Abstract
The adiponectin axis is a major regulator of
metabolic, cardiovascular and inflammatory tone.
Current understanding of the adiponectin receptors,
R1 and R2, is rudimentary constraining
our ability to target these atypical seven transmembrane
receptors. Hence, we have started to
characterise R1 and R2.We previously reported that
R1 exhibits robust (60%) cell-surface expression
(CSE) under steady-state conditions (no serum starvation)
whilst R2 is undetectable and showed these
differences were predicated by the non-conserved
N-terminal, intracellular trunks [1].
Here we hypothesised that (i) CSE of R1/R2 is
regulated, (ii) R1/R2 are subject to palmitoylation
and this regulates CSE/function (as in GPCRs). To
address these hypotheses we have employed bioinformatics,
cell-based and in vivo approaches.
We demonstrate that (i) serum starvation
increases R2 CSE and adiponectin stimulates internalisation
of R1/R2 (all p < 0.05). (ii) Bioinformatics
analysis revealed a putative conserved ‘canonical’
palmitoylation site in the juxtamembrane region of
R1(124) and R2(135), plus additional non-conserved
sites. This was confirmed using mutagenesis/acylbiotinyl
exchange chemistry. Palmitoylation of
R1(124) or R2(135) was shown to be required for efficient CSE of R1 and R2 and coupling to downstream
signalling effectors including AMPK, AKT and
ERK in cell lines and in vivo in mouse skeletal muscle
respectively (all p < 0.05).
These results provide increasing evidence that
CSE of R1 and R2 is under complex, differential
regulation and is essential for coupling adiponectin
to downstream signalling effectors. Further studies
are required to elaborate the detailed molecular
mechanisms that may provide novel therapeutic
opportunities.
Original language | English |
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Pages (from-to) | 114-115 |
Journal | Obesity Research and Clinical Practice |
Volume | 8 |
Issue number | Suppl 1 |
DOIs | |
Publication status | Published - Dec 2014 |
Event | The Australian and New Zealand Obesity Society and the Australian Lifestyle Medicine Association Annual Scientific Meeting: Obesity is everyone’s challenge - Novotel on Brighton Beach, Sydney, Australia Duration: 16 Oct 2014 → 18 Oct 2014 |