Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to differential local and systemic effects. — ASN Events
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  3. Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to differential local and systemic effects.

Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to differential local and systemic effects. (#240)

Sahar Keshvari 1 , Darren Henstridge 2 , Mark Febbraio 2 , Jon Whitehead 1
  1. Mater Research_UQ, Woolloongabba, QLD, Australia
  2. Garvan Institute, Sydney, NSW, Australia

The adiponectin axis regulates cardiometabolic tone making it an attractive therapeutic focus. However, strategies to target the receptors, AdipoR1 and AdipoR2, are limited by a rudimentary understanding of these atypical proteins. To address this, we previously employed molecular/cellular approaches to characterise AdipoR1 and AdipoR2 and demonstrated that cell-surface expression1 and temporal signalling profiles2 differed. We hypothesised such differences would promote differential effects in vivo and have explored this by characterising the effects of electrotransfer-mediated overexpression of AdipoR1 or AdipoR2 in the Tibialis Anterior (TA) muscle of lean (chow) or obese (10 wk HFD) mice (n=6/group).

In lean mice, overexpression of AdipoR1 or AdipoR2 increased phosphorylation of downstream effectors AMPK, AKT and ERK (all p<0.05), but not p38MAPK.  The magnitude of these effects was reduced in obese mice, consistent with the development of adiponectin resistance (circulating adiponectin was not reduced after 10 wk HFD). Both AdipoR1 and AdipoR2 increased glut-4 mRNA (2-fold, p<0.05) and this was unaffected by obesity.  In contrast, only AdipoR2 increased pparα and a downstream target gene Acox1 (all p<0.05) and this effect was blunted by obesity.  Surprisingly, exclusive overexpression of AdipoR2 in TA muscle of obese mice resulted in marked systemic effects which included (i) increased circulating adiponectin levels and (ii) decreased body weight gain and reduced epididymal fat mass and markers of adipose tissue inflammation (all p<0.05).

These results demonstrate both overlapping and discrete effects of AdipoR1 and AdipoR2 and suggest increased expression/transduction via either AdipoR1 or AdipoR2 may be sufficient to enhance downstream signalling and regulated glucose uptake, but activation of the PPARα axis is specific to AdipoR2.  Our most striking observation is the apparent systemic impact of muscle-specific overexpression of AdipoR2.  We are exploring the mechanisms that underpin these findings, which may ultimately reveal novel therapeutic strategies to enhance cardiometabolic function. 

  1. Keshvari, S. et al. Biochem Biophys Res Commun 432, 28-33, (2013).
  2. Keshvari, S. and Whitehead, J. P. Mol Cell Endocrinol 409, 121-9, (2015).