Poster Presentation Australian & New Zealand Obesity Society 2015 Annual Scientific Meeting

Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to differential local and systemic effects. (#249)

Sahar Keshvari 1 , Darren Henstridge 2 , Mark Febbraio 3 , Jon Whitehead 1
  1. Mater Research_UQ, Woolloongabba, QLD, Australia
  2. Baker IDI, Melbourne, VIC, Australia
  3. Diabetes and Obesity, Garvan Institute, Sydney, NSW, Australia

Hypoadiponectinemia and adiponectin insensitivity contribute to obesity-related cardiometabolic disorders.  However, therapeutic strategies are constrained by a rudimentary understanding of the adiponectin receptors, AdipoR1 and AdipoR2, which are atypical seven transmembrane domain containing proteins. To address this we previously employed molecular and cellular approaches to characterise the receptors, demonstrating that cell-surface expression and temporal signalling profilesof AdipoR1 and AdipoR2 differed1,2.  In the current study we tested the hypothesis that such differences would promote differential effects in vivo 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 TA muscle from 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, despite unchanged circulating adiponectin, consistent with the development of adiponectin resistance. 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 was blunted by obesity.  Surprisingly, exclusive overexpression of AdipoR2 in TA muscle of obese mice resulted in marked systemic effects including (i) increased circulating adiponectin and (ii) decreased body weight gain, 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.  The 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).