How the gut talks to the brain?

Carel le Roux

Diabetes Complications Research Centre

University College Dublin

Imperial College London

University of Gothenburg

Conflict of interest

NovoNordisk,

Johnson & Johnson,

ONO pharmaceuticals,

Covidien,

Fractyl,

GI Dynamics,

Roche,

AstraZeneca

Arcuate nucleus

Afferent factors in appetite regulation

LeptinGO

Insulin

PYY

GLP-1

OXM

Ghrelin

Vagus

CCK

Food Intake

Energy Expenditure

Rehfeld J, 2004

DISCOVERY OF GASTROINTESTINAL HORMONES

0

10

20

30

40

250 500 1000 1000 2000 3000

Lean

Obese

PYY

(pmol/L)

Test meal (kcal)

500 mL 900 mL

Calorie Intake vs PYY dose response

*

*

*

*

* *

le Roux et al Endocrinology 2006

PYY3-36 dose response in humans

Calorie intake Satiety

* P<0.05

20

10

5

0

Doses pmol/kg/min

Saline

mm

fro

m b

aselin

e

15

0.2 0.4 0.5 0.6 0.7 0.8

* * * *15

-15

-30

Doses pmol/kg/min

Saline

Calo

ries (

% o

f salin

e)

0

0.2 0.4 0.5 0.6 0.7 0.8

* *

le Roux et al. Endocrinology. 2006*P ≤.05 vs. saline

Effect of PYY3-36 on food intake

Obese Lean

4000

3000

2000

1000

0Saline PYY

24

-Hr

Calo

ric I

nta

ke (

kcal)

P=0.02

0

4000

3000

2000

1000

Saline PYY

24

-Hr

Calo

ric I

nta

ke (

kcal) P=0.001

Batterham, le Roux et al N Engl J Med 2003

Changes in appetite

Batterham, le Roux et al. N Engl J Med. 2003

10

-10

-20

Minutes

0

Ch

an

ge f

rom

baselin

e (

mm

)

0

30 60 90 120 150 180

20

30

210

Infusion

Peptide YY3-36

Saline

Obese Group

Atkinson’s experiment

BP

SBP

Recipient BP

Recipient SBP

Weight loss and food intake

Sham BW match Bypass

le Roux, Bueter, Lutz et al Gastroenterology 2009

Post surgery response

le Roux, Aylwin et al Ann Surg 2009

“Banding” “Bypass”

Surgical principles

Lifestyle / Meds+1.6%

Banding-13%

Bypass-25%

Weight loss 42

40

36

32

28

24

0 1 2 3 4 6 8 10Years of follow-up

BM

I

kg

/m

2

Long term weight loss maintenance

Sjöström, L. et al. N Engl J Med 2004

Visual analogue scores

How full

0 30 60 90 120 150 1800

25

50

75

100

VAS - How full are you?

Time from end of standard meal (min)

How hungry

0 30 60 90 120 150 1800

25

50

75

100Pre-op

1 month

3 months

6 months

VAS - How hungry are you?

Time from end of standard meal (min)

le Roux, Borg et al 2006 Brit J Surg

PYY response after bariatric surgery

0

10

20

30

40

50

-30 0 15 30 60 90 120 150 180

Lean

Obese

RYGB

Lap Band

Time point (min)

PYY

pmol/L

MEAL

le Roux et al Ann Surg 2006

Blocking gut hormones with octreotide

Gastric banding Gastric bypass

1000

800

600

400

200

0Saline Octreotide

Kcal

1000

800

600

400

200

0Saline Octreotide

Kcal

*

le Roux et al. Ann Surg. 2007*P <0.05

preoperative

Bueter M, le Roux CW & Ashrafian H, unpublished

Clinic – Anecdotal Dietary Change

postoperative

“I Don’t Enjoy Burgers Anymore” Syndrome

Paradoxical – as dietary weight loss increases preference for fatty food and sugars

• High Fat (Flavoured)

• Low Fat (Flavoured)

• Standard High Fat (Control)

le Roux, Spector, Lutz et al Am J Physiol Regul Integr Comp Physiol 2011

Assessment of food preference

Assessment of food preference

le Roux, Spector, Lutz et al Am J Physiol Regul Integr Comp Physiol 2011

Appetative behaviour after RYGB

PRE

POSTPRE

POST

LAS

T C

OM

PLE

TED

RA

TIO

(CLI

CK

S)

0

300

600

900

1200

1500

1800

2100

2400

2700

BREAKPOINT

RYGB CONTROLS

*

Miras, Spector, le Roux et al.

Am J Clin Nutr 2012

*

Reduction in appetative behaviour: reversableMeillon, Miras, le Roux et al (unpublished)

Dose response curve

LEAN

Satiety

OBESE

Bypass surgery

Meal Size

Physio

logic

al ra

nge

Hypothesis

BMI

Time

40

30

20

Leptin

Insulin

↑ Gut hormones, ↑ energy

expenditure, taste

RYGB

Acknowledgements

Science Foundation Ireland, WellcomeTrust, 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, Almantas Maleckas, 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, Dimitri Pournaras, Alan Osborn

Florida State University

Prof Alan Spector

Oswaldo Hospital, Soa Paulo

Ricardo Cohen

Catholic University of Chile

Camilo Boza

Saudi Arabia

Al-Qahtani, Ghalia Abdeen