1

Sleep and Obesity – Sleep and Obesity – does the egg come before the chicken?does the egg come before the chicken?

Francesco P Cappuccio MD MSc FRCP FFPH FAHA

Cephalon Professor of Cardiovascular Medicine & Epidemiology

University of Warwick, Warwick Medical School, Coventry, UK

2

Historical backgroundHistorical background

Steady decline in total sleep time during the past

100 years, generally attributed to lifestyle changes (increased shift work, longer working hours in less physically

demanding jobs, increased and extended sedentary leisure time

activities, ...)

Parallel increase in the prevalence of overweight

and obesity, particularly evident in the last 25 years,

also attributable to lifestyle changes (increased physical

inactivity, energy intake, …)

Recent indication of a possible association between

short sleep duration and obesity

3

Is there a link between the growing obesity epidemic and the decline in sleeping time?

7.56.8

9.0

0.01.02.03.04.05.06.07.08.09.0

10.0

1910 1975 2005

Average sleep duration (hours)in US adults in the last century

25.2

26.9

23.0

21.0

22.0

23.0

24.0

25.0

26.0

27.0

28.0

1910 1975 2005

Average Body Mass Index in US adults in the last century

BMI and Sleep Duration in US Adults Over TimeBMI and Sleep Duration in US Adults Over Time

4

Prevalence of overweight and obesity Prevalence of overweight and obesity in children and adults in the USAin children and adults in the USA

0

5

10

15

20

25

30

35

402 to 5

6 to 11

12 to 19

20 to 39

40 to 59

60+

20+

%

Adults

Children

5

Mean sleep duration in healthy Mean sleep duration in healthy young adults around the worldyoung adults around the world

0

1

2

3

4

5

6

7

8

9

hr

Men

Women

Steptoe A et al. Arch Int Med 2006;166:1689-92

6

Sleep duration and self-rated health problemsSleep duration and self-rated health problems

0

10

20

30

40

50

6 6.5 7 7.5 8 8.5

hours

% p

oo

r h

ealt

h

Steptoe A et al. Arch Int Med 2006;166:1689-92

Japan

Taiwan

Korea

Thailand

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Weight Relative RiskFirst author Year Sample size Deaths(%) (95% CI)

Kojima (men) 2000 2,438 147 1.00% 1.93 (1.12 to 3.35)

Kojima (women) 2000 2,884 109 1.00% 0.90 (0.50 to 1.61)

Heslop (men) 2002 6,022 2,303 9.00% 1.00 (0.89 to 1.12)

Heslop (women) 2002 1,006 262 2.00% 0.98 (0.70 to 1.37)

Kripke (men) 2002 480,841 45,200 14.00% 1.11 (1.04 to 1.17)

Kripke (women) 2002 636,095 32,440 14.00% 1.07 (1.01 to 1.14)

Mallon (men) 2002 906 165 0.00% 1.11 (0.32 to 3.80)

Mallon (women) 2002 964 101 1.00% 1.00 (0.58 to 1.73)

Amagai (men) 2004 4,419 289 1.00% 2.41 (1.34 to 4.34)

Amagai (women) 2004 6,906 206 0.00% 0.70 (0.21 to 2.35)

Patel 2004 82,969 5,409 9.00% 1.08 (0.96 to 1.22)

Ferrie 2007 9,871 566 3.00% 1.25 (0.93 to 1.67)

Hublin (men) 2007 9,529 1,850 9.00% 1.26 (1.12 to 1.42)

Hublin (women) 2007 10,265 1,850 8.00% 1.21 (1.05 to 1.39)

Lan (men) 2007 1,748 816 4.00% 0.98 (0.76 to 1.26)

Lan (women) 2007 1,331 522 2.00% 1.14 (0.77 to 1.69)

Gangwisch (32-59) 2008 5,806 273 1.00% 0.67 (0.43 to 1.05)

Gangwisch (60-86) 2008 3,983 1,604 6.00% 1.27 (1.07 to 1.52)

Ikehara (men) 2009 41,489 8,548 4.00% 1.28 (1.01 to 1.62)

Ikehara (women) 2009 57,145 5,992 5.00% 1.28 (1.04 to 1.59)

Stone 2009 8,101 1,922 7.00% 1.02 (0.87 to 1.19)

Combined effect: p<0.0001 100% 1.13 (1.07 to 1.19)

0.1 1 10

Relative Risk (log scale)

Reference Short sleep

Heterogeneity: I2=44%; p=0.0049Egger’s test: p=0.48

1,374,718 110,574

Cappuccio FP et al. 2009; submitted

Short duration of sleep and all-cause mortalityShort duration of sleep and all-cause mortality

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Obesity Epidemic and Sleep DurationObesity Epidemic and Sleep Duration

Association or Causation?

7.56.8

9.0

0.01.02.03.04.05.06.07.08.09.0

10.0

1910 1975 2005

Sleep duration in US adults Sleep duration in US adults

25.2

26.9

23.0

21.0

22.0

23.0

24.0

25.0

26.0

27.0

28.0

1910 1975 2005

BMI in US adultsBMI in US adults

9 von Kries R et al. Int J Obesity 2002;26:710-6

Sleep duration and obesity in 6,862 children Sleep duration and obesity in 6,862 children (age 5-6 yrs)(age 5-6 yrs)

02468

10121416

<=10h 10.5-11h =>11.5h

Duration of sleep

Overweight Obese

%

10

Weight Odds RatioFirst author Year Country Sample size

(%) (95% CI)

Locard 1992 France 1,031 9.00% 2.25 (1.27 to 3.97)

BenSlama 2002 Tunisia 167 6.00% 11.02 (4.75 to 25.60)

Sekine 2002 Japan 8,941 14.00% 1.19 (0.99 to 1.41)

Von Kries 2002 Germany 6,645 12.00% 2.16 (1.55 to 3.01)

Agras 2004 USA 150 5.00% 1.99 (0.79 to 5.01)

Giugliano 2004 Brazil 165 1.00% 5.64 (0.72 to 44.17)

Padez 2005 Portugal 4,390 14.00% 1.15 (0.93 to 1.43)

Reilly 2005 UK 6,426 14.00% 1.45 (1.19 to 1.76)

Chaput 2006 Canada 422 7.00% 2.64 (1.25 to 5.56)

Chen 2006 Taiwan 656 13.00% 1.75 (1.28 to 2.40)

Seicean 2007 USA 509 5.00% 2.23 (0.87 to 5.70)

Combined effect: p<0.0001 100% 1.89 (1.46 to 2.43)

0.1 1 10

Odds Ratio (log scale)

29,502

Heterogeneity: Q=46.6; p<0.001Begg’s test: p=0.12

Short sleep if obeseShort sleep if lean

Short duration of sleep and obesity in Short duration of sleep and obesity in childrenchildrenage 2 to 20 years

Sensitivity analysis: from 1.61 (1.33 to 1.96) to 2.07 (1.54 to 2.79)

Cappuccio FP et al. Sleep 2008; 31: 619-26

11Stranges S et al. Am J Epidemiol. 2008; 167: 321-9

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

<=5 6 7 8 9+

BMI BMI (kg/m(kg/m22))

Odds Ratio Odds Ratio Obesity Obesity

Short Sleep Duration and BMI/ObesityShort Sleep Duration and BMI/ObesitySignificant cross-sectional associations

-0.35 (-0.57;-0.12)P <0.001

1.65 1.65 (1.22-2.24)(1.22-2.24)

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Sensitivity analysis: from 1.50 (1.39 to 1.61) to 1.59 (1.44 to 1.76)

Cappuccio FP et al. Sleep 2008; 31: 619-26

Short duration of sleep and obesity in Short duration of sleep and obesity in adultsadultsage 15 to 102 years

Weight Odds RatioFirst author Year Country Sample size(%) (95% CI)

Vioque 2000 Spain 1,772 3.00% 3.35 (2.22 to 5.06)

Shigeta 2001 Japan 437 1.00% 1.97 (1.03 to 3.77)

Kripke 2002 USA 497,037 12.00% 1.52 (1.46 to 1.58)

Cournot 2004 France 3,127 4.00% 1.38 (0.97 to 1.96)

Hasler 2004 Switzerland 457 0.00% 10.8 (0.99 to 118.1)

Bjorkelund 2005 Sweden 1,460 1.00% 1.52 (0.68 to 3.40)

Gangwisch 1 2005 USA 3,682 5.00% 1.84 (1.40 to 2.42)

Gangwisch 2 2005 USA 3,324 6.00% 1.38 (1.07 to 1.78)

Gangwisch 3 2005 USA 2,582 4.00% 0.95 (0.67 to 1.35)

Singh 2005 USA 3,158 5.00% 1.70 (1.27 to 2.28)

Moreno 2006 Brazil 4,878 9.00% 1.22 (1.06 to 1.40)

Vahtera 2006 Finland 26,468 11.00% 1.43 (1.35 to 1.52)

Watari (men) 2006 Japan 19,894 2.00% 1.95 (1.20 to 3.19)

Watari (women) 2006 Japan 5,418 0.00% 2.97 (0.77 to 11.50)

Bjortvan 2007 Norway 8,860 3.00% 1.88 (1.22 to 2.89)

Chaput (men) 2007 Canada 323 1.00% 4.01 (1.73 to 9.33)

Chaput (women) 2007 Canada 417 1.00% 2.64 (1.25 to 5.56)

Ko 2007 Hong Kong 4,793 9.00% 1.30 (1.13 to 1.49)

Tuomilehto 2007 Finland 2,770 7.00% 1.30 (1.05 to 1.61)

Fogelholm (men) 2007 Finland 3,377 6.00% 1.46 (1.13 to 1.89)

Fogelholm (women) 2007 Finland 4,264 6.00% 1.75 (1.36 to 2.26)

Stranges 2008 UK 5,021 6.00% 2.01 (1.56 to 2.60)

Combined effect: p<0.0001 100% 1.55 (1.43 to 1.68)

0.1 1 10

Odds Ratio (log scale)

Heterogeneity: Q=64.0, p<0.001Begg’s test: p=0.09

603,519

Short sleep if obeseShort sleep if lean

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Prospective studiesProspective studies

Author

(year)

Country Sample

size

Age - Gender Study details Main findings

Hasler (2004)

Switzerland 45727 at baseline

Men and women

Prospective single age cohort

F-up: 13 y

Less weight gain in those with longer sleep

Gangwish (2005)

USA 3,20832-49 at baseline

Men and women

Longitudinal population based (N-HANES)

F-up: 8-10 y

Highest increase in BMI in those sleeping 2-4h pn

Biorkelund (2005)

Sweden 49838-60 at baseline

Women

Prospective population study

F-up: 32 y

Short sleepers gained more weight that long sleepers

14Stranges S et al. Am J Epidemiol. 2008; 167: 321-9

BMI BMI

OR OR Obesity Obesity

0.03 (-0.03; 0.08)P = 0.36

1.05 1.05 (0.60-1.82)(0.60-1.82)

Short Sleep Duration and BMI/ObesityShort Sleep Duration and BMI/ObesityNo prospective associationsNo prospective associations

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Appetite/satiety

Leptin and Ghrelin

Insulin resistance/sensitivity

Insulin, Adiponectin

Other hormonal mechanisms

Cortisol, SNS, Thyroid, GH

Endothelial Function

E-selectin, Soluble intercellular adhesion molecules- (sICAM-1)

Inflammation/Immune system

C-reactive Protein (CRP), Interleukin 6 (IL-6), Tumor necrosis factor (TNF-), Fibrinogen

Possible Mechanisms

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Sleep and Metabolic functions

S Taheri et al. PLoS Med 2004;1(3):e62;210-7

A U-shaped association between sleep duration and BMI. Short sleep associated with low leptin and high ghrelin

BMI

Leptin

Ghrelin

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Sleep and Metabolic functions

Spiegel K et al. JCEM 2004;89:5762-71

18Gale SM et al. J Nutr 2004;134:295-8

LACK OF SLEEP

less

more

19Vgontzas AN et al. J Int Med 2003;254:32-44

20Vgontzas AN et al. J Int Med 2003;254:32-44

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Sleep duration and Incidence of Diabetes (1987-2004) in men, age 40-70 yrs, in Massachusetts

0

1

2

3

4

5

6

<=5 6 7 8 9+

Hours of Sleep

Ris

k R

atio

Yaggi HK et al. Diabetes Care 2006;29:657-61

Adjusted for multiple confounding

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Short Sleep duration and Diabetes

Elevation of evening cortisol levels

predisposing to insulin resistance

Increase in sympathetic tone, inhibiting

pancreatic function and leading to increased

glucose intolerance

Weight gain and reduction in leptin

Reduction of testosterone levels

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Inflammation and Sleep

Inflammatory markers are elevated in individuals undergoing short term sleep deprivation studies.

Short sleep may lead to increased secretion of inflammatory cytokines, which in turn may lead to an increase in cardiovascular risk

Miller MA et al. Curr Vasc Pharmacol 2007; 5(2):93-102.

24Vgontzas AN et al. J Int Med 2003;254:32-44

25Vgontzas AN et al. J Int Med 2003;254:32-44

26

Activation of the immune system and inflammatory cytokines may affect sleep

Many inflammatory responses are somnogenic

However, in advance stages of inflammation the

sleep promoting effects are diminished with the result

of reduced NREM and increased wakefulness

(Ann NY Acad Sci 2001;933:201-10)

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Bi-directional model of the sleep deprivation-obesity association

Short SleepShort Sleep(Sleep deprivation)(Sleep deprivation)

ObesityObesity

Environment(work, social, physical)

Glucose intolerance/Insulin resistance Increased appetite ( ↓ leptin ↑ ghrelin)

More time to eat

Increased fatigueAltered thermoregulation

Activation of inflammatory markersSedentary extra time

↑ caloric intake

↓ energy expenditure

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Bi-directional model of the sleep deprivation-obesity association

Short SleepShort Sleep(Sleep deprivation)(Sleep deprivation)

ObesityObesity

Environment(work, social, physical)

Glucose intolerance/Insulin resistance Increased appetite ( ↓ leptin ↑ ghrelin)

More time to eat

Increased fatigueAltered thermoregulation

Activation of inflammatory markersSedentary extra time

↑ caloric intake

↓ energy expenditure

Sleep disordered breathingDisrupted and short sleep

Inflammatory cytokines and the brain

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Conclusions

The ‘epidemic’ of obesity is paralleled by a ‘silent epidemic’ of reduced sleep duration.

These trends are detectable in adults as well as in children as young as 5 years.

Short sleep duration is associated with increased risk of obesity both in adults and in children.

Evidence from prospective studies does not always confirm a temporal sequence

A plausible mechanism could be the effect of short sleep on appetite through the ghrelin-leptin system

Bi-directional effects (obesity causes lack of sleep) might also explain the association

More research needed to understand the mechanisms by which short sleep is linked to chronic conditions of affluent societies, such as obesity, diabetes and hypertension.

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SLEEP, HEALTH & SOCIETYSLEEP, HEALTH & SOCIETYUniversity of Warwick, Warwick Medical SchoolUniversity of Warwick, Warwick Medical School

sleepresearch@warwick.ac.uksleepresearch@warwick.ac.uk

Leads:Leads: FP Cappuccio & MA MillerFP Cappuccio & MA Miller

Warwick Team:Warwick Team: E Peile, O Franco, S Stranges, N-B Kandala, FM Taggart, E Peile, O Franco, S Stranges, N-B Kandala, FM Taggart,

C Ji, G Ward, A Bakewell, A Currie, A Lowe, D CooperC Ji, G Ward, A Bakewell, A Currie, A Lowe, D Cooper

Collaborators: Collaborators:

WarwickWarwick S Williams, D BanejeeS Williams, D Banejee

R.C.P.R.C.P. R Pounder R Pounder

U.C.L.U.C.L. MG Marmot, E Brunner, M Kumari, M Shipley, JE Ferrie, MG Marmot, E Brunner, M Kumari, M Shipley, JE Ferrie,

M KivimakiM Kivimaki

SurreySurrey D-J Djik, S Archer D-J Djik, S Archer

Boston Boston ((Harvard)Harvard) C Czeisler, SW Lockley, CP Landrigan, JP SullivanC Czeisler, SW Lockley, CP Landrigan, JP Sullivan

Naples (Federico II)Naples (Federico II) P StrazzulloP Strazzullo

AvellinoAvellino (CNR)(CNR) G BarbaG Barba

Buffalo (SUNY)Buffalo (SUNY) J Dorn, R Donhaue, M TrevisanJ Dorn, R Donhaue, M Trevisan

Funding:Funding: Cephalon Inc., Wingate Foundation, Whitehall II, Cephalon Inc., Wingate Foundation, Whitehall II,

RDF University of Warwick, NHS WorkforceRDF University of Warwick, NHS Workforce