How the gut talks to the brain?

Carel le Roux

Experimental Pathology

University College DublinImperial College LondonUniversity of Gothenburg

Conflict of interest

HerbalifeNovoNordisk, Johnson & Johnson, ONO pharmaceuticals, Covidien, Fractyl, GI Dynamics, Roche, AstraZeneca

Arcuate nucleus

Afferent factors in appetite regulation

Leptin GO

Insulin

PYYGLP-1OXM

Ghrelin

Vagus

CCK

Food IntakeEnergy Expenditure

GLP-1 effects in humans

Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 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.

GLP-1 secreted upon the ingestion of food

1.-cell:Enhances glucose-dependent insulin secretion in the

pancreas1

3.Liver: reduces hepatic glucose output2

2.α-cell:Suppresses postprandial

glucagon secretion1

4.Stomach: slows the rate of gastric

emptying3

5.Brain:Promotes satiety and

reduces appetite4,5

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.

Plasma glucose (mmol/L)

Incretin: β-cell response (oral vs IV glucose)

C-peptide (nmol/L)

Oral glucose (50 g)Isoglycaemic intravenous (IV) glucose

12

2

0

Crossover of healthy subjects (N = 6)

0 60 120 180

4

6

8

10

Pla

sm

a g

luc

os

e (

mm

ol/

L)

0 60 120 180

0.0

0.5

1.0

1.5

2.0

*

*

*

*

**

*

Incretin Effect

C-p

ep

tid

e (

nm

ol/

L)

Time (min) Time (min)

Nauck et al. J Clin Endocrinol Metab 1986*P ≤.05

Incretin effect reduced in type 2 diabetes

0

20

40

60

80

Ins

uli

n (

mU

/L)

0 30 60 90 120 150 180

Time (min)

** *

** **

0

20

40

60

80

0 30 60 90 120 150 180

Time (min)

**

*

*P ≤.05

Patients with type 2 diabetesControl subjects

Intravenous Glucose

Oral Glucose

Ins

uli

n (

mU

/L)

Nauck et al. Diabetologia 1986

0

10

20

30

40

250 500 1000 1000 2000 3000

LeanObese

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

asel

ine

15

0.2 0.4 0.5 0.6 0.7 0.8

* * * *15

-15

-30

Doses pmol/kg/min

Saline

Cal

ori

es (

% o

f sa

line)

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-H

r C

alo

ric

Inta

ke (

kcal

)

P=0.02

0

4000

3000

2000

1000

Saline PYY

24-H

r C

alo

ric

Inta

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

Minutes0

Ch

ang

e fr

om

bas

elin

e (m

m)

0

30 60 90 120 150 180

20

30

210

Infusion

Peptide YY3-36

Saline

Obese Group

PYY causes nausea at high doses

Plasma PYY end of infusion pmol/L (SEM)

VAS nausea baseline mm (SEM)

VAS nausea end of infusion mm (SEM)

Saline 13 ± 4.9 10.8 ± 2.2 10.8 ± 2.2

BachemA 146 ± 37* 9.7 ± 2.1 50.7 ± 10.3*

BachemB 94 ± 17* 10.8 ± 3.4 39.5 ± 10.5*

Polypep 90 ± 26* 9.0 ± 2.8 39.3 ± 12.2*

le Roux et al. Ann Clin Biochem. 2008

Oxyntomodulin and energy expenditure

OXMSaline

OXMSaline

OXMSaline

% Daily activity-related energy expenditure

0 50 100 150

0 50 100 150

0 50 100 150

% Daily total energy expenditure

% Physical activity level

p=0.022

p=0.045

p=0.0495

26%

9%

10%

Wynne et al. Diabetes. 2005

Atkinson’s experiment

BPSBP

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 / MedsLifestyle / Meds +1.6% +1.6%

BandingBanding -13%-13% BandingBanding -13%-13%

BypassBypass -25%-25%

Weight loss Weight loss 4242

4040

3636

3232

2828

2424

4242

4040

3636

3232

2828

2424

0 1 2 3 4 6 8 100 1 2 3 4 6 8 10 0 1 2 3 4 6 8 100 1 2 3 4 6 8 10Years of follow-upYears of follow-up

BM

I kg

/mB

MI

kg

/m22

BM

I kg

/mB

MI

kg

/m22

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-op1 month3 months6 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

LeanObeseRYGBLap Band

Time point (min)

PYY pmol/L

MEAL

le Roux et al Ann Surg 2006

PYY response pre & post RYGB

Months post-op0 1 3 6

0

2500

5000

7500***

***

PYY AUCpmol/l/min

le Roux et al Ann Surg 2009

*** ***

12 24

Good and poor weight loss after RYGB

le Roux et al. Ann Surg. 2007.

Weight loss GLP-1

50

40

30

20

10

0Good Poor

% W

eig

ht

loss

12000

8000

4000

0Good Poor

GL

P-1

pm

ol/L

/min

* *

*P <0.05

Blocking gut hormones with octreotide

Gastric banding Gastric bypass

1000

800

600

400

200

0Saline Octreotide

Kca

l

1000

800

600

400

200

0Saline Octreotide

Kca

l

*

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

Dose response curve

LEAN

Satiety

OBESE

Bypass surgery

Meal Size

Phy

siol

ogic

al r

ange

Activation to High-Calorie Foods after Gastric Bypass

OFCOFCACCACC

High-calorie food > Objects, n=19, cluster threshold Z>2.1 , P<0.05Scholtz, Miras, le Roux, Goldstone et al Gut 2013

AmygdalaAmygdala

Ventral Ventral striatumstriatum

Medial frontal Medial frontal cortexcortex

y 36R x 6

z -6

y -2

vACCvACC

Ventral Ventral striatumstriatum

CaudateCaudate

Pre > Post bypass Post bypass > Pre

Appetative behaviour after RYGBL

AS

T C

OM

PL

ET

ED

RA

TIO

(C

LIC

KS

)

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: reversable

Meillon, Miras, le Roux et al (unpublished)

Hypothesis

BMI

Time

40

30

20

Leptin Insulin

↑ Gut hormones, ↑ energy expenditure, taste

RYGB

Acknowledgements

Science Foundation Ireland, Wellcome Trust, Moulton Foundation, NIHRUniversity College Dublin,Catherine Godson, Donal O’Shea, Neil Docherty, Karl Neff, Sabrina Jackson, Sinead McDermott, Stephen Kearney, Jessie Elliott Trinity College DublinJohn ReynoldsUniversity of GothenburgTorsten Olbers, Lars Fandriks, Almantas Maleckas, Lena Carlsson, Per-Arne SvenssonImperial College LondonSteve Bloom, Mohammad Ghatei, Alex Miras, Andrew Frankel, Fred Tam, Julian Teare

King’s College LondonFrancesco Rubino, Stephanie Amiel, Simon Aylwin, Ameet Patel, Cynthia BorgUniversity of ZurichThomas Lutz, Marco BueterMusgrove Hospital, TauntonRichard Welbourn, Rob Andrews, Dimitri Pournaras, Alan OsbornFlorida State UniversityProf Alan SpectorOswaldo Hospital, Soa PauloRicardo CohenCatholic University of ChileCamilo BozaSaudi ArabiaAl-Qahtani, Ghalia Abdeen