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

IF 6.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Diabetes Pub Date : 2024-09-20 DOI:10.2337/db24-0097
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
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引用次数: 0

摘要

下丘脑对膳食脂肪的先天性免疫反应是肥胖症发病机制的基础,而小胶质细胞在其中起着至关重要的作用。Progranulin(PGRN)是一种进化保守的分泌蛋白,含有七个半颗粒蛋白(GRN)基团。它被多种蛋白酶裂解成 GRNs。在中枢神经系统中,PGRN 在小胶质细胞中高度表达。为了研究小胶质细胞衍生的 PGRN 在新陈代谢调节中的作用,我们建立了一个小胶质细胞特异性缺失 Grn(编码 PGRN 的基因)的小鼠模型。小胶质细胞特异性 Grn 基因缺失的小鼠表现出依赖饮食的代谢表型。在正常饮食条件下,小胶质细胞 Grn 基因缺失会导致空腹高血糖和下丘脑小胶质细胞异常激活等不良后果。然而,当喂食高脂饮食(HFD)时,这些小鼠表现出有益的影响,包括减少肥胖、葡萄糖失调和下丘脑炎症。这些不同的表型似乎与营养过剩期间下丘脑中抗炎性 PGRN 在细胞外裂解为促炎性 GRN 的情况增加有关。为证实这一点,抑制 PGRN 的裂解可减轻 HFD 诱导的下丘脑炎症和肥胖的发展。我们的研究结果表明,在营养过剩期间,小胶质细胞衍生的 PGRN 的细胞外裂解在促进下丘脑炎症和肥胖方面起着重要作用。因此,抑制 PGRN 分裂的疗法可能有益于防治节食引起的肥胖症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.
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来源期刊
Diabetes
Diabetes 医学-内分泌学与代谢
CiteScore
12.50
自引率
2.60%
发文量
1968
审稿时长
1 months
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.
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