g.cooney@garvan.org.au

Molecular Metabolism

Obesity and Insulin Resistance

Increased body fat (obesity) is one of the most important current health problems because obesity is associated with the development of a number of serious and common diseases such as heart disease, stroke, type 2 diabetes, arthritis and cancer. The broad aim of our projects is to understand how different genes contribute to the way the body balances food intake and energy expenditure to maintain healthy body weight and what goes wrong when this balance breaks down and obesity develops.

Project 1:  Circadian Rhythms and energy metabolism

Many important genes of metabolism are expressed in a circadian rhythm synchronized with the light/dark cycle and feeding/sleeping patterns. The modern lifestyle is associated with disrupted eating and sleeping patterns and an increase in obesity but whether this is accompanied or caused by a disruption in the circadian rhythms of gene expression is not known. This project investigates whether circadian gene expression is altered in situations of obesity and insulin resistance and whether changing the expression of circadian genes can predispose to obesity.

Project 2: Mitochondrial metabolism and insulin resistance

Another research project is aimed at determining the role of muscle mitochondrial capacity in regulating glucose and lipid metabolism. In muscle the fibre type and number of mitochondria are correlated with insulin sensitivity. This project will determine whether increasing mitochondrial number by over-expressing mitochondrial transcription factors can also improve insulin action in muscle.

Project 3:  Metabolic phenotyping

We are also investigating how deletion of the genes c-Cbl and Grb14 in mice contribute to lean and insulin sensitive phenotypes (respectively) with the aim of identifying novel pathways for regulating energy expenditure, body fat and insulin action.

Selected References

• Mark E Cleasby, Jonathan R Davey, Tracie A Reinten, Michael W Graham, David E James, Edward W Kraegen and Gregory J Cooney.Acute bidirectional manipulation of muscle glucose uptake by in vivo electro-transfer of constructs targeting glucose transporter genes. Diabetes (in press) 2005.

• Molero, J.C., Jensen, T.E., Withers, P.C., Couzens, M., Herzog, H., Thien, C.B., Langdon, W.Y., Walder, K., Murphy, M.A., Bowtell, D.D., James, D.E., Cooney, G.J. c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action. J Clin Invest. 114:1326-1333, 2004.