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

The increasing prevalence of metabolic syndrome (MetS) and type 2 diabetes (T2D) is a global issue (Zafar et al., 2018). Insulin resistance is considered one of the main clinical features observed in obese individuals and is central to the pathogenesis of obesity-induced MetS and T2D (Kubota et al., 2017, Misra et al., 2018). Insulin resistance is caused by singular or multiple defects the insulin-signaling cascade in skeletal muscles, adipose tissue and the liver (Frojdo et al., 2009). Among other important functions, insulin regulates glucose uptake and lipid metabolism by binding to the corresponding insulin receptor (Insr) (Saltiel and Kahn, 2001, Malik et al., 2004, Kasuga, 2019, Pelletier et al., 2020). Impaired Insr function is one of the primary factors underlying insulin resistance (Johnson & Olefsky, 2013). In obese individuals, surface Insr expression is down-regulated and Insr tyrosine activity is reduced (Olefsky et al., 1982, Caro JF et al., 1987, Ahmad F et al., 1997, Boucher et al., 2014), leading to severe impairment in the activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, accompanied by the development of glucose and lipid metabolism disorders such as glucose intolerance and ectopic lipid accumulation (Qiang et al., 2016, Sakaguchi et al., 2017).

Adipose tissue, which is used for the storage of triglycerides (TGs), is targeted by insulin and secretes adipokines such as adiponectin to maintain systemic energy and metabolic homeostasis (Rosen and Spiegelman, 2014, Choe et al., 2016). A lack of Insr expression in adipose tissue leads to lipodystrophy and abnormal fat factor secretion, ultimately resulting in metabolic dysfunction (Groeneveld et al., 2016, Softic et al., 2016). In contrast, selective enhancement of insulin action in differentiated 3T3-L1 cells effectively improves salutary cytokine secretion and systemic metabolism (Blumer et al., 2008). However, the precise mechanism underlying the obesity-induced aberrant protein or mRNA levels of Insr in adipose tissue yet to be elucidated in detail.

In previous studies, the proteasome system has been shown to play a vital role in regulating insulin signaling, specifically, this mechanism focuses on the ubiquitin-dependent proteasomal degradation of Insr and Insr substrates. For example, some E3 ubiquitin ligases repress insulin receptor signaling and decrease cell surface Insr levels (Xu et al., 2008, Yi et al., 2013, Tawo et al., 2017). In addition to the ubiquitin-dependent proteasomal degradation of Insr, the mechanisms by which ubiquitin-independent proteasomal degradation of Insr and the proteasome subunit–associated mechanisms regulate insulin signaling remain unclear.

Immunoglobulin superfamily containing leucine rich repeat (Islr) was first discovered in humans in 1997; it contains a highly conserved leucine-rich repeat (LRR) domain and an immunoglobulin (Ig)-like domain (Nagasawa et al., 1997) that are both involved in protein-protein interactions (Homma et al., 2009). A recent study suggested that Islr plays a role in bone development (Maeda et al., 2016). Additionally, we previously reported that Islr is involved in WNT signaling regulation in the satellite cells of skeletal muscle and is, therefore, essential for skeletal muscle regeneration in mice (Zhang et al., 2018). Microarray data obtained by analyzing 22 different tissues from 10- to 12-week-old C57BL/6 mice revealed that Islr expression was higher in adipose tissue than in other tissues (GDS3142) (Thorrez et al., 2008). Another microarray study demonstrated that Islr expression was higher in the adipose tissues of C57BL/6 J male mice that exhibited high weight gain after being fed a high-saturated fat diet for 4 weeks compared to that in the adipose tissues of mice with low weight gain (GDS2319) (Koza et al., 2006). Interestingly, in the current study we also observed Islr upregulation in the adipocytes of white adipose tissue (WAT) in mice exposed to a high-fat diet (HFD). To our knowledge, this is the first study to demonstrate that Islr regulates insulin receptor alpha subunit (Insrα) levels by interacting with proteasome subunit alpha type 4 (Psma4) in obese mice. Further, Islr ablation protected mice from insulin resistance; this indicates that Islr may be a potential therapeutic target for treating obesity-related diseases.

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