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.

中文翻译：

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小胶质细胞衍生的颗粒蛋白前体的细胞外切割促进饮食诱导的肥胖


下丘脑对膳食脂肪的先天免疫反应是肥胖发病机制的基础，其中小胶质细胞起着关键作用。颗粒蛋白前体 （PGRN） 是一种进化上保守的分泌蛋白，包含七个半颗粒蛋白 （GRN） 基序。它被多种蛋白酶裂解成 GRN。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 在代谢调节中的作用，我们建立了一个小鼠模型，该模型具有编码 PGRN 的 Grn 基因的小胶质细胞特异性缺失。小胶质细胞特异性 Grn 基因耗竭的小鼠表现出饮食依赖性代谢表型。在正常的饮食喂养条件下，小胶质细胞 Grn 基因耗竭产生了空腹高血糖和下丘脑小胶质细胞异常激活等不良结局。然而，当喂食高脂饮食 （HFD） 时，这些小鼠表现出有益的效果，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 PGRN 细胞外裂解为促炎 GRN 的增加有关。支持这一点，抑制 PGRN 切割减轻了 HFD 诱导的下丘脑炎症和肥胖进展。我们的结果表明，在营养过剩期间，小胶质细胞衍生的 PGRN 的细胞外切割在促进下丘脑炎症和肥胖方面起着重要作用。因此，抑制 PGRN 切割的疗法可能有助于对抗饮食诱导的肥胖。