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.