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, which encodes PGRN. Mice with microglia-specific Grn depletion displayed diet-dependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn depletion produced adverse outcomes, such as 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 appeared to be 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.