Extracellular cleavage of microglia-derived progranulin promotes diet-induced obesity

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posted on 2024-09-20, 16:25 authored by 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

ABSTRACT

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 depletion displayed diet-dependent metabolic phenotypes. Under normal diet-fed conditions, microglial Grn 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.

ARTICLE HIGHLIGHTS

• 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 microglia Grn knockout mice.

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