Weight regain

Carel le Roux University College Dublin

Conflict of interest

Consilient Health,

NovoNordisk,

Johnson & Johnson,

ONO pharmaceuticals,

Covidien,

Fractyl,

GI Dynamics,

Roche,

AstraZeneca

Lilly

Boehringer Ingelheim

Recidivism after volitional weight loss

BMI

Time

40

30

20

Volitional weight loss

Homeostatic

response promotes

weight regain

Settling

point

Reduced-

obese state

Age-related weight gain

Years

Body w

eig

ht

(kg)

Months

Small weight gain represents natural history

Adapted from Lean MEJ How does sibutramine work? IJO (2001) 25, Suppl 4 S8-S11

STORM: MEAN BODY WEIGHT CHANGES

104

102

100

98

96

94

92

90

880 122 4 6 8 10 14 16 18 20 22 24

Month

Bo

dyw

eig

ht

(kg

) Control

Sibutramine

Weight loss Weight maintenance

NB: Same diet and exercise for both sibutramine and control

XENDOS: Effect of Xenical on weight

compared to placebo over 4 yearsC

ha

ng

e in

bo

dyw

eig

ht (k

g)

Week

–4.1 kg

–6.9 kg*

*p<0.001 vs placebo + lifestyle

Placebo + lifestyle (n=564) Xenical + lifestyle (n=850)

–12

0

–10

–6

–2

–4

–8

26 156 2080 52 104 130 182

Adapted from Torgerson JS et al. Diabetes Care 2004; 27: 155–161

0 1 2 3 4 6 8 10 15 20

Follow-up, years

5

0

-5

-10

-15

-20

-25

-30

-35Mean

weig

ht

ch

an

ge (

%)

Banding

Vertical

banded

gastroplasty

Control

Gastric

bypass

Body weight change: Swedish Obese Subjects study

Sjöström L, et al. JAMA 2012; 307:56–65.

Weight loss distribution after bariatric surgery

(n=877) (n=513)

Manning et al. Surg Endosc 2015;29:1484–91.

RYGBP, Roux-En Y gastric bypass; SG, sleeve gastrectomy.

(n=877) (n=513)(n=877) (n=513)

What are the pathognomonic

symptoms of obesity?

Eugenia Martinez

Vallejo Nude

Eugenia Martinez Vallejo

Nude

by Juan Carreño de Miranda

In 1680, she was brought to court

to be admired as a monstrous

manifestation of nature. She was

six years old at the time, and

already weighed 70 kg. She

attended celebrations and

gatherings in the palace in order

to be seen by the royals and their

guests.

Defining end points for metabolic surgery

Carel le Roux

University College

Dublin

Imperial College London

University of Gothenburg

Where are the neurons situated

that code for hunger and satiety?

Obesity has genetic determinants: GWAS

pathway analyses link CNS genes to obesity

Tissues sorted by physiological system – genes from CNS showed association (in red)

Locke AE et al. Nature 2015;518:197–206

6

5

4

3

0

1

2

-Lo

g1

0(p

va

lue

)

Physiological system

CNS, central nervous system; GWAS, Genome-Wide Association Study

Courtesy Prof Licio Velloso

Via neurons in the arcuate nucleus

AgRP, Agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; NPY, neuropeptide Y; POMC, pro-opiomelanocortin Secher et al. J Clin Invest 2014;124:4473–88; van Can et al. Int J Obes (Lond) 2014;38:784–93

Successful weight loss treatments

increase satiety and reduce hunger

Arcuate

nucleusPOMC/

CART

NPY/

AgRP

Appetite

Diets/

Medication/

Bariatric surgery

HungerSatiety

Brain Regions Activated in Response to

Palatable Food or Food-Associated Cues

Kenny et al. Neuron 69:664-679, 2011

Normal physiology of weight regainDulloo AG et al. Int J Obes Relat Metab Disord. 1996

Obesity and Its Care: A Battle of Forces

that Influence the Fat Mass Set Point

Body fat mass set point

Abnormal

dietary

constituents

Unhealthy

muscle

Sleep

deprivation

Stress Disrupted

circadian

rhythms

Weight

gain

inducing

medications

Years of Exposure

Obesity and Its Care: A Battle of Forces

that Influence the Fat Mass Set Point

Abnormal

dietary

constituents

Unhealthy

muscle

Sleep

deprivation

Stress Disrupted

circadian

rhythms

Weight

gain

inducing

medications

Healthy

diet

Regular

physical

activity

More and

better

sleepStress

reduction

Stable

eating

patterns

Weight

stabilizing

alternatives

Body fat mass set point

Years

MedicationsSurgery

Dose response curve

Miras and le Roux. Cell Metabolism 2017

LEAN

Satiety

OBESE

Intervention

Meal Size

Ph

ysio

logic

al ra

nge

Recidivism after volitional weight loss

BMI

Time

40

30

20

Volitional weight loss

Homeostatic

response promotes

weight regain

Settling

point

Reduced-

obese state

Early Stage Phase 2aPhase 1 Phase 3Phase 2b

PYY LigandJNJ-9321

GT-002

NN9747

Regulatory/

approved

MC4R AgonistPL-8905

MIC-1GDF-15

NPY5 AntagonistS-237648

GLP-1/GIPdual agonist

ZP-DI-70

GLP-1/GIP

TAK-94

NMUR2-agonistNMU-7005

GLP-1R agonistEfpeglenatide

Ghrelin analogAZP-531

GOAT inhibitorGLW-01

SGLT2/PhenCana/phen

MA0ITesofensine

GLP-1/Glucagon

dual agonistMOD-6031

JNJ-5111

BI456906

NN9030

NN9277

AmylinBI473494

NN9838

Amylin/Calcitonin

Dual agonistKBP-089

Anti-FGFR1/KLBBFKB8488A

NGM313

SGLT1/2iLIK066

GLP-1/Glucagon

dual agonistMEDI0382

Amylin/Calcitonin

Dual agonistKBP-042

MetAP2 inhibitorKBP-089

Activin T2R mAbBimagrumab

5HT2cR agonistlorcaserin

CNS CombosQsymia

Contrave

Novartis Genentech Takeda Arena Zealand

Astra Zeneca Opko Biologics Shionogi Rhythm

Lilly/Nordic JandJ Alizé Palatin

Novo Nordisk BI/Zealand Sanioni/Medics Zafgen Scohia

Sanofi

GIP/GLP-1/Glucagon

triple agonistNN9423

The tools of the future?

GLP-1R/GCGSAR425899

GLP-1R agonistLiraglutide

GLP-1R agonistSemaglutide

Overall treatment strategy

Typical algorithm

(progress through algorithm as clinically required)

Professionally-directed lifestyle change

Weight loss surgery

Combination therapies

Self-directed lifestyle change

Add medications

Hypothesis

BMI

Time

40

30

20

Leptin

Insulin

↑ Gut hormones, ↑ energy

expenditure, taste

Intervention

AcknowledgementsFunding: Science Foundation Ireland, Vetenskapsrådet, Wellcome Trust, Moulton

Foundation, NIHR, EKF Diagnostics, AnaBio

Metabolic Medicine group University

College Dublin

Neil Docherty, Loai Shakerdi, Meera

Nair, Natasha Kapoor, Werd Al-Najim

University College Dublin

Catherine Godson, Donal O’Shea,

Ronan O’Connell, Ronan Cahill, Donal

Brennan, John Garvey, Helen

Heneghan

Trinity College Dublin

John Reynolds, Conor Murphy, Jessie

Elliott

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, Julian Teare

King’s College London

Francesco Rubino, Stephanie Amiel,

Simon Aylwin, Ameet Patel, Cynthia

Borg, Royce Vincent

University of Zurich

Thomas Lutz, Marco Bueter

Musgrove Hospital, Taunton

Richard Welbourn, Rob Andrews,

Dimitri Pournaras, Alan Osborn

Florida State University

Alan Spector

Oswaldo Hospital, Soa Paulo

Ricardo Cohen

Catholic University of Chile

Camilo Boza

Saudi Arabia

Al-Qahtani, Ghalia Abdeen

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