Arrestins in Metabolic Regulation - Progress in Molecular Biology and Translational Science - page 411

recruitment of PPAR g coregulators through a b -arrestin-1/PPAR g inter-
action. 63,64 b -Arrestin-1 exhibits antiobesity effects through inhibition of
the PPAR g /RXR a heterodimer formation and promotion of PPAR g /
NCoR repressive complex, thus repressing PPAR g -mediated adipogenesis
and inflammatory response. It is still unclear which upstream signal may reg-
ulate the association or disassociation of b -arrestin-1 with PPAR g .
Interestingly, we found that knockout of b -arrestin-1 led to an increased
expressionof adipogenic proteins such as PPAR g , Fabp4, CD36, Lpl, andFasn,
without significant effects on the expression of PPAR d , Acox1, Acadm,
RXR a ,C/EBP a , and Glut4, suggesting that b -arrestin-1 might mediate
PPAR g -dependent expression of adipogenic proteins, lipid metabolic pro-
teins, and adipokines differently. It is worth noting that we found that
rosiglitazone-stimulation decreased the b -arrestin-1/PPAR g associationwith-
out influencing PPAR g /RXR a heterodimer formation. Recently, two ele-
gant studies have added very strong evidence that the PPAR g ligands can be
subcategorized based on their ability tomaintain PPAR g -controlled transcrip-
tion (for adipogenesis) and to antagonize the Cdk5-mediated phosphorylation
of PPAR g (for insulin sensitization). 65,66 Compounds that block the obesity-
linked phosphorylation of PPAR g by Cdk5 without reducing its classical tran-
scriptional activation property have potent antidiabetic activitywhile not caus-
ing the fluid retention, weight gain, or interference with bone formation that
are serious side effects of the thiazolidinedione class of PPAR ligands. Thus, it
would be of interest to investigate whether b -arrestin-1 affects Cdk5-
phosphorylation of PPAR g and whether mediation of PPAR g activity by
either b -arrestin-1 or Cdk5 shares the same or similar underlying mechanisms.
Nevertheless, all these data illustrate that new classes of drugs specifically mod-
ulating PPAR g activities could be developed against metabolic diseases.
4. CONCLUSIONS
The evidence summarized in this chapter has clearly shown that
b -arrestins are actively involved in the regulation of pathways that are crucial
for metabolic regulation, not only through the classical mechanisms of reg-
ulating GPCRs that are known to be critical in whole-body energy balance,
body weight control, carbohydrate and lipid homeostasis but also through
the novel mechanisms related to the so-called b -arrestin-biased signaling.
It is worth pointing out that b -arrestins also regulate other non GPCR
receptors and transcription factors, mostly via direct interaction or by for-
ming diverse signal complexes, to influence body metabolism. Furthermore,