THE PATHOPHYSIOLOGY OF OBESITY

Robert W. O’Rourke

ASMBS chapter 2

Weight can be controlled by ‘deciding’ to eat less and

exercise more.

Voluntary efforts to reduce weight are resisted by

potent compensatory biologic responses. Jeffrey

Freidman.

The current epidemic of obesity is partly caused by the

fact that we all possess an ancient metabolism selected to

protect us from starvation,

Dieting and exercise achieve significant,

durable weight loss only rarely in the obese. Why is

this failure rate so high?

Friedman alludes to powerful biologic systems

that defend body weight

The genetic, evolutionary, and

environmental forces that have molded these

regulatory systems to create the modern epidemic.

satiety and hunger ,

metabolic rate ,

thermogenesis , and adipocyte

biology .

SATIETY AND HUNGER

Leptin :

Secreted by adipose tissue in response to a meal,

circulates through the bloodstream as a hormone to bind

its receptor in the hypothalamus and effect satiety.

Serum leptin levels are low after a nighttime fast.

When we diet and reduce adipose tissue mass,

postprandial leptin levels decrease over the course of

weeks. This causes us to eat progressively more .

In 1994, Dr. Jeffrey Friedman and his

laboratory at the Rockefeller University cloned the

leptin gene .

Exogenous leptin, while a cure for Ob mice and

Ob humans, had little therapeutic effect in obese

humans in the general population

In fact, common human obesity is characterized by

elevated leptin levels and resistance to leptin’s

satiety effects in a situation not dissimilar from

insulin resistance

COMPLICATED MEDIATORS

METABOLIC RATE

“fast burners” and “slow burners”

TEE(total energy expeniture)

REE (resing energy expenditure) 60-70%

NREE 30-40%

In conditions of energy deficit, total energy expenditure

(TEE) is decreased beyond that expected by loss of fat and

fat-free mass alone by decreasing in voluntary physical

activity.

In obese subjects who achieve 10–20 %

body weight loss and whose TEE decreases up to 20 %

more

relative to predicted values from loss of fat and fat-free

mass.

Obese subjects who maintain weight loss have

lower

resting metabolic rates than lean subjects

In contrast to diet-induced weight loss, bariatric

surgery-induced weight loss is paradoxically

associated with increased TEE :

the durable efficacy of surgery

Regulation of metabolic is toward negative rather

than positive energy balance:

The system is better designed to prevent

leanness than avoid adiposity.

The mechanisms underlying the regulation of

energy expenditure and metabolic rate are multiple,

but the sympathetic nervous system and

hormonal system are dominant.

THERMOGENESIS

Lavoisier :, “Life is combustion.”

All cellular biochemical reactions are less

than 100 % efficient and thus generate heat.

Most active in brown adipose tissue (BAT) and

skeletal muscle.

Skeletal muscle thermogenesis occurs during

exercise , during movement not associated with

exercise (NEAT ), and during

cold - induced shivering.

Skeletal muscle energy utilization efficiency

during exercise is increased in weight loss subjects

and decreased in subjects who gain weight, and

lower levels of NEAT have been demonstrated in

obese humans .

Differences in skeletal muscle thermogenesis

contribute to the pathogenesis of obesity

Diet - induced thermogenesis (DIT) increases

mitochondrial heat production and decreases

energy extraction, limiting exposure to

postprandial increases in nutrient flux.

Obese humans having lower DIT responses

ADIPOCYTE BIOLOGY

Humans demonstrate differences in kinetics of

adipocyte hypertrophy, proliferation,

differentiation, and metabolism.

Obese humans have higher adipocyte

proliferative capacity.

Early-onset childhood obesity, have a

greater number of adipocytes.

Energy balance are regulated by homeostatic

systems.

although Personal choice plays a role in the

pathogenesis of obesity but subconscious

mechanisms are more important.

All of biology has but one goal: maintenance of

homeostasis.

In the case of energy homeostasis, this buffeting

comes in the form of periodic alterations in food

resources, physical activity, illness,

temperature, and environmental and

physiologic variables.

The term allostasis was proposed by Sterling and Eyer at the University of Pennsylvania in 1988 to describe the process by which biologic systems evolved to achieve stability not through strict adherence to a homeo-static mean but rather through a dynamic response to exter-nal stimuli. Biologist Conrad Hal Waddington proposed the term homeorhesis.

.

When we ask obese patients to lose

significant weight with diet and exercise, we

are asking them to

step outside their allostatic range, an

impossible task from a biologic

perspective

This is why diets fail.

WHY DO WE BECOME OBESE?

Rare reports of a paucity of adipose

tissue secondary to congenital and

acquired lipodystrophy syndromes and

genetic errors of metabolism.

Genetics ,environmental and

evolutionary selective pressures.

WHY DO WE OVEREAT?

Evolution selects for physiology and behavior that

optimizes reproductive fitness, a goal that

conflicts to some extent with that of longevity.

Surplus nutrition increases fertility rates in

younger age of onset of puberty in Western societies.

METABOLIC THRIFT

Throughout evolution, the constant pressure of famine led

to selection of genes that regulated metabolism in a highly

“thrifty” manner.

Polymorphisms in metabolic genes were strongly selected for

if they imparted metabolic thrift, or a tendency toward

overweight, obesity, and energy conservation

blossoming of the obesity

phenotype

C H E F D U S E R V I C E D E N U T R I T I O N E T G A S T R O E N T É R O L O G I E P É D I A T R I Q U E S ,

H Ô P I T A L T R O U S S E A U

His survey of obesity and overweight in under the age of 20 ,

in 22 European countries showed that France was ranked

18th for males and 22nd for females.

More effective prevention appears to be the main reason.

The French authorities maintain that the lower prevalence of

childhood obesity is to due to the French National Nutrition

and Health Programme, since 2001.

promote healthy dietary habits, multiple school

interventions and changes in the built environment to

promote physical activity.

A G E – S TA N D A R D I Z E D P R E VA L E N C E O F O B E S I T Y ( B M I > = 3 0 ) , A G E S 2 0 - Y E A R S , M A L E S , 2 0 1 3

It would be truly surprising whether educational

interventions aimed at preventing childhood obesity

had been successful in France even though they

dramatically failed worldwide.

France was one of the first countries in the world

to implement national actions to reduce childhood

obesity

. One of the best examples was the Fleurbaix-Laventie Ville

Santé study, a nutritional and physical activity educational

programme, which was set up in two small towns in northern

France in the early 1990s and led to the famous EPODE

international obesity network being established in many

countries all over the world [8]. The educational programme

began in 1992 and a follow-up survey was carried out for

12 years until 2004. The authors reported that the prevalence

in childhood overweight increased from 1992 to 2000 and

then the trend plateaued and reversed

Much higher rates of paediatric overweight and obesity are

observed in countries such as Tonga and Chile than in the

USA or Europe .

Obviously, the obesogenic environment is much less

important in those countries than in the latter two, one might

consider that prevention programmes are also missing in those

developing countries. However, prevention is poor in many other

countries, such as Romania, Colombia, Panama and

Moldova, and they have lower childhood overweight and

obesity rates than the USA and most of Europe.

Finally, a different genetic susceptibility appears to

be the most likely explanation for the variation in the

prevalence between the countries.

The french are just less genetically predisposed

to obesity.

WHY ADIPOSE TISSUE?

Hummingbirds

Hamsters store up to 50 % of their body weight in

their cheek pouches.

Geese: foie gras

Human:

ADIPOSE TISSUE

In vertebrates

Energy dense

Over 2 months worth of calories in fat within adipose tissue.

Brain development requires a constant supply of calories.

Human body fat percentage is highest during the rapid

neonatal growth phase

Adipose tissue is a particularly good strategy for metabolic

thrift in humans.