<b>Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity</b>

<p dir="ltr"><b>ABSTRACT</b></p><p dir="ltr">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 <i>Grn</i> gene, that encodes PGRN. Mice with microglia-specific <i>Grn</i> depletion displayed diet-dependent metabolic phenotypes. Under normal diet-fed conditions, microglial <i>Grn</i> 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 diet-induced obesity.<br></p><p dir="ltr"><b>ARTICLE HIGHLIGHTS</b></p><p><br></p><p dir="ltr">• The mRNA expression of progranulin (PGRN), a precursor protein of granulins (GRNs), increases specifically in hypothalamic microglia during high-fat diet (HFD) feeding.</p><p><br></p><p dir="ltr">• Mice with microglia-specific depletion of the PGRN-encoding gene <i>Grn</i>, exhibit fasting hyperglycemia and aberrant activation of hypothalamic microglia under normal diet-fed conditions, whereas they resist the development of obesity, glucose dysregulation, and hypothalamic inflammation under HFD-fed conditions.</p><p><br></p><p dir="ltr">• The enhanced cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus under HFD-fed conditions underlies the diet-dependent metabolic phenotypes of microglia <i>Grn</i> knockout mice.</p><p><br></p><p dir="ltr">• Inhibition of hypothalamic PGRN cleavage attenuates HFD-induced obesity and hypothalamic inflammation.</p>