Table 1.
Canonical and Non-Canonical Metabolic Functions of β-Arrestins Revealed by the Use of Cell-Type Specific Mutant Mouse Models
Cell type | Mutant mouse strain | Key metabolic phenotypes | Likely molecular mechanism(s) | References |
---|---|---|---|---|
Phenotypes due to canonical β-arrestin functions | ||||
Adipocytes | Adipo-βarr2-KO | Decrease in adiposity (HFD mice) Improved glucose homeostasis Relative lack of metabolic deficits in response to HFD feeding | Lack of βarr2-mdeiated inhibition of β3-adrenergic receptor signaling | [34] |
Hepatocytes | Hep-βarr2-KO | Impaired glucose homeostasis | Lack of βarr2-mediated inhibition of glucagon receptor signaling | [49] |
Hep-βarr2-OE | Relative lack of metabolic impairments due to HFD feeding | Enhanced βarr2-mediated inhibition of glucagon receptor signaling | [49] | |
Phenotypes due to non-canonical β-arrestin functions | ||||
Adipocytes | Adipo-βarr1-KO | Impaired glucose tolerance and insulin sensitivity (HFD mice) | Increases myostatin expression in BAT due to the lack of nuclear βarr1activity | [51] |
Adipo-βarr1-OE | Improved glucose tolerance and insulin sensitivity (HFD mice) | Reduced myostatin expression in BAT due to enhanced nuclear βarr1 activity | [51] | |
β-Cells | Beta-βarr2-KO | Impaired insulin release and glucose tolerance (HFD mice) | Impaired CAMKII function due to βarr2 deficiency | [21] |
Beta-βarr2-OE | Increased insulin secretion and improved glucose tolerance (HFD mice) | Enhanced CAMKII activity (likely mechanism) | [21] | |
Beta-βarr1-KO | Reduced efficacy of SU drugs to promote insulin secretion | Impaired Epac2 function due to βarr1 deficiency | [22] | |
Skeletal muscle cells | SKM-βarr2-KO | Slight improvements in glucose and insulin tolerance (HFD mice) | Enhanced insulin-induced Akt activation in SKM due to βarr2 deficiency | [76] |
AgRP neurons | AgRP-βarr1-KO | Impaired glucose tolerance and insulin sensitivity (HFD mice) | Lack of βarr1 prevents insulin from silencing AgRP neurons | [83] |
AgRP-βarr1-OE | Improved glucose homeostasis and insulin tolerance | Enhanced insulin sensitivity of AgRP neurons | [83] |
Abbreviations: SU, sulfonylurea; HFD, high-fat diet; SKM, skeletal muscle; KO, knockout; OE, overexpression.