How the gut talks to the brain?

1. How the gut talks to the brain? Carel le Roux Experimental Pathology University College Dublin Imperial College London University of Gothenburg

2. Conflict of interest Herbalife NovoNordisk, Johnson & Johnson, ONO pharmaceuticals, Covidien, Fractyl, GI Dynamics, Roche, AstraZeneca

4. Arcuate nucleus

5. Leptin GO Insulin Afferent factors in appetite regulation Food Intake Energy Expenditure Vagus CCK Ghrelin PYY GLP-1 OXM

6. GLP-1 effects in humans GLP-1 secreted upon the ingestion of food 5.Brain: Promotes satiety and reduces appetite4,5 2.α-cell: Suppresses postprandialglucagon secretion1 3.Liver: reduces hepatic glucose output2 1.-cell:Enhances glucose-dependent insulin secretion in the pancreas1 4.Stomach: slows the rate of gastric emptying3 Adaptedfrom1Nauck MA, et al. Diabetologia1993;36:741–744; 2Larsson H, et al. Acta PhysiolScand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.

7. Incretin: β-cell response (oral vs IV glucose) 2.0 * * 1.5 * Incretin Effect * * 1.0 * C-peptide (nmol/L) * 0.5 0.0 0 60 120 180 Crossover of healthy subjects (N = 6) Oral glucose (50 g)Isoglycaemic intravenous (IV) glucose Plasma glucose (mmol/L) C-peptide (nmol/L) 12 10 8 6 Plasma glucose (mmol/L) 4 2 0 0 60 120 180 Time (min) Time (min) Mean (SE)Data from Plasma glucose values converted to mmol/L from mg/dL using conversion factor of 0.0555; C-peptide values converted to nmol/L from ng/mL using conversion factor 0.333. Nauck et al. J Clin Endocrinol Metab 1986 *P ≤.05

8. Incretin effect reduced in type 2 diabetes * * * * * * * * * * Intravenous Glucose Oral Glucose Control subjects Patients with type 2 diabetes 80 80 60 60 Insulin (mU/L) Insulin (mU/L) 40 40 20 20 0 0 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Time (min) Time (min) Nauck et al. Diabetologia 1986 *P ≤.05

9. Calorie Intake vs PYY dose response * * * * PYY (pmol/L) * * 900 mL 500 mL Test meal (kcal) le Roux et al Endocrinology 2006

10. PYY3-36 dose response in humans Satiety Calorie intake 20 * * 15 * * * * 15 0 10 Calories (% of saline) mm from baseline -15 5 -30 0 Saline Saline 0.2 0.2 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 Doses pmol/kg/min Doses pmol/kg/min * P<0.05 le Roux et al. Endocrinology. 2006 *P ≤.05 vs. saline

11. Effect of PYY3-36 on food intake Obese Lean 4000 4000 P=0.02 P=0.001 3000 3000 2000 2000 24-Hr Caloric Intake (kcal) 24-Hr Caloric Intake (kcal) 1000 1000 0 0 Saline Saline PYY PYY Batterham, le Roux et al N Engl J Med 2003

12. Changes in appetite Obese Group Saline 30 20 10 Change from baseline (mm) 0 Peptide YY3-36 -10 Infusion -20 0 30 60 90 120 150 180 210 Minutes Batterham, le Roux et al. N Engl J Med. 2003

13. PYY causes nausea at high doses le Roux et al. Ann Clin Biochem. 2008

14. Oxyntomodulin and energy expenditure 26% OXM p=0.022 Saline 0 50 100 150 % Daily activity-related energy expenditure 9% OXM p=0.045 Saline 0 50 100 150 % Daily total energy expenditure 10% OXM p=0.0495 Saline 0 50 100 150 % Physical activity level Wynne et al. Diabetes. 2005

15. Atkinson’s experiment Recipient BP BP Recipient SBP SBP

16. Weight loss and food intake Sham BW match Bypass le Roux, Bueter, Lutz et al Gastroenterology 2009

17. Post surgery response le Roux, Aylwin et al Ann Surg 2009

18. Surgical principles “Banding” “Bypass”

19. Long term weight loss maintenance 42 40 36 32 28 24 Weight loss Lifestyle / Meds +1.6% Banding -13% BMI kg/m2 Bypass -25% 0 1 2 3 4 6 8 10 Years of follow-up Sjöström, L. et al. N Engl J Med 2004

20. Visual analogue scores le Roux, Borg et al 2006 Brit J Surg

21. PYY response after bariatric surgery MEAL PYY pmol/L Time point (min) le Roux et al Ann Surg 2006

22. PYY response pre & post RYGB *** *** PYY AUC pmol/l/min 24 12 Months post-op le Roux et al Ann Surg 2009

23. Good and poor weight loss after RYGB GLP-1 Weight loss 12000 50 * * 40 8000 30 GLP-1 pmol/L/min % Weight loss 20 4000 10 0 0 Good Good Poor Poor le Roux et al. Ann Surg. 2007. *P <0.05

24. Blocking gut hormones with octreotide Gastric bypass Gastric banding * 1000 1000 800 800 600 600 Kcal Kcal 400 400 200 200 0 0 Saline Saline Octreotide Octreotide le Roux et al. Ann Surg. 2007 *P <0.05

25. Dose response curve LEAN OBESE Bypass surgery Satiety Physiological range Meal Size

26. Activation to High-Calorie Foods after Gastric Bypass R x 6 y 36 Caudate vACC ACC OFC Ventral striatum Pre > Post bypass Post bypass > Pre Medial frontal cortex y -2 z -6 Ventral striatum Amygdala High-calorie food > Objects, n=19, cluster threshold Z>2.1 , P<0.05 Scholtz, Miras, le Roux, Goldstone et al Gut 2013

27. Appetativebehaviour after RYGB Miras, Spector, le Roux et al. Am J Clin Nutr 2012

28. Reduction in appetativebehaviour: reversable Meillon, Miras, le Roux et al (unpublished) *

29. Hypothesis BMI Leptin Insulin 40 30 RYGB 20 ↑ Gut hormones, ↑ energy expenditure, taste Time

30. Acknowledgements Science Foundation Ireland, Wellcome Trust, Moulton Foundation, NIHR University College Dublin, • Catherine Godson, Donal O’Shea, • Neil Docherty, Karl Neff, Sabrina Jackson, Sinead McDermott, Stephen Kearney, Jessie Elliott Trinity College Dublin • John Reynolds University of Gothenburg • Torsten Olbers, Lars Fandriks, AlmantasMaleckas, Lena Carlsson, Per-Arne Svensson Imperial College London • Steve Bloom, Mohammad Ghatei, Alex Miras, Andrew Frankel, Fred Tam, Julian Teare King’s College London • Francesco Rubino, Stephanie Amiel, Simon Aylwin, Ameet Patel, Cynthia Borg University of Zurich • Thomas Lutz, Marco Bueter Musgrove Hospital, Taunton • Richard Welbourn, Rob Andrews, DimitriPournaras, Alan Osborn Florida State University • Prof Alan Spector Oswaldo Hospital, Soa Paulo • Ricardo Cohen Catholic University of Chile • CamiloBoza Saudi Arabia • Al-Qahtani, Ghalia Abdeen