DPCP CHUV Lausanne, Oct

2013

Abdul G. Dulloo

Department of Medicine / PhysiologyUniversity of Fribourg

Switzerland

Est-ce que les régimes amaigrissants font

grossir

?

TraitementTraitement de de ll’’obobéésitsitéé

““ Eat less & Exercise more Eat less & Exercise more ””

Les conseils d’Hippocrate 400 BC

Limitations Limitations àà

longlong--termeterme

des des traitementstraitements

nonnon--invasifsinvasifs

Cha

ngem

entd

e po

ids(

kg)

thérapie comportementale

Régime à300 kcal/jour

Années après traitement Wadden 1989

Cha

nge

in w

eigh

t(kg

)

Years

Ad libitum (normal fat diet)

Least compliant

Most compliant

Clinical trial with

low-fat diet

therapyAstrup et al Proc Nutr Soc 61: 299-309 (2002)

Low-fat diet

Intervention

Le Le marchmarchéé

de la de la minceurminceur

• Les régimes à l’alimentation variée • Les denrées de remplacement

• Les monorégimes • Les denrées de complément

• Les cures de jeûne • Les produits amaigrissants

• Les régimes cétogènes (low CHO) • Les produits ‘light ’

• Les régimes ‘ dissocié ’ • Les produits en vente directe

• Les régimes de produits spécifiques

• Les ‘cures miracles ’

• Les programme comportementaux

A low

CHO(Atkins) diet

is

a high

fat diet

!

2003

(Low-moderate

fat)

(Atkins diet

/High fat )

Albert Stunkard (1958)

La plupart

des personnes

obèses

ne resteront

pas en traitement.

La plupart

de ceux

qui resteront

en traitement ne perdront

pas de poids.

La plupart

de ceux

qui réussiront

à

perdre du poids, reprendront

ce

poids.

TraitementTraitement de de ll’’obobéésitsitééFacts

Counter-acting factors(Psychological & Metabolic)

Spontaneous weight setting

Maintenance

Restoration

Rebound

Constraint-ve energy balance

Relaxingor Escape

Evolution of body weight in response to dieting Evolution of body weight in response to dieting (Adapted from Guy(Adapted from Guy--Grand, 1988)Grand, 1988)

New weight setting

Weight

(Fat) overshoot

?

hunger driveslowed metabolism

Is weight cycling detrimental to health? Is weight cycling detrimental to health? A review of the literature in humansA review of the literature in humans

Erik Erik MulsMuls et al. IJO, 19 (et al. IJO, 19 (SupplSuppl 3):S483):S48--50, 50, 19951995

WC affects body composition (fat overshooting)

WC makes subsequent weight loss more difficult

WC decreases resting energy expenditure

WC increases dietary preference for fat

WC promotes cardiovascular diseases

Points of controversy

Montani

et al. Int J Obes 30:S58-66 (2006)

National Task Force on the Prevention and Treatment of Obesity (1994)

Conclusion of a panel of Experts (USA)addressing concerns about the effects of dieting and weight cycling

and provided guidance on the risk-to-

benefit ratio of attempts at weight loss :

‘

the available evidence is not sufficiently compelling to override the potential benefits of moderate weight loss

in significantly obese patients ’

Published in JAMA 272: 1196-1202 (1994)

DefinitionDieting

(e.g., self-reported

weight

loss

dieting

in the past

year) Dietary

restraint

(e.g., the Cognitive Restraint

scale

from

the Three-Factor Eating

Questionnaire)

•

Prospective studies

reviewed25 prospective studies

containing

40 relevant comparisons. Only

non-obese participants (mean

BMI between

18.5 and 30) and averaged

at

least 12 years

old.

Results•

Neither

Dieting

nor

restrained

eating

predicted

future weight

loss. •

15 of the 20 comparisons

(75%) that

examined

measures

of dieting

significantly

predicted

future weight

gain•

only

1 of 20 (5%) that

examined

restrained

eating

measures

did

so.

Two

plausible explanations(1) Dieters

and restrained

eaters

do not differ

in terms

of an underlying

proneness

toward

weight

gain, but restrained

eating

represents

a more effective means

of preventing

it; and

(2) normal weight

individuals

who

diet

do so

because

they

are resisting

a powerful

predisposition

toward

weight

gain which

dieting

ultimately

fails

to prevent.

Dieting

and restrained

eating

as prospective predictors of weight

gain

Lowe et al. Frontiers in Psychology (sept 2013)

Conclusions• Dieters may be more prone to future weight gain

• Dieters have a genetic propensity for obesity

•

Dieting per se may promote subsequent weight gain, independent of genetic factors, in an essentially normal-

weight cohort (90% of normal weight as adolescents)

Design Association between dieting & weight gain in 4129 individual twins whose weight & height were obtained from longitudinal surveys at 16, 17, 18 and 25 years & examined in relation to the number of lifetime intentional weight loss (IWL) episodes of > 5 kg at 25 yrs

Does

dieting

make

you

fat? A twin

studyPietiläinen

et al. Int J Obes 2012;36:456-64

Gain in BMI from 16 to 25 years by lifetime Intentional Weight Loss (IWL) frequency

& baseline BMI percentile at 16 yrs Pietiläinen

et al. Int J Obesity (2012) 36,

456–464

Lower normal BMI

Higher Normal BMI

Dieting promote subsequent weight gain to a greater extent in those initially normal weight

Counter-acting factors(metabolic and psychological)

Spontaneous weight setting

Maintenance

Restoration

Rebound

Constraint-ve energy balance

Relaxingor Escape

Evolution of body weight in response to dietingEvolution of body weight in response to dieting(Adapted from B. Guy(Adapted from B. Guy--Grand, 1988)Grand, 1988)

New weight setting

Weight

(Fat) overshoot

?

Is body weight

(fat) overshooting a common

feature

of weight

recovery

in the non-obese

?

Body weight(kg)

Semistarvation Refeeding

Energy intakeEnergy intake (kcal/d x 1000 )

Minnesota ExperimentMinnesota Experiment(Keys et al. 1950)(Keys et al. 1950)

3.3 kg of

wt

overshoot

Post-starvation

energy

overconsumption & weight

overshooting

in non-obese human

subjects

Study

Type of Energy

intake

after

Wt

(Fat) energy

deprivation

n 100% wt

recovery

overshoot

(kg)

Benedict (1907)

Total fast

5 ↑

2.7

Benedict et al. (1919)

Semi-starvation

11 ↑

3.1

Schwaben (1947) Food rationing

700 ↑

6.5

Keys

et al. (1950) Semi-starvation

12 ↑

3.3 (4.6) #

(Minnesota Expt.)

Nindl

et al. (1997)

Army

training 10 ? 5.0 (4.0) #

Friedl

et al. (2000) US Rangers

10 ↑

2.4 (4.2) #

#

Excess

fat, measured by hydrostatic weighing or DEXA

Dulloo et al. Proc. Nutr. Soc. (2012); 71: 379-389

Post-starvation caloric

overcompensation

& fat overshooting

:

what could be driving it ?

•

Feedback signals

from

adipose tissue stores (sensing fat depletion) on food

intake

!

but caloric overcompensation is persisting well after 100% recovery of body fat

•

Psychobiological

response

to food

deprivation

?

•

Feedback signals

from

lean

tissue (sensing lean tissue depletion) on appetite

control ?

AgeGrowth Adult

Body weight Modern life

Evidence from

experimental starvation

and refeeding

The Classic Minnesota Experiment

(Keys et al 1950)Re-analysis by

Dulloo, Jacquet & Girardier (1994-1998)

Post-starvation caloric

overcompensation

& fat overshooting

:

what could be driving it ?

The Minnesota Experiment (directed by Ancel Keys )

Aim: 1944: Quantitative information for relief program rehabilitating starvation victims of World War II

Subjects: Caucasians-Americans (conscientious objectors of war, priests) 34 out of 100 volunteers were selected

Selection : On basis of physical, biochemical, criteria physiological, psychological examinations

Site of study: Under the University Memorial Stadium (Gate 27)

Bodyweight

Control Semistarvation

Refeeding

Refeedingperiod restricted ad libitum

Weeks Weeks No hyperphagia Low fat intake 20% by energy

Food intake ++++++++++++++++++++++++++++++++++++++++++++++++BMR + + + + + + +Body composition + + + + +

Hyperphagia High fat intake 35% by energy

Design of the Minnesota ExperimentDesign of the Minnesota Experiment (Keys et al. 1950)(Keys et al. 1950)

n = 32 (normal weight healthy men)

Weight

loss: 25-29%

2650 MJ/ d

3000 MJ/ d

3350 MJ/ d

2300 kcal/d

3500 kcal/d

1500-1700 kcal/d

Predictors

of the total hyperphagic

response (integrated

hyperphagia)

Independent variables

r2

-----------------------------------------------------------------

•

Fat to be

recovered

(step 1) 0.32

•

Prior energy

intake

deficit

(step 2) 0.68

•

FFM to be

recovered

(step 3) 0.80-----------------------------------------------------------------

Stepwise regression analysis ----------------------------------------------------------------

Dulloo, Jacquet, Girardier

Am J Clin Nutr 65: 717-723 (1997)

Pattern of changes fat mass & FFM in Minnesota Experiment (Dulloo, Jacquet, Girardier

Am J Clin Nutr 65: 717-723 (1997)

Fat massFFM

% Control values

% Control values

Catch-up fat in part driven

by

suppressed

thermogenesis

?

Recovery

rate Fat > FFM, even

before

hyperphagia

Body weight(kg)

Semistarvation Refeeding

Energy intakeEnergy intake(kcal/d x 1000 )

20100

-10-

20

Suppressed Suppressed ThermogenesisThermogenesis (

adjusted BMR

% initial BMR% initial BMR)

‘‘Minnesota ExperimentMinnesota Experiment’’ Revisited Revisited Adapted from Dulloo, Girardier & Jacquet (IJO 1996), AJCN 1998)

-10% - 20%

-10%

- 25%

Minnesota Experiment RevisitedMinnesota Experiment RevisitedDulloo, Jacquet Girardier Am J Clin Nutr 1998;68:599-606

Feedback control system between

fat stores & thermogenesis

Concept of dual-adaptive thermogenesisDulloo et al. Int J Obesity 25 (Suppl. 5):S22-S29. (2001)

Leptin-SNS- Thyroid

axis

Starvation Refeeding

Energy

intake

Non-specificThermogenesis

adipose-specificThermogenesis

Suppressed

thermogenesis specific

for 'catch-up fat'

50% 100%

Body fat(% initial value)

Thermogenesis

(Down) (Down)

100% 50% 0%

40

60

2200

2600

2000

7 14 210Semi

starvation Refeeding

Days

of refeeding

RefedControl

** **

5

25

45

Body fat(g)

Body protein (g)

Energy intake(kJ wk-1 )

Energyexpenditure

(kJ wk-1)

***

****

1200Suppressed

thermogenesis

specific

for 'catch-up fat'

catch-up fat

Catch-up

fat

resulting

only

from

suppressed

thermogenesis: a rat model

Adapted from Dulloo et al.(1991)

Suppressed Suppressed thermogenesisthermogenesis

favouringfavouring

catchcatch--up fat up fat (on a low(on a low--fat diet): fat diet): Glucose redistributionGlucose redistribution

Adiposetissue

Skeletal muscle

Fat

Thermogenesis

Decreased Glucose utilisationIncreased Glucose

utilisation for lipogenesis catch-up fat

HyperinsulinemiaInsulin

Hyperresponsiveness

Insulin resistance

Euglycemia

Adipostat

Signal(s) ?

↑

AdipogenesisLimits

adipocyte hypertrophy(Summermatter et al. Diabetes 2011)

(Marcelino et al. Diabetes 2012)

↓ PI3K activity(Summermatter et al. FASEB J (2008)

↓

Subsarcolemmal mitochondria(Crescenzo et al. Diabetes (2006)

↓

Muscle relaxation time

Pattern of changes fat mass & FFM in Minnesota Experiment (Dulloo, Jacquet, Girardier

Am J Clin Nutr 65: 717-723 (1997)

Fat massFFM

% Control values

% Control values

Catch-up fat in part driven

by

suppressed

thermogenesis

Recovery

rate Fat > FFM, even

before

hyperphagia

Fraction of protein

oxidised

(P

ratio

) in Minnesota men during

semi-starvation

as a function

of adiposity

Dulloo

& Jacquet Br J Nutr (1999) 82: 339-356

The leaner

the individual,

the greater

the proportion of weight

loss

as FFM

the stronger

the feedback signal driving

food

intake

The greater

the risk

for fat overshooting

and

becoming

fatter

?

y = 88.514x-1.1577

R2 = 0.4759

0.0

2.0

4.0

6.0

8.0

10.0

12.0

5.0 10.0 15.0 20.0 25.0 30.0

Initial % body fat

Fat O

vers

hoot

(kg)

r = 0.70

♦

Minnesota Experiment

◊

Army

Ranger Experiments

◊◊

Dulloo

et al. Proc Nutr Soc (2012);71:379-389

Inverse relationship

between

post-caloric

restriction fat overshooting

and initial adiposity

The leaner

the individual

before

caloric

restriction,

the greater

the fat overshot

after

weight

regain

Compartmental

model for autoregulation

of body weight & body composition during

weight

recovery

Dulloo

& Jacquet Br J Nutr (1999)

Control of Energy

Intake Notions of ‘signals from FFM driving appetite’

•

Relationship between

serum

amino

acid

concentration and fluctuations in appetite.Mellinkoff

et al. J Appl Physiol. 1956;8(5):535-8.

•

A protein-stat mechanism

for regulation

of growth

and maintenance of the lean

body mass.

Millward

DJ. Nutr Res Rev 1995; 8: 93-120

•

Poststarvation

hyperphagia

and body fat overshooting

in humans: a role

for feedback signals

from

lean

and fat

tissues.Dulloo

AG, Jacquet J, Girardier

L. Am J Clin Nutr. 1997;65):717-23.

•

Body composition and appetite: fat-free mass (but not fat mass or BMI) is

positively

associated

with

self-determined

meal

size and daily

energy

intake

in humans.Blundell et al. Br J Nutr. 2012; 107:445-9.

Functional analyses of identified secreted proteins from C2C12 skeletal myoblasts.

Henningsen

et al. Mol Cell Proteomics 2010 9: 2482

635 secreted

proteins

•

35 growth

factors, •

40 cytokines

•

36 metallopeptidases

+ 400 new secreted proteins

(2013)

How dieting makes some fatter ..? Dulloo

et al.

Proc Nutr Soc (2012) 71:379-389

•

A common

feature

of weight

regain in non-obese

•

A consequence

of differential

rates of protein

vs fat repletion

(which can be faster as a result of suppressed

thermogenesis specific for fat stores replenishment)

•

Non-obese individuals

are more likely

to deplete

protein and fat mass (as % of initial levels) –

and hence

trigger

feedback signals

from

fat and lean

tissues that

operate on food

intake

and thermogenesis.

•

To-date, these

feedback signals

(adipostats

and protein- stats

remain

undefined)

Fat overshooting

AgeGrowth Adult

Body weight

obese

lean

Weight cycling during growth and young adults?Weight cycling during growth and young adults?

• Weight loss program in adolescents• Common fluctuations (teething, fever, ...) • Chronic diseases with remissions• Food shortage (poverty, war, famine, ...)• Slimming in athletes (competition)• Dieting for a slim image

Montani

et al. Int J Obes 30 (suppl.4): S58-66 (2006)

Comparison

with

media models

Underweight

Normal

Overweight

Obese

Body Mass Index (BMI) From

Dittmar

(2006)

Body dissatisfaction Unhealthy

body-shaping

behaviours

(vomiting, pills, smoking)

Girls prevalence (%)

BoysPrevalence

(%)

USA 56 28Canada 53 22Belgium 40 14Estonia 49 15Finland 45 10Greece 60 34Latvia 45 22Poland 54 19

Prevalence

of weight

control behaviour

during

last 12 months

in

non-overweight

adolescents

Ojala

et al. Int J Behav Nutr Phys Act (2007) 4: 50.

1990’s‘Hales & Barker’ theory

Developmental Origins of Health and Disease

Maternal stress Infection, Undernutrition

Placental dysfunction Smoking, Alcohol

Small babies Large babies

Gestational diabetes

‘Catch-up growth’ trajectories to cardio-vascular & metabolic diseases

Eriksson JG, Forsén T, Tuomilehto J, Winter PD, Osmond C, Barker DJP• Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 1999;318:427–431

Ong KKL, Ahmed ML, Emmett PM, Preece MA, Dunger DB• Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000;320:967–971

Cianfarani S, Germani D, Branca F.• Low birthweight and adult insulin resistance: the "catch-up growth" hypothesis. Arch Dis Child Fetal Neonatal Ed. 1999;81:F71-3

Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. • Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005: 1802-9.

catchcatch--upup of linear growthof linear growth

CatchCatch--up growthup growth

State of hyperinsulinemia

ThinThin--short short babies/infants babies/infants

Later CV &Later CV &metabolic diseasesmetabolic diseases

catchcatch--upup of fat tissue of fat tissue catchcatch--upup of lean tissue of lean tissue

Dulloo AG, Jacquet J, Montani JP. Pathways from weight fluctuations to metabolic diseases: focus on maladaptive thermogenesis during catch-up fat.

Int J Obes Relat Metab Disord 2002; 26 (Suppl 2):S46-57

2

3

4

2 3 4

○●

●○○

●

10

12

□■

□

□

■

■

9

11

(Small for gestational

age, n=29)

AGA

SGAAGA

Lean

mas

s (k

g)Fa

t mas

s (k

g)

Age (yrs)

The 1st

longitudinal study

of body composition (by DEXA scanning) in human

infants born

small

for gestational

age

(SGA)

0.20

0.25□■

□□

■

■ SGA

Fat

mas

s/lean

mas

s ra

tio

0.30

AGA Figure built from a reanalysis of raw data derived from Ibanez et al. JCEM (2006) and published in:

Dulloo et al. Int J Obesity 30 (suppl. 4): S23-S35 (2006)

(Appropriate

for gestational

age, n= 22))

Infants born

small

show hyperinsulinemia

& lower

insulin

sensitivity

(HOMA index)

SGA

But also preferential catch-up fat

Ibanez et al. JCEM (2006)

AgeGrowth Adult

Body

wei

ght

thin/short at

birth

Increased risks for later obesity, type 2 diabetes,

CV diseases+ Catch-up growth

obese

lean

Impaired

growth during

infancy

and childhood

Dietary

restraint/weight

cyclingBMI <30 Higher CV

risks,

Higher

obesity risks

Unintentional

weight

loss/recovery

Dulloo et al. Int J Obesity 30 (suppl. 4): S23-S35 (2006)

Large epidemiological studies

Catch-up fat

Catch-up fat

From From weightfluctuationsweightfluctuations to obesity & chronic metabolic diseasesto obesity & chronic metabolic diseases

From Fernandez_Twinn & Ozanne. Physiol Behav (2006)Adapted from Hales & Barker Br Med Bull (2001)

AgeGrowth Adult

Body weight

From weight (BMI) fluctuations From weight (BMI) fluctuations to obesity & chronic metabolic diseasesto obesity & chronic metabolic diseases

Low

birth

weight and/or Catch-up growth

Unintentional weight

loss/recovery

Dietary

restraint & Weight

cycling

BMI <30Higher CV

risks,

Higher

obesity

risks

Increased risks for laterCV diseases, diabetes, obesity

obese

Higher

obesity

risksPremature

BMI rebound

Dulloo et al. Int J Obesity 30 (suppl. 4): S23-S35 (2006)