Pub Date : 2024-08-19DOI: 10.1038/s42255-024-01113-9
Jens Juul Holst
The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15–25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy. Holst reflects on the development of GLP-1-based drugs for the therapy of obesity, from early observations to remarkable results in more recent clinical trials, discussing physiological, pharmacological and clinical considerations related to their use.
{"title":"GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management","authors":"Jens Juul Holst","doi":"10.1038/s42255-024-01113-9","DOIUrl":"10.1038/s42255-024-01113-9","url":null,"abstract":"The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15–25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy. Holst reflects on the development of GLP-1-based drugs for the therapy of obesity, from early observations to remarkable results in more recent clinical trials, discussing physiological, pharmacological and clinical considerations related to their use.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002783","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 : 2024-08-19DOI: 10.1038/s42255-024-01105-9
Sharanya Sivanand, Yetis Gultekin, Peter S. Winter, Sidney Y. Vermeulen, Konstantine M. Tchourine, Keene L. Abbott, Laura V. Danai, Florian Gourgue, Brian T. Do, Kayla Crowder, Tenzin Kunchok, Allison N. Lau, Alicia M. Darnell, Alexandria Jefferson, Satoru Morita, Dan G. Duda, Andrew J. Aguirre, Brian M. Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J. Irvine, Omer H. Yilmaz, Caroline A. Lewis, Dennis Vitkup, Alex K. Shalek, Matthew G. Vander Heiden
Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize. Sivanand et al. survey different types of cancers and study how the metabolic profile of the primary cancer site influences the metabolism of the metastatic cells, thus influencing sites of metastasis.
{"title":"Cancer tissue of origin constrains the growth and metabolism of metastases","authors":"Sharanya Sivanand, Yetis Gultekin, Peter S. Winter, Sidney Y. Vermeulen, Konstantine M. Tchourine, Keene L. Abbott, Laura V. Danai, Florian Gourgue, Brian T. Do, Kayla Crowder, Tenzin Kunchok, Allison N. Lau, Alicia M. Darnell, Alexandria Jefferson, Satoru Morita, Dan G. Duda, Andrew J. Aguirre, Brian M. Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J. Irvine, Omer H. Yilmaz, Caroline A. Lewis, Dennis Vitkup, Alex K. Shalek, Matthew G. Vander Heiden","doi":"10.1038/s42255-024-01105-9","DOIUrl":"10.1038/s42255-024-01105-9","url":null,"abstract":"Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize. Sivanand et al. survey different types of cancers and study how the metabolic profile of the primary cancer site influences the metabolism of the metastatic cells, thus influencing sites of metastasis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002782","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 : 2024-08-19DOI: 10.1038/s42255-024-01087-8
Carla Horvath, Christian Wolfrum, Pawel Pelczar
Despite the high utility and widespread use of Cre driver lines, lack of Cre specificity, Cre-induced toxicity or poor experimental design can affect experimental results and conclusions. Such pitfalls must be considered before embarking on any Cre-based studies in metabolic research.
{"title":"A safety guide for transgenic Cre drivers in metabolism","authors":"Carla Horvath, Christian Wolfrum, Pawel Pelczar","doi":"10.1038/s42255-024-01087-8","DOIUrl":"10.1038/s42255-024-01087-8","url":null,"abstract":"Despite the high utility and widespread use of Cre driver lines, lack of Cre specificity, Cre-induced toxicity or poor experimental design can affect experimental results and conclusions. Such pitfalls must be considered before embarking on any Cre-based studies in metabolic research.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002781","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 : 2024-08-16DOI: 10.1038/s42255-024-01088-7
Chun-Kwan O, Juliana C. N. Chan
A human experiment confirms the higher susceptibility of South Asians to adverse metabolic consequences with weight gain compared with white Europeans, which is attributed to underlying differences in muscle and adipose biology.
{"title":"Insights into optimal BMI from the GlasVEGAS study","authors":"Chun-Kwan O, Juliana C. N. Chan","doi":"10.1038/s42255-024-01088-7","DOIUrl":"10.1038/s42255-024-01088-7","url":null,"abstract":"A human experiment confirms the higher susceptibility of South Asians to adverse metabolic consequences with weight gain compared with white Europeans, which is attributed to underlying differences in muscle and adipose biology.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992024","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 : 2024-08-16DOI: 10.1038/s42255-024-01101-z
James McLaren, Xuan Gao, Nazim Ghouri, Dilys J. Freeman, Janice Richardson, Naveed Sattar, Jason M. R. Gill
South Asians (SAs) develop type 2 diabetes at lower body mass index values than white Europeans (WEs). This basic human experimental study aimed to compare the metabolic consequences of weight gain in SA and WE men without overweight or obesity. Fourteen SAs and 21 WEs had assessments of body composition, metabolic responses to mixed-meal ingestion, cardiorespiratory fitness and physical activity, and a subcutaneous abdominal adipose tissue biopsy, before and after 4–6 weeks of overfeeding to induce 5–7% weight gain. Here we show that body mass index and whole-body adipose tissue volume increases similarly between ethnic groups, but SAs gain less lean tissue. SAs experience a substantially greater decrease in insulin sensitivity compared with WEs (38% versus 7% decrease, P = 0.009), have fewer small (37.1% versus 60.0%, P = 0.003) and more large (26.2% versus 9.1%, P = 0.005) adipocytes at baseline and have a smaller decrease in very small adipocytes with weight gain (−0.1% versus −1.9%, P < 0.0001). Ethnic differences in adipocyte morphology are associated with SA’s greater adverse metabolic changes with weight gain. ClinicalTrials.gov registration: NCT02399423 . Modest weight gain leads to greater adverse metabolic consequences in South Asian compared to European men, in part driven by differences in adipocyte morphology.
{"title":"Weight gain leads to greater adverse metabolic responses in South Asian compared with white European men: the GlasVEGAS study","authors":"James McLaren, Xuan Gao, Nazim Ghouri, Dilys J. Freeman, Janice Richardson, Naveed Sattar, Jason M. R. Gill","doi":"10.1038/s42255-024-01101-z","DOIUrl":"10.1038/s42255-024-01101-z","url":null,"abstract":"South Asians (SAs) develop type 2 diabetes at lower body mass index values than white Europeans (WEs). This basic human experimental study aimed to compare the metabolic consequences of weight gain in SA and WE men without overweight or obesity. Fourteen SAs and 21 WEs had assessments of body composition, metabolic responses to mixed-meal ingestion, cardiorespiratory fitness and physical activity, and a subcutaneous abdominal adipose tissue biopsy, before and after 4–6 weeks of overfeeding to induce 5–7% weight gain. Here we show that body mass index and whole-body adipose tissue volume increases similarly between ethnic groups, but SAs gain less lean tissue. SAs experience a substantially greater decrease in insulin sensitivity compared with WEs (38% versus 7% decrease, P = 0.009), have fewer small (37.1% versus 60.0%, P = 0.003) and more large (26.2% versus 9.1%, P = 0.005) adipocytes at baseline and have a smaller decrease in very small adipocytes with weight gain (−0.1% versus −1.9%, P < 0.0001). Ethnic differences in adipocyte morphology are associated with SA’s greater adverse metabolic changes with weight gain. ClinicalTrials.gov registration: NCT02399423 . Modest weight gain leads to greater adverse metabolic consequences in South Asian compared to European men, in part driven by differences in adipocyte morphology.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01101-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992049","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 : 2024-08-15DOI: 10.1038/s42255-024-01089-6
Zhe Zhao, Sarah A. Stern
Dopamine D1 receptors of the nucleus accumbens (NAc) can be divided into different transcriptomic subtypes, and are crucial for reward processing and regulating feeding behaviour. One subtype — the NAc SERPINB2+ neuron— is identified as necessary for the specific control of food intake and energy balance, and could serve as a target for addressing obesity and eating disorders.
{"title":"Homeostatic feeding in hedonic centres","authors":"Zhe Zhao, Sarah A. Stern","doi":"10.1038/s42255-024-01089-6","DOIUrl":"10.1038/s42255-024-01089-6","url":null,"abstract":"Dopamine D1 receptors of the nucleus accumbens (NAc) can be divided into different transcriptomic subtypes, and are crucial for reward processing and regulating feeding behaviour. One subtype — the NAc SERPINB2+ neuron— is identified as necessary for the specific control of food intake and energy balance, and could serve as a target for addressing obesity and eating disorders.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986200","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}
Orchestrating complex behaviors, such as approaching and consuming food, is critical for survival. In addition to hypothalamus neuronal circuits, the nucleus accumbens (NAc) also controls appetite and satiety. However, specific neuronal subtypes of the NAc that are involved and how the humoral and neuronal signals coordinate to regulate feeding remain incompletely understood. Here we decipher the spatial diversity of neuron subtypes of the NAc shell (NAcSh) and define a dopamine receptor D1-expressing and Serpinb2-expressing subtype controlling food consumption in male mice. Chemogenetics and optogenetics-mediated regulation of Serpinb2+ neurons bidirectionally regulate food seeking and consumption specifically. Circuitry stimulation reveals that the NAcShSerpinb2→LHLepR projection controls refeeding and can overcome leptin-mediated feeding suppression. Furthermore, NAcSh Serpinb2+ neuron ablation reduces food intake and upregulates energy expenditure, resulting in reduced bodyweight gain. Our study reveals a neural circuit consisting of a molecularly distinct neuronal subtype that bidirectionally regulates energy homeostasis, providing a potential therapeutic target for eating disorders. The work deciphers the spatial diversity of neuronal subtypes of the nucleus accumbens shell and identifies a subset of dopamine receptor-expressing neurons marked by Serpinb2 that control food seeking and consumption.
{"title":"A subset of dopamine receptor-expressing neurons in the nucleus accumbens controls feeding and energy homeostasis","authors":"Yiqiong Liu, Ying Wang, Zheng-dong Zhao, Guoguang Xie, Chao Zhang, Renchao Chen, Yi Zhang","doi":"10.1038/s42255-024-01100-0","DOIUrl":"10.1038/s42255-024-01100-0","url":null,"abstract":"Orchestrating complex behaviors, such as approaching and consuming food, is critical for survival. In addition to hypothalamus neuronal circuits, the nucleus accumbens (NAc) also controls appetite and satiety. However, specific neuronal subtypes of the NAc that are involved and how the humoral and neuronal signals coordinate to regulate feeding remain incompletely understood. Here we decipher the spatial diversity of neuron subtypes of the NAc shell (NAcSh) and define a dopamine receptor D1-expressing and Serpinb2-expressing subtype controlling food consumption in male mice. Chemogenetics and optogenetics-mediated regulation of Serpinb2+ neurons bidirectionally regulate food seeking and consumption specifically. Circuitry stimulation reveals that the NAcShSerpinb2→LHLepR projection controls refeeding and can overcome leptin-mediated feeding suppression. Furthermore, NAcSh Serpinb2+ neuron ablation reduces food intake and upregulates energy expenditure, resulting in reduced bodyweight gain. Our study reveals a neural circuit consisting of a molecularly distinct neuronal subtype that bidirectionally regulates energy homeostasis, providing a potential therapeutic target for eating disorders. The work deciphers the spatial diversity of neuronal subtypes of the nucleus accumbens shell and identifies a subset of dopamine receptor-expressing neurons marked by Serpinb2 that control food seeking and consumption.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01100-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986310","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 : 2024-08-15DOI: 10.1038/s42255-024-01127-3
Yong-Uk Lee, Bennett W. Fox, Rui Guo, Brian J. Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L. Safak Yilmaz, Cole M. Haynes, Frank C. Schroeder, Albertha J. M. Walhout
{"title":"Publisher Correction: Host–microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency","authors":"Yong-Uk Lee, Bennett W. Fox, Rui Guo, Brian J. Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L. Safak Yilmaz, Cole M. Haynes, Frank C. Schroeder, Albertha J. M. Walhout","doi":"10.1038/s42255-024-01127-3","DOIUrl":"10.1038/s42255-024-01127-3","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01127-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988367","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 : 2024-08-15DOI: 10.1038/s42255-024-01110-y
Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, Yutong Sun, Fan Yao, Michael A. Curran, Hao Zhu, Li Ma
Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR–STAT3–CXCL1–CXCR2 axis and a LIFR–STAT3–cholesterol–ERRα–hepatocyte growth factor axis that form bidirectional hepatocyte–neutrophil cross-talk to repair and regenerate the liver. The liver tumour suppressor LIFR plays a key role in liver repair and regeneration by orchestrating cholesterol-driven neutrophil hepatocyte growth factor production and hepatocyte–neutrophil cross-talk.
{"title":"LIFR regulates cholesterol-driven bidirectional hepatocyte–neutrophil cross-talk to promote liver regeneration","authors":"Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, Yutong Sun, Fan Yao, Michael A. Curran, Hao Zhu, Li Ma","doi":"10.1038/s42255-024-01110-y","DOIUrl":"10.1038/s42255-024-01110-y","url":null,"abstract":"Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR–STAT3–CXCL1–CXCR2 axis and a LIFR–STAT3–cholesterol–ERRα–hepatocyte growth factor axis that form bidirectional hepatocyte–neutrophil cross-talk to repair and regenerate the liver. The liver tumour suppressor LIFR plays a key role in liver repair and regeneration by orchestrating cholesterol-driven neutrophil hepatocyte growth factor production and hepatocyte–neutrophil cross-talk.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986308","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 : 2024-08-14DOI: 10.1038/s42255-024-01085-w
Yuping Zheng, Jishun Chen, Vinitha Macwan, Charneal L. Dixon, Xinran Li, Shengjie Liu, Yuyun Yu, Pinglong Xu, Qiming Sun, Qi Hu, Wei Liu, Brian Raught, Gregory D. Fairn, Dante Neculai
Lipid droplets (LDs) are organelles specialized in the storage of neutral lipids, cholesterol esters and triglycerides, thereby protecting cells from the toxicity of excess lipids while allowing for the mobilization of lipids in times of nutrient deprivation. Defects in LD function are associated with many diseases. S-acylation mediated by zDHHC acyltransferases modifies thousands of proteins, yet the physiological impact of this post-translational modification on individual proteins is poorly understood. Here, we show that zDHHC11 regulates LD catabolism by modifying adipose triacylglyceride lipase (ATGL), the rate-limiting enzyme of lipolysis, both in hepatocyte cultures and in mice. zDHHC11 S-acylates ATGL at cysteine 15. Preventing the S-acylation of ATGL renders it catalytically inactive despite proper localization. Overexpression of zDHHC11 reduces LD size, whereas its elimination enlarges LDs. Mutating ATGL cysteine 15 phenocopies zDHHC11 loss, causing LD accumulation, defective lipolysis and lipophagy. Our results reveal S-acylation as a mode of regulation of ATGL function and LD homoeostasis. Modulating this pathway may offer therapeutic potential for treating diseases linked to defective lipolysis, such as fatty liver disease. S-acylation of adipose triacylglyceride lipase, the rate-limiting enzyme of lipolysis, is shown to be required for lipolysis and lipid droplet homoeostasis in mice.
{"title":"S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes","authors":"Yuping Zheng, Jishun Chen, Vinitha Macwan, Charneal L. Dixon, Xinran Li, Shengjie Liu, Yuyun Yu, Pinglong Xu, Qiming Sun, Qi Hu, Wei Liu, Brian Raught, Gregory D. Fairn, Dante Neculai","doi":"10.1038/s42255-024-01085-w","DOIUrl":"10.1038/s42255-024-01085-w","url":null,"abstract":"Lipid droplets (LDs) are organelles specialized in the storage of neutral lipids, cholesterol esters and triglycerides, thereby protecting cells from the toxicity of excess lipids while allowing for the mobilization of lipids in times of nutrient deprivation. Defects in LD function are associated with many diseases. S-acylation mediated by zDHHC acyltransferases modifies thousands of proteins, yet the physiological impact of this post-translational modification on individual proteins is poorly understood. Here, we show that zDHHC11 regulates LD catabolism by modifying adipose triacylglyceride lipase (ATGL), the rate-limiting enzyme of lipolysis, both in hepatocyte cultures and in mice. zDHHC11 S-acylates ATGL at cysteine 15. Preventing the S-acylation of ATGL renders it catalytically inactive despite proper localization. Overexpression of zDHHC11 reduces LD size, whereas its elimination enlarges LDs. Mutating ATGL cysteine 15 phenocopies zDHHC11 loss, causing LD accumulation, defective lipolysis and lipophagy. Our results reveal S-acylation as a mode of regulation of ATGL function and LD homoeostasis. Modulating this pathway may offer therapeutic potential for treating diseases linked to defective lipolysis, such as fatty liver disease. S-acylation of adipose triacylglyceride lipase, the rate-limiting enzyme of lipolysis, is shown to be required for lipolysis and lipid droplet homoeostasis in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980987","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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