Everyone’s Talking About ObesityIs There More Involved Than Diet and Exercise?

Environmental Causes of Obesity:Unhealthy Diet & Inactivity

Are There Other Pieces to the Puzzle?

Development in Utero… Food Restriction During Childhood… Environmental Exposures… Stage of Life… Friends and Social Networks… Genetics… Feelings… Sleep Deprivation Variation in NEAT(Non-Exercise ActivityThermogenesis)

urban

transport

  sex

trends

Education

Comfort

SES

neighborhood

Prevalence of Obesity

Highest prevalence: Pacific islands, eg a prevalence of 79% in Nauru

Lowest prevalence: Asia (India, China, Japan, Phillipines)

High prevalence in the Middle East

Egypt, Bahrain, USA have prevalences of 25-30%

Africa has a double burden: the paradox of adult obesity and childhood malnutrition

1991 1995

2002

Obesity Trends Among U.S. AdultsBRFSS, 1991-2002

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. AdultsBRFSS, 2007

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Spread of Obesity in a Social Network over 32 Years

Obese BMI>30

Non-obese

Social connectionClose genetic 1st degree relativesNon-genetic Friends/spouses

Obese and non-obese form clusters within networkObese and non-obese form clusters within network

Dense obese clusters and non-obese clusters existDense obese clusters and non-obese clusters exist

Obesity density lower at periphery of the networkObesity density lower at periphery of the network

Framingham StudyChristakis et al. N Engl. J Med 2007;357:370-9.

Each level has direct & indirect influences on the other levels

degree of personal control

direct

indirect

The Consumer’s Social Context

Environmental agents and/or nutrition act during development to alter pathways 1) control of adipose tissue development 2) increase the number of fat cells

3) Mechanisms controlling food intake and metabolism4) insulin sensitivity and lipid metabolism thereby altering the “setpoint” or sensitivity for

developing obesity later in life.

Developmental Origins of Obesity: Role of Nutrition in Humans

High birth weight….increased incidence of adult obesity.

– Overweight mothers

– Gestational diabetes Low birth weight (due to nutritional deficiency) results

in increased incidence of adult obesity if there is catch-up growth in first few years of life.

Breastfeeding for 4-6 months is probably protective against childhood obesity.

Endocrine Disrupting ChemicalsHERBICIDES2,4,-D2,4,5,-TAlachlorAmitroleAtrazineLinuronMetribuzinNitrofenTrifluralin

FUNGICIDESBenomylEthylene thioureaFenarimolHexachlorobenzeneMancozebManebMetiram - complexTri-butyl-tinVinclozolinZineb

INSECTICIDESAldicarbbeta-HCHCarbarylChlordaneChlordeconeDBCPDicofolDieldrinDDT and metabolitesEndosulfanHeptachlor / H-epoxideLindane (gamma-HCH)MalathionMethomylMethoxychlorOxychlordaneParathionSynthetic pyrethroidsTransnonachlorToxaphene

INDUSTRIAL CHEMICALSBisphenol - A PolycarbonatesButylhydroxyanisole (BHA)CadmiumChloro- & Bromo-diphenyl etherDioxin (2,3,7,8-TCDD)FuransLeadManganeseMethyl mercuryNonylphenolOctylphenolPBDEsPCBsPentachlorophenolPenta- to Nonylphenolsp-tert-PentylphenolPhthalatesStyrene

Testosterone synthesis inhibitor Estrogen receptor agonistThyroid hormone transport inhibitor Androgen receptor antagonist

Landhuis, C. E. et al. Pediatrics 2008

BMIs for Short, Moderate, and Long Sleepers

The association was independent of television viewing, childhood socioeconomic status, adult smoking, adult physical activity and parental control measure

Keys to Understanding Obesity

Human beings have a very large storage capacity of fat (normally: 30-40 billion fat cells that each store ½ ug lipids which is equivalent to 100 000 kcal; in obesity the number of fat cells is increased to as many as 80 billion fat cells that store 1 ug of lipids which is equivalent to 1 000 000 kcal

Most people are susceptible to obesity; very few are resistant

Population Changes Occur on a Background of the General

Disposition in the Population

“Despite obesity having strong genetic determinants, the genetic composition of the population does not change

rapidly. Therefore, the large increase in…[obesity] must reflect major changes in non-genetic factors.”

Hill, James O., and Trowbridge, Fredrick L. Childhood obesity: future directions and research priorities. Pediatrics. 1998; Supplement: 571.

Individual Predisposition Body weight is determined by

an interaction between genetic (susceptibility genes), environmental and psychosocial factors acting through the physiological regulation of energy intake and expenditure.

Susceptibility genes are not alone sufficient to explain the development of a disease and are not essential for the development of the disease.

Over 600 genes, markers and chromosomal regions associated with obesity and over 1000 animal knockouts associated with obesity

No single gene is associated with wasting

BM

I

Predisposing environment

Genetic resistance

Moderate predisposition

Strong predisposition

Genetic obesity

The Interaction Between the Environment and the Individual

“Nature loads the gun, but nurture pulls the trigger.”--Steve Humphries

Elementary my dearWatson, the culpritis in the family…

Watch the genes !

“Overweight people have overweight pets and don't share any genes with their pets.”

Why Study Rare Monogenic Forms of Obesity?

Obesity is the extreme of the same genetic and environmental factors responsible for variation throughout the distribution of BMI.

This finding implies that genes that influence obesity will also be associated with BMI in the normal range, and similar environmental influences will affect BMI in the clinical and normal range.

Child with genetic deficiency of leptinCan be “cured” byRecombinant leptin

For this childHuman Genomics was the answer!

ENERGY DEFICIT

ENERGY EXCESS

SET-POINT

Weight Gain and Life Phases

Childhood onset? Puberty and teens? Increased intake/decreased activity at milestones Time constraints ”A disease of convenience” Musculoskeletal injuries Psychological stressors and emotional crises Sick leave Smoking cessation Medications (which ones?) Age (1-2 lbs/year) Biological factors

Energy Imbalance

Consuming 100 kcal/day more than you burn will equal approximately a 10 pound weight gain per year.

Only 10 extra kcal/day will give you a 1 lb gain/year.

Copyright ©2006 American Heart Association Levine, J. A. et al. Arterioscler Thromb Vasc Biol 2006;26:729-736

Components of total daily energy expenditurein a free-living sedentary adult

Levine, J. A. et al. Arterioscler Thromb Vasc Biol 2006;26:729

Time allocation (A) and energetic (B) components of NEAT in sedentary lean and

obese individuals

Foster-Schubert, K. E. et al. Endocr Rev 2006;27:779-793

Hypothalamic Targets of Circulating Adiposity Signals

Neural control of body weight

The brain stem receives signals from the blood stream and from the peripheral nervous system via the vagus and passes on to the hypothalamus. The hypothalamus also receives

signals from higher centers and the blood stream

Reward and Food

New neural pathways defend an increase in body weight

This is to defend against lack of food

Redundancy

A series of redundant regulatory loops defends the body weight (fat mass)

If one is weak or attenuated, others can take over Even when one gene is knocked out, other

pathways can compensate Experimental knockouts of AgRP, NPY, ghrelin have

little effect on the body weight of mice

Adipocytes

weight gain

Leptin

Hypothalamus

Response to obesity:

food intake

energy utilization

sympathetic activity

Leptin

Hypothalamus

Response to starvation:

food intake

energy utilization

fertility

temperature

parasymphatic activity

weight reduction

The body ”remembers” the highest previous body weight

(that has been present for how long…?)

The Drive to Restore Adipose Tissue Mass …

Decreased thyroid and immune function Decreased fertility Increased appetite for fat and sugar (concentrated

forms of energy) Decreased basal metabolic rate Decreased fat oxidation (to conserve stores) Increased insulin sensitivity, low leptin, low

sympathetic activity (Snitker et al 2000 Obes Rev)

Alternatives to Dieting

Becoming active and adopting a healthy diet does not result in significant weight loss for most people

Focusing on weight loss as a public health goal will be ineffective and possibly counter-productive, given that there is no safe and effective method to produce significant long-term weight loss in the vast majority of individuals…

Campos P et al. Response: lifestyle not weight should be the primary target. Int J Epidemiol 2006; 35: 81-2.

What is the Goal of Treatment?

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TreatmentTreatmentTimeTime

Healthy Weight Maintenance A weight reduction of 5-10% is achievable in 3-9

months A plateau is reached, or weight is gained from

previous loss The goal then is maintenance for 2-5 years The plateau is a good sign and means that

weight is not being regained but is discouraging to most patients

Physical activity plays the primary role is this phase

Medications, lack of crises and support are also important elements

Wing & Hill Annu Rev Nutr 2001; 21: 323

Large amounts of fat and rapid carbohydrates overwhelm body weight regulating mechanisms

”Passive overeating”

Satiety Protein > carbohydrates > fat Energy in the form of fluid is not ”recorded” Water ingestion before eating?

*Mattes RD et al. Physiol Behav 2001; 74: 551Malik VS et al. Am J Clin Nutr 2006; 84: 274

Nuts, fruit and vegetables may protect against

weight gain

Barriers to Physical Activity Lack of sporty identity is not necessarily “just” a

perception, but it may be related to real skills, motor abilities, fitness and/or experiences of (past) physical activity

Lack of company Lack of self-efficacy Not aware of health benefits of moderate-intensity

physical activity Costs, lack of money Increasing NEAT could be a help, at least in preventing

further obesity