Biology Reference
In-Depth Information
weight.
14
First, Agouti-related peptide exerts its physiological effects by
antagonizing the actions of
a
-MSH on MCRs. Furthermore, binding of
Agouti-related peptide to MC3R and MC4R decreases basal, agonist-
independent, receptor signaling. Studies using bioluminescence resonance
energy transfer assays showed that binding of Agouti-related peptide pro-
motes the interaction of
b
-arrestins with MC3R and MC4R and initiates
receptor endocytosis,
15
pointing out a newmechanism by which the inverse
agonist Agouti-related peptide reduces MCR density at the cell surface and
fine tunes the response of MCR-expressing cells to melanocortins.
Orexin-A (OxA) and -B (OxB), also called hypocretins, are neurotrans-
mitters produced by neurons in the hypothalamus that regulate arousal,
wakefulness, and appetite.
16
Orexins increase the craving for food. OxA
stimulates glucose uptake in 3T3-L1 adipocytes, and increases energy uptake
and lipogenesis.
17
Orexin-knockout mice showed impaired brown adipose
tissue thermogenesis.
18
OxA binds to both orexin receptors 1 and 2 (OxR1
and OxR2) with similar affinity, whereas OxB has less affinity for OxR1
compared with OxR2.
19
Both OxR1 and OxR2 interact with
b
-arrestin-1
and -2 in an agonist dose-dependent manner, but with a two orders of mag-
nitude lower affinity than observed for G protein activation.
20,21
A potency
shift of OxA-induced ERK1/2 phosphorylation between early (2 min; pre-
dominantly G protein-mediated) and late (90 min; predominantly
b
-arrestin-mediated) signaling responses has been observed. Furthermore,
the OxA-induced receptor-arrestin-ubiquitin complex differs between
OxR subtypes. Compared with OxR2, OxR1 dissociates from either form
of
b
-arrestin more rapidly, with a stronger initial interaction and more rapid
recycling back to the plasma membrane. Consistently, OxA-dependent
ERK1/2 phosphorylation in the presence of OxR2 is more sustained com-
pared with that of OxR1. Temporal profiling of OxA-dependent receptor-
b
-arrestin and
b
-arrestin-ubiquitin proximity suggests tangible subtype-
specific differences in receptor trafficking and function. Importantly, these
delicate differences in protein complex formation, stability, and duration
might be useful in targeting these receptors for therapeutic purposes.
2.2. The peripheral signals
In response to different nutrients, the gastrointestinal tract produces over 20
enteroendocrine hormones that act locally, peripherally, and centrally to
affect food intake and regulate the digestion, absorption, distribution, and
metabolism of nutrients. The enteroendocrine hormones include serotonin
(5-hydroxytryptamine; 5-HT), ghrelin, glucagon-likepeptide (GLP)-1and-2,
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