Current Research Projects

Understanding adiponectin biology

Our aim is to identify therapeutic strategies that will improve insulin sensitivity and metabolism by increasing circulating adiponectin levels or increasing adiponectin sensitivity. Adiponectin is produced and secreted by adipocytes and it regulates carbohydrate and lipid metabolism in liver and skeletal muscle. Adiponectin circulates in a range of multimeric forms and the most metabolically active, High Molecular Weight (HMW) multimers are preferentially reduced in obese subjects and patients with Type 2 diabetes (see journal article).

We reported that post-translational modifications (PTMs) of adiponectin are essential for efficient multimerization and secretion, thereby establishing these steps as potential therapeutic targets (see journal article). Our recent work has identified a dietary factor that increases these PTMs, with a concomitant increase in the production of HMW adiponectin. We are also investigating the putative role of novel PTMs in adiponectin clearance.

In complementary studies we are beginning to dissect the cell biology of the adiponectin receptors, AdipoR1 and AdipoR2, which mediate adiponectin’s beneficial effects. The adiponectin receptors represent a new class of 7 transmembrane domain receptor and we have recently identified a novel AdipoR1 interacting protein that modulates AdipoR1 and adiponectin signalling. 

Investigating the coordination of insulin signalling

Insulin receptor substrate-1 (IRS-1) plays a central role in insulin signalling and also acts as a nexus for integration of heterologous signalling cascades. Defects in IRS-1 function contribute to the aetiology of insulin resistance and type 2 diabetes (see journal article).

We are currently defining the mechanisms that facilitate efficient IRS-1 function in healthy cells and the processes that lead to dysregulation of IRS-1 in insulin resistant cells. Using in silico and functional approaches (including characterisation of recombinant mutant proteins) we have recently identified novel Ser/Thr phosphorylation events that alter the subcellular distribution of IRS-1 and compromise the ability of IRS-1 to interact with upstream and downstream effectors.

We are also exploring the mechanisms by which glucocorticoids impair glucose uptake. Glucocorticoids are widely used to treat a large variety of clinical conditions including inflammatory disorders and asthma. Treatment often leads to a clinically significant abnormality in glucose homeostasis, requiring treatment with oral hypoglycaemic drugs.

Our recent investigations have established that glucocorticoids impair basal and insulin-stimulated glucose uptake in insulin responsive cell types via a mechanism that impairs distal signalling / trafficking events and we are currently exploring several candidate effectors. 

IMPDH biology – obesity and intracellular energy

Our recent in vitro and in vivo work has identified the enzyme inosine monophosphate dehydrogenase (IMPDH) as a potential anti-obesity target. IMPDH catalyses the rate-limiting step in the de-novo biosynthesis of guanine nucleotides (GTP). We previously established that IMPDH was regulated by insulin and implicated in lipid accretion by virtue of its regulated association with intracellular lipid droplets (see journal article). 

More recently, we have taken a number of complementary approaches to define the role of IMPDH in adipogenesis – the process which underpins the increase in fat mass associated with obesity – and shown that inhibition of IMPDH reduces diet-induced obesity.

Detailed characterisation of IMPDH proteins has also revealed divergence between isoforms and we are currently exploring these differences which may confer cell plasticity in a cell-type specific, isoform-specific manner.

Associate Professor Whitehead is currently offering postgraduate projects in his laboratory. Click here for more information.