BMI > 25 = obese (27 if over 35 yrs); BMI > 30 = morbidly obese
healthy people could have BMI indicating obesity (i.e. bodybuilders)
waist to hip ratio greater than 0.9
Þ increased risk of obesity-related diseases
desired weight: defined by insurance companies as the height-weight yielding the lowest insurance risk
greater than 120% of ideal weight
Þ increased mobidity
greater than 150% of ideal weight
Þ increased mortality
1/3 of Americans have BMI > 27
more common in African American, increased age (plateau at 45 - 55); poverty class
related diseases
diabetes: 4x risk (increaed more so in Af. Am, Nat. Am, Hisp., Asian)
hypertension: 2x
coronary artery disease: 1 - 1.8x
also sudden death, heart/respiratory failure, fatty liver, nephrosis
Energy and Metabolism: Application to Obesity
Energy Turnover
energy input = energy output + energy storage (mostly fat)
input is difficult to measure in free-living humans because they under-report intake by ~20% (obese people more so)
energy input and output in healthy individuals is balanced over a long period of time Þ constant weight
short term deviations of energy output are compensated for by subconscious changes in intake
most short term changes in intake are compensated by storage rather than energy output; however:
long term forced feeding induces a higher basal metabolic rate
during long periods of starvation, basal metabolism is decreased
these principles also apply to statically obese people
it is unknown whether dynamic obesity (gaining weight) is the result of excessive input, or reduced output or a combo
Energy Expenditure
energy expenditure can be measured by a double-labeled isotopic water method or in a sealed respiratory chamber
inter-species energy expenditure is exponentially proportional to body weight
where does the energy go? in sedentary individuals:
75% is the resting metabolic rate (usually 20 kcal/kg/day)
7% is spent in diet-induced thermogenesis (energy used to digest a meal)
18% is in spontaneous muscle activity (fidgeting) and deliberate movements
= ~2000 kcal/day
heightened activity can increase expenditure as much as 3000 kcal/day
Pathogenesis of Obesity
obesity is a heterogeneous set of diseases of which the etiology and pathogenesis are not well understood
very few cases can be explained by hormonal (insulin excess; cortisol excess; growth hormone deficiency) causes or
lesions in the hypothalamus
Abnormalities of Appetite Regulation
– lesions of ventralmedial hypothalamous decrease levels of leptin receptor
animal studies show this could cause obesity by making the subject unaware of its excess weight
Þ
their calorie intake is governed only by the availability and palatability of the food
Þ
adjustments in energy expenditure are only proportional to the change in body weight
human studes show that many obese people are unaware of their caloric intake (self-reported intakes are often low)
when given liquid diets of unknown varying caloric density, obese people consumed a constant amount of the drink, while normal people adjusted intake to consume a constant calorie load
Þ
non-obese have intrinsic caloric regulation; obese have intrinsic regulation of volume
Abnormalities in Energy Expenditure
– obese individuals may have either a normal or increased level of total energy expenditure rather than lowered
basal metabolic rate is increased due to increased lean body mass required to support more adipose
when normalized to body size, energy expenditure above BEE may or may not be decreased
this includes diet-induced thermogenesis, muscular activity
Þ
suggests possible reduced energy cost in absorbing and storing nutrients in obese patients or reduced muscle activity, but
physical activity and exercise are decreased in some but not all obese individuals
many obese individuals are unable to maintain a low weight on a reduced calorie diet relative to their normal counterparts
Þ
implicates energy expenditure rather than energy intake as a cause
Abnormalities in Set Point
hypothesis: ratio of adipose mass to lean body mass is fixed, partly by genetic factors
in rats: starvation/force feeding leads to weight loss/gain, return to normal diet results in return to previous weight
both normal and obese mice return to their previous static weight
Þ set point
the same thing appears to happen in humans
Þ obese people may simply have a higher set point
Genetic Abnormalities
childhood obesity is often familial
mono and dizygotic twin studies show a genetic link
genetic factors are likely to be coupled tightly to environmental factors
junk food, high fat food (denser calories, not necessarily just fat, stress, urban living, passive entertainment)
Molecular Abnormalities
leptin
: secreted by adipocytes in amounts proportional to adipose mass (ob gene; autosomal recessive)
deficiency is only rarely found as the cause of obesity
most obese people have elevated levels proportional to the degree of obesity (due to increased adipose)
more likely cause is the receptor or a downstream component
i.e. NeuroPeptide Y (NPY): stimulates food intake in hypothalamus; Glucagon-Like Peptide 1 (GLP-1), corticotropin-releasing factor: both stimulate cortisol
Þ Ý intake
Serotonin
, Norepinepherine also regulate food intake
leptin receptor
: localized in ventralmedial hypothalamus, other areas of brain (db gene; autosomal recessive)
Fat Cell Abnormalities
fat cell size is always increased in obesity
number
of fat cells may be increased (especially in childhood obesity, or long-term obesity)
if there is a minimum level of storage, then increased numbers could predispose obesity
elevations in lipoprotein lipase may increase lipids being pulled from the blood and stored in adipose
increased sensitivity to alpha adrenergic stimulation to store fat may play a role
a decrease or dysfunction of brown adipose may lead to obesity
ox/phos is decoupled (uncoupling protein I) to produce heat from lipids
humans have little brown adipose, but uncoupling proteins have been found in other tissues (uncoupling protein II
Þ white adipose; uncoupling protein III Þ muscle)
uncouplers can be stimulated by catacholamines via
b3 receptors (possible link to leptin receptor)
Hormonal Abnormalities
insulin, cortisol: favor fat deposition; almost always in excess in obesity
growth hormone: decreases fat and stimulates lean mass is often deficient
hormones are probably not primary causes of obesity; more likely effector mechanisms of the primary cause
Treatment of Obesity
because etiology and pathogenesis are largely unknown, treatments are often ineffective
caloric restriction (1200 - 1800 kcal/day) is effective short term in 25% of patients
severe caloric restriction (500 - 1000 kcal/day) with adequate protein is 70% effective, but not maintained more than 3 yrs
abnormal set point?
behavioral therapy can be successful
exercise can only increase output (100 - 300 kcal/day) in the average patient; however may help maintain lean mass during weight loss
surgical reduction or bypass of the stomach can reduce weight by up to 1/3 and improve complications of obesity
1% mortality risk associated; patient may adapt and still take in excess energy
leptin therapy is now possible, but unknown whether it will work
leptin can be replaced IV if patient is deficient (only found in two families in the world so far)
pharmacologic doses may help people who have normal levels
leptin receptor deficiency may be treatable via gene therapy
Conclusions
obesity is a highly prevalent disease caused by a whole bunch of factors that we don’t know anything about
we have methods available to make anyone lose weight, but we cannot prevent subsequent weight gain
