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Early programming of obesity

Dariusz Gruszfeld,

Children’s Memorial Health Institute, Warsaw1

Outline

• Epidemiology of obesity

• Genetic & modifiable risk factors of obesity

• Role of maternal and early child’s nutrition

• Potentisl mechanisms of early programming

• Transgenerational programming effect

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Obesity epidemic

• 66% overweight adults in US

• >30% obese adults in US

• observed in both developed and

developing countries

Mokdad AH, JAMA 20053

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Obesity epidemic - a modern-day

health crisis

• The speed, with which obesity has risen in India and

China, as they adopt Western diets and lifestyles

suggests, that genetic factors are not the only

explanation • Gluckman P., Univ Press, Cambridge 2006

• Shaw J.E., Diabetes Res. Clin. Pract., 2010

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From: Prevalence of Childhood and Adult Obesity in the Un ited States, 2011-2012

JAMA. 2014;311(8):806-814. doi:10.1001/jama.2014.732

Prevalence of High Body Mass Index by Selected Cut Points for Youth Aged 2 to 19 Years, by Sex, Age, and Race/Hispanic Origin, United States, 2011-2012a

• Childhood obesity doubled in children and quadrupled in adolescents in the past 30 years

• Ogden CL, Journal of the American Medical Association 2014

• National Center for Health Statistics. Health, United States, 2011

• In 2012, more than one third of children and adolescents were overweight or obese

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Consequences of obesity in children

• high blood pressure,

• early development of atherosclerosis,

• type 2 diabetes,

• type 2 diabetes, previously thought to only occur in

adulthood

• nonalcoholic fatty liver disease,

• polycystic ovary disorder

• disordered breathing during sleep

Shivpuri A, Int J Clin Pediatr Dent. 2012; Daniels SR, . Int J Obes (Lond). 2009 8

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• over the past century,

there was a trend

toward increasing life

span over time

• a shorter life span for

the current generation

of children because of

obesity and related

comorbidities?

Olshansky SJ, N Engl J Med 20059

Obesity

Genetic factorsEnvironmental

factors

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Genetic factors

• The Human Genome Project http://www.genome.gov

– a number of genetic associations have been

described for obesity and related disorders

• However, the findings are unlikely to prevent

the epidemic

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Modifiable factors

• Modifiable risk factors described

– diet,

– inactivity,

– stress

• Clinical trials demonstrated beneficial effect of

correcting some of risk factors

– effects - usually small and short lived

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Breastfeeding and obesity

• OR = 0,76 (0,71;0,81)

– better learned self-regulation

of food intake

– enhanced satiety

– presence of factors, present

in breast milk but not in

infant formula, including

leptin

WHO 2013 13

Maternal nutrition as a

programming factor

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Fetal malnutrition

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Odds ratio for the metabolic syndrome according to birth weight among 407 men born in Hertfordshire (adjusted for adult body mass index).

Hales C N , and Barker D J P Br Med Bull 2001;60:5- 20

metabolic syndrome = ‘the small-baby syndrome’ ?

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The ‘thrifty phenotype’ hypothesis

• the fetus, in response to suboptimal early

environment, makes metabolic adaptations

to maximize chances of surviving postnatally

in conditions of ongoing deprivation

Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001 16

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Maternal undernutrition studies

– association between

intrauterine malnutrition and

subsequent development of

obesity in individuals

exposed to famine

• the Dutch Hunger Winter

1944-1945

– effects of exposure on

susceptibility to obesity

dependent on the timing of

exposure

Ravelli G.P., N. Engl. J. Med., 1976 www.dutchfamine.nl17

Leningrad Blockade, 1941- 1944

− findings differ from

studies of subjects

exposed to

maternal

starvation during

the Dutch Hunger

Winter

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The additional risk of catch-up growth

• Subjects growth restricted during fetal life,

who subsequently grow rapidly are the most

affected and show increased adiposity in later

adult life

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Catch-up growth – animal studies

Obesity 200621

Glucose utilization rate (ng · min−1 · mg−1 tissue) , as assessed by hyperinsulinemic-euglycemic clamps associated with labeled 2-deoxygl ucose, in individual tissues from refed

and control rats.

Cettour-Rose P et al. Diabetes 2005;54:751-756

Copyright © 2014 American Diabetes Association, Inc.22

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Maternal under/overnutrition

• maternal under-nutrition is rarely a problem in

Western societies

• The number of LBW births increased steadily in the

UK, despite falling birth rates• Office of National Statistics. Mortality Statistics

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LBW infants can be born not only to

malnourished mothers

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Maternalundernutrition

Lowbirthweight

Normalbirthweight

Maternaloverweight

Lowbirthweight

Normalbirthweight

High birthweight

Maternaldiabetes

Lowbirthweight

Normalbirthweight

High birthweight

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How maternal obesity influences the

fetus?

• Insulin resistance

– ↑ glucose

• Larsson G, Diabetes Care 1986

• Maternal obesity associated with chronic

inflammation and oxidative stress

• Leibowitz KL, World J Pediatr 2012

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U-shaped effect of mother’s

under or overnutrition (or GDM)

Dis

ease

risk

Birthweight

Dis

ease

risk

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Mechanism

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Central energy balance system

Adapted from E.C. Cottrell, Physiology & Behavior 200829

Figure 2 Weight Gain of MC4-R–Deficient Mice and Control Littermates Each line represents the weight gain of an individual mouse. (A) Weight gain of female homozygous (−/−) mutant mice (closed squares) and wild-type (+/+) F2 controls (open circles). The ...

Dennis Huszar , Catherine A Lynch , Victoria Fairchild-Huntress , Judy H Dunmore , Qing Fang , Lucy R Berkemeier ,...

Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice

Cell, Volume 88, Issue 1, 1997, 131 - 141

Deffects in central energy balance

system

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Leptin resistance

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Body weights and leptin tranport rates in thin and fat mice.

Banks W A , and Farrell C L Am J Physiol Endocrinol Metab 2003;285:E10-E15

©2003 by American Physiological Society32

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Trophic Action of Leptin on

Hypothalamic Neurons

Bouret SG, Science. 2004

• hypothalamic nuclei only begin to be

populated during fetal life, with continued

neural development postnatally

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PJ Turnbaugh et al. Nature 000, 1-5 (2008) doi:10.1038/nature07540

16S rRNA gene surveys reveal familial similarity and reduced diversity of the gut microbiota in obese individuals

Gut microbiota and obesity

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Early protein hypothesis

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Protein intake

AA

GH IGF - 1

Insulin

Fat tissue

IGF BP 2IGF BP 3

BCAA

(+/-)

(+)

(+)

(+)

(+)

**

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The overall prevalenceof obesity in formula-fedchildren was 7.1% (32children); the prevalenceof obesity was 5.6percentage points higherin the HP than in the LPgroup.

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Serum AA concentrations at 6m.

P<0.001 P<0.001 n.s.

MILANO PEDIATRIA 2010 38

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Am J Clin Nutr 2011; 94:1776S-1784S

HP increases concentrations of total and free IGF1 andurinary C-peptide and decreased serum glucoseconcentrations.

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Epigenetic mechanism

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Adapted from: Catalano PM, J Clin Endocrinol Metab 2003

Transgenerational effects – ‘the vicious cycle’?

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• F2 offspring of F1 women who were exposed to

famine at any stage of their own fetal life had similar

birthweight but were 0.6 cm shorter and had a 1.2

kg/m3 higher ponderal index at birth

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Summary

• Human and animal studies support an idea of ‘early

programming’ of obesity

• Maternal nutritional factors contribute to fetal

programming

• Early postanatal nutrition additionally influences the

risk of later obesity

• Epigenetics plays an important role in early

programming of obesity as well as in

transgenerational programming effect

• ‘Early life programming’ offers hope that investment

in early life could help to prevent obesity44

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THANK YOU FOR YOUR ATTENTION47