Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Investigating adipose tissue lipid metabolism as a key regulator of whole-body glucose tolerance (#201)

Marin E Healy 1 , Xiao Y Zeng 1 , Jacqueline Stoeckli 1 , James R Krycer 1 , Daniel J Fazakerley 1 , Greg J Cooney 1 , David E James 1
  1. University of Sydney, University Of Sydney, NSW, Australia

Adipose tissue plays a far reaching role in whole-body fuel homeostasis beyond its role as a lipid reserve. First, it synthesises specific lipid species via de novo lipogenesis that can modulate either adipose tissue expansion itself or metabolism in other tissues of the body. Second, specific kinds of brown or beige adipocytes contribute to whole-body energy expenditure due to their unique capacity to produce heat from glucose and fat via mitochondrial oxidation.  One factor that links both of these processes is the enzyme Acetyl-CoA Carboxylase (ACC), which catalyses the conversion of acetyl-CoA to malonyl-CoA.  There are 2 ACC family members—ACC1 is found in cytosol and provides malonyl-CoA for lipogenesis, while ACC2 is localized to mitochondria and moderates import and oxidation of fat in mitochondria. Overall, ACC activity stimulates fat synthesis and blocks fat oxidation, resulting in net accumulation of fat. High lipogenesis and adipose fat accumulation are strongly associated with insulin resistance and glucose intolerance; conditions which are characteristic of type 2 diabetes (1). Therefore, to explore the adipose-specific functions of ACC, we created adipose-specific ACC1 and ACC2 double knockout (ADKO) mice to simultaneously block lipogenesis and promote fat oxidation in adipose tissue. When fed an adipogenic high-fat high-sugar Western diet for 2 weeks, the ADKO mice have an improvement in glucose tolerance and a striking 50% decrease in brown adipose tissue mass compared to control mice, and this precedes any changes in white adipose tissue mass. Additionally, ADKO mice tend to have increased glucose uptake into white adipose tissue. Our data demonstrate that ACC enzyme activity is integral in brown adipose tissue metabolism, potentially by controlling thermogenesis. For the first time, we identify adipose tissue ACC enzymes as key regulators of whole-body glucose homeostasis and propose ACC inhibition as a novel strategy to prevent type 2 diabetes.

  1. J. Berndt, P. Kovacs, K. Ruschke, N. Kloting, M. Fasshauer, M. R. Schon, A. Korner, M. Stumvoll, M. Bluher. (2007) Fatty acid synthase gene expression in human adipose tissue: association with obesity and type 2 diabetes. Diabetologia 50:1472-1480.