Perilipin 1 (Plin1) deficiency promotes inflammatory responses in lean adipose tissue through lipid dysregulation

Abstract

Lipid droplets are specialized cellular organelles that contain neutral lipid metabolites and play dynamic roles in energy homeostasis. Perilipin 1 (<i>Plin1</i>), one of the major lipid droplet-binding proteins, is highly expressed in adipocytes. In mice, <i>Plin1</i> deficiency impairs peripheral insulin sensitivity, accompanied with reduced fat mass. However, the mechanisms underlying insulin resistance in lean <i>Plin1</i> knockout (<i>Plin1</i>^-/-) mice are largely unknown. The current study demonstrates that <i>Plin1</i> deficiency promotes inflammatory responses and lipolysis in adipose tissue, resulting in insulin resistance. M1-type adipose tissue macrophages (ATMs) were higher in <i>Plin1</i>^-/- than in <i>Plin1</i>^+/+ mice on normal chow diet. Moreover, using lipidomics analysis, we discovered that <i>Plin1</i>^-/- adipocytes promoted secretion of pro-inflammatory lipid metabolites such as prostaglandins, which potentiated monocyte migration. In lean <i>Plin1</i>^-/- mice, insulin resistance was relieved by macrophage depletion with clodronate, implying that elevated pro-inflammatory ATMs might be attributable for insulin resistance under <i>Plin1</i> deficiency. Together, these data suggest that <i>Plin1</i> is required to restrain fat loss and pro-inflammatory responses in adipose tissue by reducing futile lipolysis to maintain metabolic homeostasis.