Islr regulates insulin sensitivity by interacting with Psma4 to control insulin receptor alpha levels in obese mice

Insulin resistance is the leading cause of type 2 diabetes (T2D), and dysfunctional insulin receptor signaling is a major manifestation of this insulin resistance. In T2D, the corresponding insulin receptor levels are aberrantly down-regulated, which is one of the major factors underlying obesity-induced insulin resistance in adipose tissue. However, the precise mechanism of insulin receptor impairment in obese individuals remains unclear. In the current study, we established that immunoglobulin superfamily containing leucine-rich repeat (Islr) is highly expressed in adipocytes of mice fed a high-fat diet. We further demonstrated that Islr mediates the ubiquitin-independent proteasomal degradation of insulin receptor alpha (Insrα) by specifically interacting with proteasome subunit alpha type 4 (Psma4). Islr knockout increased the corresponding Insrα subunit levels and enhanced insulin sensitivity in adipocytes, ultimately improving systemic metabolism. Further, siRNA-mediated down-regulation of Islr expression in the white adipose tissue of obese mice increased insulin sensitivity. Overall, Islr regulates insulin sensitivity by interacting with Psma4 to control the ubiquitin-independent proteasomal degradation of Insrα in obese mice, indicating that Islr may be a potential therapeutic target for ameliorating insulin resistance.