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The role of glucagon and GLP-1 in the regulation of appetite.

The role of glucagon and GLP-1 in the regulation of appetite. Katherine Simpson , Jennifer Parker, Niamh Martin, Ben Field, James Minnion , Mohammad Ghatei and Steve Bloom Dept. Investigative Medicine Academic Trainees Annual Event 5 th May 2011. Obesity and type 2 diabetes mellitus.

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The role of glucagon and GLP-1 in the regulation of appetite.

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  1. The role of glucagon and GLP-1 in the regulation of appetite. Katherine Simpson, Jennifer Parker, Niamh Martin, Ben Field, James Minnion, Mohammad Ghatei and Steve Bloom Dept. Investigative Medicine Academic Trainees Annual Event 5th May 2011

  2. Obesity and type 2 diabetes mellitus 25% of adults in England are obese (BMI>30 kg/m2) (Health and Social Care Information Centre, 2010)

  3. Type 2 diabetes • Insulin resistance and high circulating glucagon • GLP-1 analogues: exenatide, liraglutide GLP-1 and glucagon co-agonism: reduced body weight improved glucose profile marginal reduction in food intake increased energy expenditure (Pocai A et al Oct 2009 and Day JW et al Oct 2009)

  4. Gut-brain axis

  5. Pre-proglucagon processing

  6. Pre-proglucagon processing

  7. Pre-proglucagon processing

  8. Glucagon and GLP-1 • Peripherally administered: decreases food intake in animals • Peripheral effects prevented by: Vagotomy or lesions in the AP and NTS • Human studies: Peripheral administration decreases meal size • c-fos peripheral GLP-1: AP, NTS, amygdalaand PVN

  9. Aims: to answer the following questions • What is the effect of co-administration of glucagon and GLP-1 on food intake? (2) Which CNS areas are responsible for this effect?

  10. Effects of glucagon on food intake

  11. Effects of GLP-1 on food intake

  12. ‘Subthreshold doses’ of glucagon and GLP-1

  13. Co-administration of glucagon and GLP-1 Saline GLP-1 Glucagon combined

  14. Question 2: Which CNS areas are responsible for these effects on food intake?

  15. Hypothalamus Brainstem AP NTS NTS vagal afferents

  16. 250 uM Saline s/c Glucagon 750 nmol/kg s/c 250 uM GLP-1 600 nmol/kg s/c 250 uM

  17. Dose response c-fos activation in the brainstem following glucagon administration

  18. Dose response c-fos activation in the brainstem following GLP-1 administration

  19. c-fos activation in the brainstem following co-administration of glucagon and GLP-1

  20. No significant differences in hypothalamus • Central nucleus of amygdala and reward

  21. Summary Co-administration of glucagon and GLP-1: • decreases food intake to a greater degree than either peptide alone • Increases c-fos expression in similar brainstem areas: AP and NTS

  22. Future work • Food intake and CNS pathways: - which neuronal population (2)Chronic effects of dual receptor agonism: - chronic feeding studies in rodents (3) Effects in humans: - glucagon/GLP-1 co-infusion and the effect on food intake

  23. (4) Glucose homeostasis: - glucose tolerance tests (5) Energy expenditure: - calorimetry - BAT mass and UCP-1 mRNA

  24. Acknowledgements Professor Steve Bloom Dr Niamh Martin Jenny Parker, Klara Hostomska, Jamie Plumer Dr James Minnion, Dr Ben Field and Dr Tricia Tan Professor Mohammad Ghatei Wellcome Trust

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