Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

Abstract

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

The α‐arrestin family of ubiquitin ligase adaptors links metabolism with selective endocytosis

“…ARRDC3 deficiency in mice prevented age‐related obesity and increased insulin sensitivity [Patwari et al., 2011; Shea et al., 2012]. Also, liver‐specific ARRDC3 deletion increased hepatic insulin sensitivity, which was associated with increased insulin receptor protein levels, higher glycogen levels, and lower endogenous glucose production [Batista et al., 2020]. Mice with decreased ARRDC3 levels were protected from obesity due to increased energy expenditure.…”

“…Expression analyses showed that ARRDC3 is subjected to metabolic regulation in various tissues (adipose tissues or skeletal muscles) [Patwari et al., 2011; Batista et al., 2020], and both ARRDC2 and ARRDC3 expression are regulated by fasting/feeding in murine skeletal muscle [Gordon et al., 2019]. Co‐immunoprecipitation studies revealed that ARRDC3 interacts with the insulin receptor via its C‐terminal‐tail, which contains the PY motifs but also a tyrosine residue known to be phosphorylated in certain tumours [Batista et al., 2020]. How ARRDC3 influences insulin signalling mechanistically will require further studies, but current knowledge suggests that ARRDC3 is part of a negative feedback loop.…”

Defining the underlying defect in insulin action in type 2 diabetes

“…In addition to signalling through canonical substrates and downstream elements, the insulin receptor and its signalling are also regulated, both positively and negatively, by interaction with membrane and intracellular proteins. These include glycosylphosphatidylinositol (GPI)-linked proteins, such as glypican-4 [18], membrane pyrophosphatases and phosphodiesterases, such as ectonucleotide pyrophosphatase/ phosphodiesterase 1 (PC-1) [19], α-arrestin adaptors [20] and, even, transcription factors [21] and cell-cycle regulators [22].…”

Hepatocyte androgen receptor in females mediates androgen-induced hepatocellular glucose mishandling and systemic insulin resistance

“…Figure 2C-D) in LivARKO-DHT compared to Con-DHT mice. HGP is not uncommon to have it negative[41,42] as far as insulin suppression of HGP is significantly greater in LivARKO-DHT compared to Con-DHT. Hormones and metabolites commonly associated with insulin resistance and obesity (i.e., leptin, IL-6, and tumor necrosis factor-α) showed similar patterns among Con-veh, LivARKO-veh, Con-DHT, and LivARKO-DHT mice (Figure 3C-E).…”