Hutchinson Evans Laboratory

Metabolic G protein-coupled receptor group

Dana Hutchison

Dr Dana Hutchinson
Research Only Fellow
NHMRC Career Development Fellow

Project areas | Grants | Links

Project areas

Research focus

The high prevalence of obesity and Type 2 diabetes worldwide has provoked substantial interest in identifying mechanisms involved in these diseases. As outlined recently by the World Health Organization, government and health professionals would ideally manage obesity and type 2 diabetes by encouraging increased physical activity and reduced intake of energy-rich foods, but these measures have a low success rate amongst many individuals, highlighting the need for additional pharmacological approaches.
Dr Hutchinson's laboratory targets G protein-coupled receptors for therapy for obesity and type 2 diabetes, through effects on adipocyte metabolism and increased glucose disposal in skeletal muscle.

Modulation of glucose metabolism by GPCRs

Glucose homeostasis is impaired in type 2 diabetes and identification of non-insulin ways of controlling blood glucose will be important for future therapeutic development. There is increasing recognition that glucose homeostasis can be regulated independently of insulin by activation of GPCRs. We have found that activation of the sympathetic nerves and the release of norepinephrine and activation of adrenoceptors lead to an insulin-independent mechanism that increases glucose uptake in brown fat and skeletal muscle. Our aim is to understand these novel mechanisms and if these mechanisms can be utilized to combat obesity and type II diabetes.

The role of brite adipocytes

There are two types of adipose tissue with distinct physiological functions: white adipose tissue (WAT) stores chemical energy in the form of triacylglycerol whereas brown adipose tissue (BAT) releases chemical energy in the form of heat (thermogenesis), thereby counteracting obesity and related disorders. Active BAT in human is found abundantly in newborns and children but decreases dramatically before adulthood, whilst in mice it is present throughout life. Recent studies have shown that white adipocytes can be transformed into brown – like (beige/brite) adipocytes by certain stimuli (cold exposure, rosiglitazone). We are characterizing the pharmacology of these brite adipocytes and their role in mice models of obesity and type 2 diabetes. Increased knowledge of the role of brite adipocytes will suggest new ways on how BAT can be used as a therapeutic target against obesity.

Ligand-directed signaling by GPCRs

GPCRs are activated not just by classical agonists signaling through one particular G-protein but can couple to multiple downstream effectors and G-proteins in addition to their classically linked G-protein. I have demonstrated the pleiotropic actions of GPCRs in recombinately expressed cells, with focus now aimed at demonstrating bias in more physiologically relevant cells/tissues. Activation of b2-adrenoceptors by conventional agonists increase glucose uptake in skeletal muscle but will have serious side effects in vivo (glucose production in liver, vasoreactivity, cardiac hypertrophy that occur via a b2-adrenoceptor-cAMP-PKA mediated pathway). We have identified a biased b-adrenoeptor ligand that increases glucose uptake in skeletal muscle cells without utilising the canonical cyclic AMP pathway. This may indicate a potential beneficial role of activating b2-adrenoceptors in skeletal muscle via a cyclic AMP independent manner.

Key Publications

Research Papers

Dehvari N, Hutchinson DS, Nevzorova J, Dallner OS, Sato M, Kocan M, Merlin J, Evans BA, Summers RJ, Bengtsson T. β2-Adrenoceptors increase translocation of GLUT4 via GPCR kinase sites in the receptor C-terminal tail. Br J Pharmacol 165:1442-56, 2012.

Mattsson CL, Csikasz RI, Chernogubova E, Yamamoto DL, Hogberg HT, Amri EZ, Hutchinson DS, Bengtsson T. β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis. Am J Physiol Endocrinol Metab. 301:E1108-18, 2011.

Sato M, Hutchinson DS, Halls ML, Furness SG, Bengtsson T, Evans BA, Summers RJ. Interaction with caveolin-1 modulates G protein coupling of mouse β3-adrenoceptor. J Biol Chem. 287:20674-88, 2012.

Evans BA, Broxton N, Merlin J, Sato M, Hutchinson DS, Christopoulos A, Summers RJ. Quantification of functional selectivity at the human α1A-adrenoceptor. Mol Pharmacol. 79:298-307, 2011.

Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ. Ligand-directed signalling at b-adrenoceptors. Br J Pharmacol. 159:1022-38, 2010.

Merlin J, Evans BA, Csikasz RI, Bengtsson T, Summers RJ, Hutchinson DS. The M3-muscarinic acetylcholine receptor stimulates glucose uptake in L6 skeletal muscle cells by a CaMKK-AMPK-dependent mechanism. Cell Signal. 22:1104-13, 2010.

Grants

  • Understanding G protein-coupled receptors (GPCRs): accelerating discovery from concept to clinic, NHMRC Program grant 519461 (2009-13) as Co-I B
  • Alteration of glucose metabolism by GPCR activation, NHMRC Career Development Award 545952 (2009-2016); $370,000

Member of ASCEPT, ANZOS

Collaborations:

Project: Role of GPCRs in glucose homeostasis in adipocytes and skeletal muscle

Prof Tore Bengtsson, Stockholm University, Sweden http://www.su.se/mbw/research/research-groups/integrative-biology/group-bengtsson

Prof Barbara Cannon, Stockholm University, Sweden http://www.su.se/mbw/research/research-groups/integrative-biology/emeritus-cannon

Prof Roger Summers (DDB)
Dr Bronwyn Evans (DDB)
Dr Masaaki Sato (DDB)
Dr Anette Oberg (DDB)

Project: Ligand-directed signalling at GPCRs
Prof Roger Summers (DDB)
Dr Bronwyn Evans (DDB)

Project: Metabolic effects of relaxin receptor activation
Prof Roger Summers (DDB)
Dr Martina Kocan (DDB)

Project: Cannabinoid receptor signalling in obesity
A/Prof Andrew McAinch, Victoria University, Australia http://www.vu.edu.au/contact-us/andrew-mcainch

Lab members
Jon Merlin (PhD candidate)
Sheng Ang Yu (PhD candidate)