Pub Date : 2026-01-13DOI: 10.1038/s42255-025-01423-6
In pancreatic islets, α-cells secrete glucagon in response to hypoglycaemia. We report that neighbouring δ-cells regulate this process via a negative feedback loop. Hypoglycaemia enhances this intercellular crosstalk, resulting in impaired glucagon response and systemic counter-regulation. Targeting this feedback circuit between α- and δ-cells may help to prevent recurrent iatrogenic hypoglycaemia.
{"title":"Enhanced crosstalk between α- and δ-cells promotes recurrent hypoglycaemia","authors":"","doi":"10.1038/s42255-025-01423-6","DOIUrl":"10.1038/s42255-025-01423-6","url":null,"abstract":"In pancreatic islets, α-cells secrete glucagon in response to hypoglycaemia. We report that neighbouring δ-cells regulate this process via a negative feedback loop. Hypoglycaemia enhances this intercellular crosstalk, resulting in impaired glucagon response and systemic counter-regulation. Targeting this feedback circuit between α- and δ-cells may help to prevent recurrent iatrogenic hypoglycaemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"14-15"},"PeriodicalIF":20.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1038/s42255-025-01422-7
Rui Gao, Samuel Acreman, Haiqiang Dou, Jinfang Ma, Caroline Miranda, Ruiling Zhao, Matthew T. Dickerson, Andrei Tarasov, Qi Zou, Marta Gironella-Torrent, Johan Tolö, Anne Clark, Rui Gao, Yang De Marinis, David A. Jacobson, Joan Camunas-Soler, Tao Yang, Patrik Rorsman, Quan Zhang
Somatostatin, produced by pancreatic islet δ cells, is a key intra-islet paracrine factor that regulates the secretion of the glucoregulatory hormones insulin and glucagon from β cells and α cells, respectively. Here, we show that glutamate and glucagon released by α cells cooperatively activate neighbouring δ cells through AMPA and glucagon receptors, thereby enabling spatiotemporal feedback control of glucagon secretion. Crucially, prior hypoglycaemia enhances this mechanism by sensitizing δ cells to α cell-derived factors and inducing long-lasting structural and functional changes that facilitate δ cell and α cell paracrine interaction. This culminates in somatostatin hypersecretion that impairs counter-regulatory glucagon release. These hypoglycaemia-driven effects were emulated by chemogenetic activation of α cells or high concentrations of exogenous glucagon but prevented by inhibitors of glucagon receptors or the transcription factor CREB. This plasticity represents a key component of the islet’s ‘metabolic memory’, which, through impaired counter-regulatory glucagon secretion, increases the occurrence of recurrent hypoglycaemia that complicates the management of insulin-dependent diabetes. Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.
{"title":"Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control","authors":"Rui Gao, Samuel Acreman, Haiqiang Dou, Jinfang Ma, Caroline Miranda, Ruiling Zhao, Matthew T. Dickerson, Andrei Tarasov, Qi Zou, Marta Gironella-Torrent, Johan Tolö, Anne Clark, Rui Gao, Yang De Marinis, David A. Jacobson, Joan Camunas-Soler, Tao Yang, Patrik Rorsman, Quan Zhang","doi":"10.1038/s42255-025-01422-7","DOIUrl":"10.1038/s42255-025-01422-7","url":null,"abstract":"Somatostatin, produced by pancreatic islet δ cells, is a key intra-islet paracrine factor that regulates the secretion of the glucoregulatory hormones insulin and glucagon from β cells and α cells, respectively. Here, we show that glutamate and glucagon released by α cells cooperatively activate neighbouring δ cells through AMPA and glucagon receptors, thereby enabling spatiotemporal feedback control of glucagon secretion. Crucially, prior hypoglycaemia enhances this mechanism by sensitizing δ cells to α cell-derived factors and inducing long-lasting structural and functional changes that facilitate δ cell and α cell paracrine interaction. This culminates in somatostatin hypersecretion that impairs counter-regulatory glucagon release. These hypoglycaemia-driven effects were emulated by chemogenetic activation of α cells or high concentrations of exogenous glucagon but prevented by inhibitors of glucagon receptors or the transcription factor CREB. This plasticity represents a key component of the islet’s ‘metabolic memory’, which, through impaired counter-regulatory glucagon secretion, increases the occurrence of recurrent hypoglycaemia that complicates the management of insulin-dependent diabetes. Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"159-176"},"PeriodicalIF":20.8,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s42255-025-01433-4
Anne Loft, Rasmus Rydbirk, Ellen Gammelmark Klinggaard, Elvira Laila Van Hauwaert, Charlotte Wilhelmina Wernberg, Andreas Fønss Møller, Trine Vestergaard Dam, Mohamed Nabil Hassan, Babukrishna Maniyadath, Ronni Nielsen, Aleksander Krag, Joanna Kalucka, Søren Fisker Schmidt, Mette Enok Munk Lauridsen, Jesper Grud Skat Madsen, Susanne Mandrup
Human white adipose tissue undergoes major remodelling during sustained weight gain that may compromise tissue function and drive cardiometabolic comorbidities. Although weight loss reverses many of these complications, the cellular and molecular adaptations of adipose tissue to different weight loss interventions are poorly understood. Here we show how abdominal subcutaneous adipose tissue (SAT) in men and women with severe obesity adapts to modest lifestyle-induced (8–10%) weight loss followed by substantial bariatric surgery-induced (20–45%) weight loss, using single-nucleus RNA sequencing (snRNA-seq) combined with bulk RNA-seq, and three-dimensional light-sheet fluorescence microscopy. To enable interactive exploration, all snRNA-seq data are available in a browsable format on the Single Cell Portal ( SCP2849 ). Lifestyle-induced weight loss activated proadipogenic gene programmes in progenitor cells, indicating early beneficial effects on SAT. Subsequent surgery-induced weight loss drove profound compositional and transcriptional remodelling of SAT, including increased vascularization and marked reduction of myeloid cell populations. Collectively, our study indicates that following major and sustained weight loss, SAT from individuals with severe obesity has the capacity to return to a state comparable to that observed in lean individuals. This resource highlights the compositional and transcriptional remodelling of abdominal subcutaneous adipose tissue (SAT) in humans undergoing initial lifestyle-induced weight loss followed by bariatric surgery, with implications for modulating tissue function, systemic metabolism and inflammation.
{"title":"Single-cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss","authors":"Anne Loft, Rasmus Rydbirk, Ellen Gammelmark Klinggaard, Elvira Laila Van Hauwaert, Charlotte Wilhelmina Wernberg, Andreas Fønss Møller, Trine Vestergaard Dam, Mohamed Nabil Hassan, Babukrishna Maniyadath, Ronni Nielsen, Aleksander Krag, Joanna Kalucka, Søren Fisker Schmidt, Mette Enok Munk Lauridsen, Jesper Grud Skat Madsen, Susanne Mandrup","doi":"10.1038/s42255-025-01433-4","DOIUrl":"10.1038/s42255-025-01433-4","url":null,"abstract":"Human white adipose tissue undergoes major remodelling during sustained weight gain that may compromise tissue function and drive cardiometabolic comorbidities. Although weight loss reverses many of these complications, the cellular and molecular adaptations of adipose tissue to different weight loss interventions are poorly understood. Here we show how abdominal subcutaneous adipose tissue (SAT) in men and women with severe obesity adapts to modest lifestyle-induced (8–10%) weight loss followed by substantial bariatric surgery-induced (20–45%) weight loss, using single-nucleus RNA sequencing (snRNA-seq) combined with bulk RNA-seq, and three-dimensional light-sheet fluorescence microscopy. To enable interactive exploration, all snRNA-seq data are available in a browsable format on the Single Cell Portal ( SCP2849 ). Lifestyle-induced weight loss activated proadipogenic gene programmes in progenitor cells, indicating early beneficial effects on SAT. Subsequent surgery-induced weight loss drove profound compositional and transcriptional remodelling of SAT, including increased vascularization and marked reduction of myeloid cell populations. Collectively, our study indicates that following major and sustained weight loss, SAT from individuals with severe obesity has the capacity to return to a state comparable to that observed in lean individuals. This resource highlights the compositional and transcriptional remodelling of abdominal subcutaneous adipose tissue (SAT) in humans undergoing initial lifestyle-induced weight loss followed by bariatric surgery, with implications for modulating tissue function, systemic metabolism and inflammation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"260-278"},"PeriodicalIF":20.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s42255-025-01442-3
Tyler K. T. Smith, Logan K. Townsend, William J. Smiles, Jonathan S. Oakhill, Morgan D. Fullerton, Gregory R. Steinberg
The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease. In this Review, Smith et al. summarize the most recent findings on AMPK and emphasize its role as a nutrient sensor and in regulating metabolic homeostasis, as well as how AMPK dysregulation contributes to various diseases.
{"title":"AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis","authors":"Tyler K. T. Smith, Logan K. Townsend, William J. Smiles, Jonathan S. Oakhill, Morgan D. Fullerton, Gregory R. Steinberg","doi":"10.1038/s42255-025-01442-3","DOIUrl":"10.1038/s42255-025-01442-3","url":null,"abstract":"The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease. In this Review, Smith et al. summarize the most recent findings on AMPK and emphasize its role as a nutrient sensor and in regulating metabolic homeostasis, as well as how AMPK dysregulation contributes to various diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"27-51"},"PeriodicalIF":20.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1038/s42255-025-01431-6
Franck Mauvais-Jarvis, Shalender Bhasin
Testosterone, discovered during the endocrine gold rush of the 1930s, was the first hormone chemically synthesized for replacement therapy. In both men and women, testosterone functions directly through the androgen receptor (AR) and indirectly as a prohormone, converted by aromatase into 17β-oestradiol (oestradiol), which activates the oestrogen receptors ERα and ERβ. Testosterone is also metabolized to dihydrotestosterone—a potent, non-aromatizable AR agonist—through steroid 5α-reductases. Testosterone and its metabolites signal through AR- and ER-mediated genomic and rapid non-genomic actions. Long recognized for its role as a sex hormone, mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms. Here, we highlight key milestones in the history of testosterone’s discovery and therapeutic applications. Additionally, we synthesize the current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans. Mauvais-Jarvis and Bhasin provide an in-depth review of testosterone’s role in maintaining cardiometabolic health, musculoskeletal integrity and energy balance, drawing on evidence from testosterone replacement therapy in humans and mechanistic research in rodent models.
{"title":"Metabolic Messengers: testosterone","authors":"Franck Mauvais-Jarvis, Shalender Bhasin","doi":"10.1038/s42255-025-01431-6","DOIUrl":"10.1038/s42255-025-01431-6","url":null,"abstract":"Testosterone, discovered during the endocrine gold rush of the 1930s, was the first hormone chemically synthesized for replacement therapy. In both men and women, testosterone functions directly through the androgen receptor (AR) and indirectly as a prohormone, converted by aromatase into 17β-oestradiol (oestradiol), which activates the oestrogen receptors ERα and ERβ. Testosterone is also metabolized to dihydrotestosterone—a potent, non-aromatizable AR agonist—through steroid 5α-reductases. Testosterone and its metabolites signal through AR- and ER-mediated genomic and rapid non-genomic actions. Long recognized for its role as a sex hormone, mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms. Here, we highlight key milestones in the history of testosterone’s discovery and therapeutic applications. Additionally, we synthesize the current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans. Mauvais-Jarvis and Bhasin provide an in-depth review of testosterone’s role in maintaining cardiometabolic health, musculoskeletal integrity and energy balance, drawing on evidence from testosterone replacement therapy in humans and mechanistic research in rodent models.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"52-61"},"PeriodicalIF":20.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145938300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s42255-025-01424-5
Xiao Zhang, Sreejith S. Panicker, Jordan M. Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F. Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, Kristann L. Magee, Brian S. Learman, Adam Kepecs, Gretchen A. Meyer, Jun Liu, Steven A. Thomas, Irfan J. Lodhi, Ormond A. MacDougald, Erica L. Scheller
Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues. Stable adipocytes resist lipolysis in healthy states but are highly susceptible to a catecholamine-independent, neurosystemic pathway-driven catabolic state.
{"title":"A catecholamine-independent pathway controlling adaptive adipocyte lipolysis","authors":"Xiao Zhang, Sreejith S. Panicker, Jordan M. Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F. Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, Kristann L. Magee, Brian S. Learman, Adam Kepecs, Gretchen A. Meyer, Jun Liu, Steven A. Thomas, Irfan J. Lodhi, Ormond A. MacDougald, Erica L. Scheller","doi":"10.1038/s42255-025-01424-5","DOIUrl":"10.1038/s42255-025-01424-5","url":null,"abstract":"Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues. Stable adipocytes resist lipolysis in healthy states but are highly susceptible to a catecholamine-independent, neurosystemic pathway-driven catabolic state.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"96-115"},"PeriodicalIF":20.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01424-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s42255-025-01426-3
Alison H. Affinati, Michael W. Schwartz
When the brain detects ongoing fuel depletion, sympathetic nervous system outflow to white adipose tissue induces lipolysis to mobilize fuel. Yet there exists a subset of ‘stable adipocytes’ that resist lipolysis via this mechanism. The discovery of a novel lipolysis mechanism reshapes our understanding of how body energy requirements are met in times of need.
{"title":"Chewing the fat: a novel mechanism for lipolysis","authors":"Alison H. Affinati, Michael W. Schwartz","doi":"10.1038/s42255-025-01426-3","DOIUrl":"10.1038/s42255-025-01426-3","url":null,"abstract":"When the brain detects ongoing fuel depletion, sympathetic nervous system outflow to white adipose tissue induces lipolysis to mobilize fuel. Yet there exists a subset of ‘stable adipocytes’ that resist lipolysis via this mechanism. The discovery of a novel lipolysis mechanism reshapes our understanding of how body energy requirements are met in times of need.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"6-7"},"PeriodicalIF":20.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose–gut axis as a therapeutic target for obesity-associated intestinal disorders. Elevated adipocyte-derived AFABP in obesity disrupts iron homeostasis in intestinal stem cells (ISCs), which impairs PPARα signalling and blocks ISC differentiation after injury.
{"title":"Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells","authors":"Zhiming Liu, Yi Chen, Jinhua Yan, Yu Yuan, Qianyi Wan, Rui Zhao, Fang Fu, Xinxin Fan, Yawen Deng, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Jinbao Ye, Haiyang Chen","doi":"10.1038/s42255-025-01425-4","DOIUrl":"10.1038/s42255-025-01425-4","url":null,"abstract":"Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose–gut axis as a therapeutic target for obesity-associated intestinal disorders. Elevated adipocyte-derived AFABP in obesity disrupts iron homeostasis in intestinal stem cells (ISCs), which impairs PPARα signalling and blocks ISC differentiation after injury.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"74-95"},"PeriodicalIF":20.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s42255-025-01432-5
Jiyeon Kim, Angelika Harbauer
Integrating work–life balance while pursuing exciting scientific questions and navigating the publishing process as a senior author are challenges that researchers often encounter, particularly in their transition to independence. In this instalment of our Career Pathways series, Jiyeon Kim and Angelika Harbauer reflect on how they have experienced this process.
{"title":"Career pathways, part 18","authors":"Jiyeon Kim, Angelika Harbauer","doi":"10.1038/s42255-025-01432-5","DOIUrl":"10.1038/s42255-025-01432-5","url":null,"abstract":"Integrating work–life balance while pursuing exciting scientific questions and navigating the publishing process as a senior author are challenges that researchers often encounter, particularly in their transition to independence. In this instalment of our Career Pathways series, Jiyeon Kim and Angelika Harbauer reflect on how they have experienced this process.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"1-3"},"PeriodicalIF":20.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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