Chae Beom Park, Chan Hee Lee, Kae Won Cho, Sunghun Shin, Won Hee Jang, Junyeong Byeon, Yu Rim Oh, Sung Jun Kim, Jae Woo Park, Gil Myoung Kang, Se Hee Min, Seyun Kim, Rina Yu, Min-Seon Kim
{"title":"小胶质细胞衍生的原粒细胞蛋白胞外裂解促进饮食诱导的肥胖症","authors":"Chae Beom Park, Chan Hee Lee, Kae Won Cho, Sunghun Shin, Won Hee Jang, Junyeong Byeon, Yu Rim Oh, Sung Jun Kim, Jae Woo Park, Gil Myoung Kang, Se Hee Min, Seyun Kim, Rina Yu, Min-Seon Kim","doi":"10.2337/db24-0097","DOIUrl":null,"url":null,"abstract":"Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily -conserved secretory protein containing seven-and-a-half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases. In the central nervous system, PGRN is highly expressed in microglia. To investigate the role of microglia-derived PGRN in metabolism regulation, we established a mouse model with a microglia-specific deletion of the Grn gene, that encodes PGRN. Mice with microglia-specific Grn gene depletion displayed dietdependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn gene depletion produced adverse outcomes like fasting hyperglycemia and aberrant activation of hypothalamic microglia. However, when fed a high fat diet (HFD), these mice exhibited beneficial effects, including less obesity, glucose dysregulation, and hypothalamic inflammation. These differing phenotypes appear linked to increased extracellular cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus during overnutrition. In support of this, inhibiting PGRN cleavage attenuated HFD-induced hypothalamic inflammation and obesity progression. Our results suggest that the extracellular cleavage of microglia-derived PGRN plays a significant role in promoting hypothalamic inflammation and obesity during periods of overnutrition. Therefore, therapies that inhibit PGRN cleavage may be beneficial for combating dietinduced obesity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":6.2000,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity\",\"authors\":\"Chae Beom Park, Chan Hee Lee, Kae Won Cho, Sunghun Shin, Won Hee Jang, Junyeong Byeon, Yu Rim Oh, Sung Jun Kim, Jae Woo Park, Gil Myoung Kang, Se Hee Min, Seyun Kim, Rina Yu, Min-Seon Kim\",\"doi\":\"10.2337/db24-0097\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily -conserved secretory protein containing seven-and-a-half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases. In the central nervous system, PGRN is highly expressed in microglia. To investigate the role of microglia-derived PGRN in metabolism regulation, we established a mouse model with a microglia-specific deletion of the Grn gene, that encodes PGRN. Mice with microglia-specific Grn gene depletion displayed dietdependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn gene depletion produced adverse outcomes like fasting hyperglycemia and aberrant activation of hypothalamic microglia. However, when fed a high fat diet (HFD), these mice exhibited beneficial effects, including less obesity, glucose dysregulation, and hypothalamic inflammation. These differing phenotypes appear linked to increased extracellular cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus during overnutrition. In support of this, inhibiting PGRN cleavage attenuated HFD-induced hypothalamic inflammation and obesity progression. Our results suggest that the extracellular cleavage of microglia-derived PGRN plays a significant role in promoting hypothalamic inflammation and obesity during periods of overnutrition. Therefore, therapies that inhibit PGRN cleavage may be beneficial for combating dietinduced obesity.\",\"PeriodicalId\":11376,\"journal\":{\"name\":\"Diabetes\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.2000,\"publicationDate\":\"2024-09-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Diabetes\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2337/db24-0097\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetes","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2337/db24-0097","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity
Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily -conserved secretory protein containing seven-and-a-half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases. In the central nervous system, PGRN is highly expressed in microglia. To investigate the role of microglia-derived PGRN in metabolism regulation, we established a mouse model with a microglia-specific deletion of the Grn gene, that encodes PGRN. Mice with microglia-specific Grn gene depletion displayed dietdependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn gene depletion produced adverse outcomes like fasting hyperglycemia and aberrant activation of hypothalamic microglia. However, when fed a high fat diet (HFD), these mice exhibited beneficial effects, including less obesity, glucose dysregulation, and hypothalamic inflammation. These differing phenotypes appear linked to increased extracellular cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus during overnutrition. In support of this, inhibiting PGRN cleavage attenuated HFD-induced hypothalamic inflammation and obesity progression. Our results suggest that the extracellular cleavage of microglia-derived PGRN plays a significant role in promoting hypothalamic inflammation and obesity during periods of overnutrition. Therefore, therapies that inhibit PGRN cleavage may be beneficial for combating dietinduced obesity.
期刊介绍:
Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes.
However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.