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.

• The mRNA expression of progranulin (PGRN), a precursor protein of granulins (GRNs), increases specifically in hypothalamic microglia during high-fat diet (HFD) feeding.

• Mice with microglia-specific depletion of the PGRN-encoding gene Grn 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.

• The enhanced cleavage of anti-inflammatory PGRN into proinflammatory GRNs in the hypothalamus under HFD-fed conditions underlies the diet-dependent metabolic phenotypes of microglial Grn knockout mice.

• Inhibition of hypothalamic PGRN cleavage attenuates HFD-induced obesity and hypothalamic inflammation.