div><h3>Results</h3><div>TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by <em>ACTA2, TGFB1, COL1A1</em> mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.</div></div><div><h3>Conclusions</h3><div>These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102309"},"PeriodicalIF":6.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794426","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}
Pub Date : 2025-12-16DOI: 10.1016/j.molmet.2025.102303
M. Yang , A. de Araujo , J. Shakir , I. Braga , R. Mendez-Hernandez , G.S.S. Tofani , A. Bali , J. de Lartigue , H. Song , J.E. McCutcheon , C.D. Morrison , G. de Lartigue
Animals adaptively adjust nutrient intake based on internal physiological need. Although protein deficiency elicits robust behavioral and endocrine responses, the sensory mechanisms that detect dietary protein and guide selective feeding remain incompletely understood. Here, we identify a population of vagal sensory neurons that respond selectively to intragastric protein and are required for adaptive regulation of protein intake. Using activity-dependent genetic labeling and in vivo calcium imaging, we show that these neurons are activated by dietary protein, exhibit enhanced responses in protein-restricted states, and are distinct from previously characterized calorie-sensing populations. Selective ablation of protein-responsive vagal sensory neurons disrupts the ability to adapt eating behavior to internal protein need, blunts motivation to work for protein rewards, and prevents behavioral updating following protein repletion. These neurons also mediate protein-specific satiety, limiting further protein intake without affecting carbohydrate consumption. Notably, protein preference is suppressed under mild caloric restriction, indicating that caloric and amino acid needs are hierarchically organized and likely monitored by separate interoceptive systems. Our findings reveal a novel vagal circuit that integrates internal protein status with nutrient-specific cues to guide adaptive protein appetite and maintain amino acid homeostasis.
{"title":"Vagal sensory neurons encode internal protein status to guide eating","authors":"M. Yang , A. de Araujo , J. Shakir , I. Braga , R. Mendez-Hernandez , G.S.S. Tofani , A. Bali , J. de Lartigue , H. Song , J.E. McCutcheon , C.D. Morrison , G. de Lartigue","doi":"10.1016/j.molmet.2025.102303","DOIUrl":"10.1016/j.molmet.2025.102303","url":null,"abstract":"<div><div>Animals adaptively adjust nutrient intake based on internal physiological need. Although protein deficiency elicits robust behavioral and endocrine responses, the sensory mechanisms that detect dietary protein and guide selective feeding remain incompletely understood. Here, we identify a population of vagal sensory neurons that respond selectively to intragastric protein and are required for adaptive regulation of protein intake. Using activity-dependent genetic labeling and in vivo calcium imaging, we show that these neurons are activated by dietary protein, exhibit enhanced responses in protein-restricted states, and are distinct from previously characterized calorie-sensing populations. Selective ablation of protein-responsive vagal sensory neurons disrupts the ability to adapt eating behavior to internal protein need, blunts motivation to work for protein rewards, and prevents behavioral updating following protein repletion. These neurons also mediate protein-specific satiety, limiting further protein intake without affecting carbohydrate consumption. Notably, protein preference is suppressed under mild caloric restriction, indicating that caloric and amino acid needs are hierarchically organized and likely monitored by separate interoceptive systems. Our findings reveal a novel vagal circuit that integrates internal protein status with nutrient-specific cues to guide adaptive protein appetite and maintain amino acid homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102303"},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781567","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}
Pub Date : 2025-12-16DOI: 10.1016/j.molmet.2025.102305
Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen
Background: Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.
Methods: Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.
Results: snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.
Conclusions: Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.
{"title":"Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis.","authors":"Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen","doi":"10.1016/j.molmet.2025.102305","DOIUrl":"10.1016/j.molmet.2025.102305","url":null,"abstract":"<p><strong>Background: </strong>Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.</p><p><strong>Methods: </strong>Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.</p><p><strong>Results: </strong>snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.</p><p><strong>Conclusions: </strong>Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102305"},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781569","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}
Pub Date : 2025-12-15DOI: 10.1016/j.molmet.2025.102308
Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser
Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used in vitro myeloid/macrophage culture and in vivo murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.
{"title":"Branched chain amino acids prime metabolic inflammation","authors":"Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser","doi":"10.1016/j.molmet.2025.102308","DOIUrl":"10.1016/j.molmet.2025.102308","url":null,"abstract":"<div><div>Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used <em>in vitro</em> myeloid/macrophage culture and <em>in vivo</em> murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102308"},"PeriodicalIF":6.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775023","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}
Pub Date : 2025-12-09DOI: 10.1016/j.molmet.2025.102299
Ethan C. Fein , Sarmistha Mukherjee , Joseph A. Baur , Patrick Seale
Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.
{"title":"The innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling","authors":"Ethan C. Fein , Sarmistha Mukherjee , Joseph A. Baur , Patrick Seale","doi":"10.1016/j.molmet.2025.102299","DOIUrl":"10.1016/j.molmet.2025.102299","url":null,"abstract":"<div><div>Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102299"},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743408","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}
Pub Date : 2025-12-04DOI: 10.1016/j.molmet.2025.102296
Matthew T. Dickerson , Prasanna K. Dadi , Reagan P. McDevitt , Jordyn R. Dobson , Soma Behera , Spencer J. Peachee , Shannon E. Gibson , Tenzin Wangmo , David A. Jacobson
Electrogenic Na+/K+ ATPases (NKAs) control β-cell Ca2+ influx and insulin secretion by integrating the signal strength of stimulatory G protein (Gs)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (Gi)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca2+ entry by impairing glycolysis-dependent NKA activation and reduces Na+ clearance efficiency during Ca2+ oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na+ influx dictates silent phase duration via the kinetics of Na+ clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating Gi-GPCR effects and augmenting Gs-coupled GLP-1 receptor-mediated cAMP production and Ca2+ entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca2+ and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca2+ oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.
{"title":"Glycolytic activation of β-cell Na+/K+-ATPases containing β1-subunits accelerates Na+ extrusion, prolonging the duration of Ca2+ oscillations but decreasing insulin secretion","authors":"Matthew T. Dickerson , Prasanna K. Dadi , Reagan P. McDevitt , Jordyn R. Dobson , Soma Behera , Spencer J. Peachee , Shannon E. Gibson , Tenzin Wangmo , David A. Jacobson","doi":"10.1016/j.molmet.2025.102296","DOIUrl":"10.1016/j.molmet.2025.102296","url":null,"abstract":"<div><div>Electrogenic Na<sup>+</sup>/K<sup>+</sup> ATPases (NKAs) control β-cell Ca<sup>2+</sup> influx and insulin secretion by integrating the signal strength of stimulatory G protein (G<sub>s</sub>)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (G<sub>i</sub>)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca<sup>2+</sup> entry by impairing glycolysis-dependent NKA activation and reduces Na<sup>+</sup> clearance efficiency during Ca<sup>2+</sup> oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na<sup>+</sup> influx dictates silent phase duration via the kinetics of Na<sup>+</sup> clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating G<sub>i</sub>-GPCR effects and augmenting G<sub>s</sub>-coupled GLP-1 receptor-mediated cAMP production and Ca<sup>2+</sup> entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca<sup>2+</sup> and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca<sup>2+</sup> oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102296"},"PeriodicalIF":6.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695663","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}
Pub Date : 2025-12-03DOI: 10.1016/j.molmet.2025.102297
Wolfgang S. Lieb , Carlos O. Oueslati Morales , Kornelia Ellwanger , Claudia Koch , Sylke Lutz , Stephan A. Eisler , Annika M. Möller , Veronika Leiss , Angelika Hausser
Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell–specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.
{"title":"Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions","authors":"Wolfgang S. Lieb , Carlos O. Oueslati Morales , Kornelia Ellwanger , Claudia Koch , Sylke Lutz , Stephan A. Eisler , Annika M. Möller , Veronika Leiss , Angelika Hausser","doi":"10.1016/j.molmet.2025.102297","DOIUrl":"10.1016/j.molmet.2025.102297","url":null,"abstract":"<div><div>Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell–specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102297"},"PeriodicalIF":6.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687531","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}
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