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 5 th May 2011

2. Obesity and type 2 diabetes mellitus 25% of adults in England are obese (BMI>30 kg/m 2 ) (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

8. 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 Glucagon and GLP-1

9. Aims: to answer the following questions (1)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. AP NTS vagal afferents Brainstem Hypothalamus

16. Glucagon 750 nmol/kg s/c GLP-1 600 nmol/kg s/c Saline 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 (1)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