Oral Presentation ANZOS Annual Scientific Meeting 2021

Intranasal Targeting Hypothalamic PTP1B and TCPTP Reinstates Leptin and Insulin Sensitivity and Promotes Weight Loss in Obesity (#123)

Garron Dodd 1 , C.E. Xirouchaki 2 3 , M. Eramo 2 3 , C.A. Mitchell 2 3 , Z.B. Andrews 2 4 , B.A. Henry 2 4 , M.A. Cowley 2 4 , T. Tiganis 2 3 5 6
  1. The University of Melbourne, Melbourne, VIC, Australia
  2. Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  3. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
  4. Department of Physiology, Monash University, Melbourne, Australia
  5. Monash Metabolic Phenotyping, Monash University, Melbourne, Australia
  6. Peter MacCallum Cancer Centre, Australia

The importance of hypothalamic leptin and insulin resistance in the development and maintenance of obesity remains unclear. The tyrosine phosphatases PTP1B and TCPTP attenuate leptin and insulin signalling and are elevated in the hypothalami of obese mice. We report that elevated PTP1B and TCPTP antagonise hypothalamic leptin and insulin signalling to repress feeding and promote white-adipose-tissue browning and contribute to the maintenance of obesity. Deletion of PTP1B and TCPTP in the hypothalami of obese mice enhanced enhances CNS leptin and insulin sensitivity, repressed represses feeding and increased increases browning, to decrease adiposity and improve glucose metabolism. The daily intranasal administration of a PTP1B inhibitor, plus the glucocorticoid antagonist RU486 that decreased decreases TCPTP expression, represses feeding, increases browning, promotes weight loss and improves glucose metabolism in obese mice.

Our findings causally link heightened hypothalamic PTP1B and TCPTP with the development of leptin and insulin resistance and the maintenance of obesity and define a viable pharmacological approach by which to reinstate hypothalamic leptin and insulin responsiveness to promote weight loss and combat obesity.