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.