Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

A hypothalamic phosphatase switch coordinates white adipose tissue browning with feeding (#12)

Garron T Dodd 1 , Zane B Andrews 2 , Stephanie Simonds 2 , Jens Bruning 3 , Natalie J Michael 2 , Michael de Veer 4 , David Spanswick 2 , Michael A Cowley 2 , Tony Tiganis 1
  1. Metabolic Disease and Obesity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. Department of Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  3. Max Plank Institute for Metabolism Research, Cologne, Germany
  4. Monash Biomedical Imaging, Monash University, Melbourne, VIC, Australia

Obesity is the single most important contributor to the development of type 2 diabetes (T2D) and effective obesity treatments will have profound implications for combating T2D.

The identification of the thermogenic beige adipocyte has opened up new ways in which to treat obesity and T2D. Beige adipocytes can interconvert between a white and beige adipocyte state, a process referred to as white adipose tissue (WAT) browning. This interconversion allows the adipose tissue to switch between an energy storage versus expenditure state. The co-ordination of energy intake with energy expenditure is essential to maintaining energy homeostasis.

To examine the role of WAT browning in this process, we measured WAT browning in the inguinal WAT (ingWAT) of fed verse food-restricted C57BL/6 mice by measuring the expression of beige adipocyte markers and beige fat activity by 18F-FDG-PET. We found that feeding induced the expression of beige adipocyte markers, enhanced beige adipocyte activity and whole-body energy expenditure. These changes in WAT browning and whole body energy expenditure are dependent upon the hypothalamic-adipose tissue axis as these effects are lost if sympathetic outflow to ingWAT is denervated. Our results indicate that the feeding-induced changes in WAT-browning are mediated by the regulation of insulin signalling within neurons of the arcuate nucleus (ARC) of the hypothalamus. By deleting the insulin receptor phosphatase, TCPTP within ARC neurons we enhanced the neuronal responsivity to insulin which resulted in elevated sympathetic outflow promoting WAT browning. These effect were attenuated by partial insulin receptor deletion within the ARC. Furthermore, TCPTP deletion within the ARC of diet-induced obese mice resulted in significant weight loss, reduced adiposity and improved whole-body insulin sensitivity. Our studies suggest that insulin signalling within neurons of the ARC coordinate WAT browning and energy expenditure with feeding for the maintenance of energy balance.

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