It is now estimated that 10 per cent of the world’s population are overweight or obese. The myriad of disorders associated with obesity, including insulin resistance, glucose intolerance and dyslipidemia eventually lead to the development of type 2 diabetes. Despite major scientific advances in our understanding of the molecular pathways leading to insulin resistance and type 2 diabetes made during the last 10-15 years, current therapeutic drugs have had limited success. In the Cellular & Molecular Metabolism Laboratory, we aim to determine the key signal transduction pathways that lead to obesity induced insulin resistance in the hope of discovering novel drug targets to treat obesity. Work in our laboratory had centred on the nexus between inflammatory processes and lipid-induced insulin resistance for several years.
Inflammation and insulin resistance
Group Leader: Dr Graeme Lancaster
In the past decade it has become apparent that hyperlipidemia, a hallmark of obesity, is linked to a state of chronic inflammation. Somehow, lipid-induced inflammation results in the the activation of key serine threonine kinases namely c-jun amino terminal kinase (JNK) and inhibitor of κB kinase (IKK) in insulin responsive tissues such as adipose tissue, skeletal muscle and liver. It is known that activation of both JNK and IKK disrupt insulin signalling and cause insulin resistance. It is thought that the mechanisms linking lipid oversupply to inflammation involves increased deposition of lipid species which are known to activate JNK and IKK in liver and/or skeletal muscle leading to insulin resistance (see Figure below). However, the precise molecular mechanisms linking these lipid species to upregulation of JNK and IKK and ultimately impaired insulin action are not fully resolved. We have several projects in this group aimed at resolving the role of inflammation in insulin resistance. 
The role of dietary fat and overnutrition in the aetiology of insulin resistance
Group Leader: Dr Clinton Bruce
Overnutrition leads to excess lipid deposition in tissues such as skeletal muscle and liver. Since these organs are not normally storage depots for fat they become pathogenic during overfeeding. When lipid is stored in these tissues they become “lipotoxic” and eventually insulin resistant. One strategy to overcome lipid storage is to increase the oxidation of the lipid by enhanicing mitochondrial capacity (see Figure below). In this group we study mechanism by which a) certain lipid species dysregulate muscle metabolism and b) we can enhance lipid oxidation. We hope to derive new drug targets that can reduce fat storage and/or increase fat oxidation when people over eat.
The role of pro-inflammatory cytokines in mediating insulin resistance
Group Leader: Dr Vance Matthews
Many years ago, we discovered that interleukin-6 (IL-6), a plieotropic cytokine produced by many cells/tissues in response to stress, is actually produced by skeletal muscle during contraction. In a series of subsequent studies we were able to show that this and other "IL-6 family" cytokines are a potential therapeutic target to treat obesity via actions on several tissues including the skeletal muscle, the liver and the brain. These projects are on-going as we aim to elucidate the precise molecular mechanism by which these cytokines signal to protect against obesity-induced insulin resistance.