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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