Arrestins in Metabolic Regulation - Progress in Molecular Biology and Translational Science - page 403

2. FUNCTIONAL ROLES OF b -ARRESTINS IN
REGULATION OF WHOLE-BODY ENERGY
BALANCE AND BODY WEIGHT CONTROL
2.1. Hypothalamic signals to peripheral tissues
In response to the body energy storage level, hypothalamic nuclei signal to dif-
ferent peripheral tissues to ensure awell-orchestrated response to food intake and
energy expenditure thereby maintaining a stable body weight. The key hypo-
thalamic neuroendocrine peptides include proopiomelanocortin (POMC),
neuropeptide Y (NPY), agouti-related peptide (AgRP), 5 orexin, melanin-
concentrating hormone (MCH), alpha-melanocyte stimulating hormone
( a -MSH), and cocaine- and amphetamine-regulated transcript (CART). 6
These peptides bind with their GPCRs on cell membranes to influence energy
homeostasis. Studies show not only that b -arrestins influence these peptide
signals bymediating receptor desensitization and endocytosis but also that recep-
tor/ b -arrestin/ubiquitin complexes are intrinsic to activation of the down-
stream pathways for organismal metabolic reactions.
The 36-amino acid peptide neurotransmitter NPY family peptides
[NPY, peptide YY (PYY), and pancreatic polypeptide] bind to four GPCRs
(Y1, Y2, Y4, and Y5). Due to their profound central effects on energy
intake, mood, and reproduction, the pharmacological profiles and distribu-
tion of NPYs and their receptors have been studied extensively. 7 NPYs bind
to Y receptors with different affinities and lead to activation of G i/o protein
and inhibition of cAMP synthesis. Desensitization and internalization of the
Y receptors are controlled by b -arrestin-2. 8 Interestingly, the receptor that is
known to internalize rapidly (Y1) exhibits the most rapid association with
b -arrestin-2, whereas the receptor that is known to internalize slowly, or
not at all, (Y2) associates slowly with b -arrestin-2, suggesting that the asso-
ciation of b -arrestin-2 with the activated receptors is a critical step for
Y receptor desensitization. 9-11
Melanocortin receptors (MC3R and MC4R) expressed in the arcuate
nucleus (MC3R) and in the nucleus paraventricular (MC4R) play
important roles in energy homeostasis. 12 a -Melanocyte-stimulating
hormone ( a -MSH), generated by processing of hypothalamic expressed
POMC, binds to MC3R and MC4R and leads to cAMP accumulation
and inhibition of food intake. 13 Agouti and AgRP act as natural inverse
agonists to diminish signaling of MC3R and MC4R and control body