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2. • Obesity is defined as having excess body fat accumulation with
multiple organ-specific pathologic consequences.
• Overweight and obesity have become global health problems.
• In 2008, 1.5 billion people were classified as overweight and more
than 1 in 10 of the world’s population were ranked as obese.
• In the United States, more than 65% of adults are currently either
overweight or obese, and more than 33% of the population is obese,
with obesity having an even higher prevalence in minority groups
such as non-Hispanic blacks and those of Hispanic ethnicity.
• The prevalence of overweight and obesity is even more alarming in
children and adolescents.
• Approximately 17% of children between 2 and 19 years of age are
obese—a percentage that has tripled since 1980.
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4. Body Mass Index
• Clinically, obesity and overweight have been defined in terms of the
BMI. The BMI is based on height and weight measurements and has
a correlation with body fat. It is now becoming clear that different
ethnic groups have different percentages of body fat for the same
BMI.
• In 1997, the World Health Organization (WHO) defined the various
classifications of overweight (BMI ≥ 25) and obesity (BMI ≥ 30). The
National Institutes of Health (NIH) subsequently adopted this
classification.
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5. Body Mass Index
• The use of a BMI cut-off of 25 as a measure of overweight raised
some concern that the BMI of some men might be a function of
muscle rather than fat weight. However, it has been shown that a
BMI cut-off of 25 can sensitively detect most overweight people and
does not erroneously detect overlean people.
• The definition for obesity in children is a BMI at or above the sex-
and age-specific 95th percentile, whereas a BMI between the 85th
and 95th percentiles is defined as being overweight. These criteria
have been selected because they correspond to adult BMIs of 30
and 25, respectively.
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7. Causes of Obesity
• The epidemic of obesity results from many causative factors, and
research is adding to the body of knowledge almost daily.
• While overweight and obesity ultimately result from an energy
imbalance of eating too many calories and not getting enough
physical activity, many factors contribute to both the development of
obesity and the body’s response to attempts to control it. Commonly
acknowledged contributing causes include genetics, metabolism,
behavior, environment, culture, and socioeconomic status.
• Medical conditions such as thyroid disorder, Cushing syndrome, and
polycystic ovarian syndrome can also contribute to weight gain and
obesity, as do many medications.
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8. Causes of Obesity
• The relationship between genetics and weight gain is complex and,
as yet, not fully understood.
• The most recent update of the human obesity gene map, completed
in 2005, suggests that there are 100 chromosomal locations relevant
to obesity.
• Many of these relate to known brain-gut controls of hunger and
satiety, metabolism, and the body’s storage mechanisms.
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9. Causes of Obesity
• Researchers believe these theories may help to explain differences
in obesity levels found in various populations.
• Identification of these genetic influences may allow for more
targeted treatment interventions in the future.
• It is yet unknown how genes and mutations may directly or indirectly
interact with environmental causes of obesity.
• One description for the complex interaction between environment
and genetics is attributed to George Bray, a noted expert on obesity,
who stated “the genetic background loads the gun, but the
environment pulls the trigger.”
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10. Causes of Obesity
• There is new evidence that behavior-based interventions may help
keep genetic influence in check.
• Though genetic research gives new insight into the genesis of
obesity, environmental influence remains the major contributor to
this worldwide issue.
• Obesity rates have reached epidemic proportions in populations with
high availability of calorie-rich foods and few opportunities for
physical activity.
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11. Causes of Obesity
• Influences such as family eating patterns, time spent on the
computer, watching television, reliance on the automobile for
transportation, easy access to food, higher energy density of food,
increased consumption of sugar- sweetened beverages, and
increasing portion sizes have all been cited as contributing factors to
overweight trends.
• More recent epidemiologic studies indicate that while decreased
physical activity plays a role in increasing rates of overweight and
obesity, diet changes due to increased availability of cheap, tasty,
highly promoted, obesogenic types of food appear to have
caused a much more steep rise in obesity.
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12. Types of Obesity
• Two types of obesity based on distribution of fat have been
described: upper body and lower body obesity.
• Upper body obesity is also referred to as central, abdominal,
visceral, or male (“android”) obesity. Lower body obesity is also
known as peripheral, gluteal-femoral, or female (“gynoid”) obesity.
• Subjects with upper body obesity are often referred to as being
shaped like an “apple,” compared with lower body obesity, which is
more “pear” shaped.
• In general, men have more intra-abdominal fat and women more
subcutaneous fat. As men age, the proportion of intra-abdominal fat
to subcutaneous fat increases. After menopause, women tend to
acquire more central fat distribution.
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14. Types of Obesity
• The obesity type is determined by dividing the waist by hip
circumference.
• Comparison of the waist measurement and hip measurement can
identify the type of obesity.
• A waist–hip ratio greater than 1.0 in men and 0.8 in women also
indicates upper body or central obesity.
• Central obesity can be further differentiated into intra-abdominal
adipose tissue (visceral fat) and subcutaneous abdominal adipose
tissue by the use of computed tomography (CT) or magnetic
resonance imaging (MRI) scans.
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16. Types of Obesity
• Waist-circumference, which is a measure of central fat distribution,
measures both subcutaneous abdominal adipose tissue and intra-
abdominal adipose tissue.
• One of the characteristics of visceral fat is the release of adipokines
(such as TNF-α and adiponectin) and fatty acids directly to the
liver before entering the systemic circulation, having a potentially
greater impact on hepatic function (e.g., the increased fatty acids
are deposited in the liver, causing fatty liver, resulting in insulin
resistance in the liver).
• Higher levels of these adipokines and circulating free fatty
acids in obese people, particularly those with upper body obesity,
are thought to be associated with many of the adverse effects
of obesity.
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18. Types of Obesity
• The presence of excess fat in the abdomen out of proportion to total
body fat is an independent predictor of risk factors and mortality.
• Both BMI and waist circumference are positively correlated with total
body adipose tissue, but waist circumference is a better predictor of
abdominal or visceral fat content than BMI.
• A waist circumference 88 cm (35 inches) or greater in women and
102 cm (40 inches) or greater in men has been associated with
increased health risk.
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19. Types of Obesity
• Weight loss causes a preferential loss of visceral fat (due to
higher turnover of visceral fat cells than subcutaneous) and can
result in improvements in metabolic and hormonal
abnormalities.
• In terms of weight reduction, some studies have shown that people
with upper body obesity are easier to treat than those with
lower body obesity.
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20. Health Risks Associated with Obesity
• The excess body fat of obesity often significantly impairs health.
• As a result, obesity is the second leading cause of preventable
death in the United States in adults under age 70, and the third
leading cause in all ages, following smoking and hypertension.
• It has been predicted that the health effects of obesity will result in a
shorter life expectancy for today’s youth.
• Obese people have a 50% to 100% increased risk of premature
death from all causes compared to people with a healthy weight.
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21. Health Risks Associated with Obesity
• Obesity affects nearly every body system.
• Cardiac disease is increased, as well as hypertension,
hypertriglyceridemia, and decreased HDL cholesterol.
• Significant weight gain increases the risk of developing type 2
diabetes, obstructive sleep apnea, gastric reflux, urinary stress
incontinence, and gallbladder disease.
• Limited mobility and increased joint disorders are functional results
of increased weight on the body’s skeletal system.
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23. Health Risks Associated with Obesity
• In women, obesity can contribute to infertility, higher risk pregnancy,
gestational diabetes, maternal hypertension, and difficulty in labor
and delivery.
• Infants who are born to obese mothers are more likely to be high
birth weight, contributing to an increased rate of cesarean section
delivery.
• Several types of cancer are seen in higher frequency in people who
are obese, including endometrial, colon, gallbladder, prostate,
kidney, and postmenopausal breast cancer.
• Obesity also causes nonalcoholic steatohepatitis and fatty liver
disease.
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37. GENETIC FACTORS IN PEOPLE WITH OBESITY
• Prader-Willi syndrome — It is a neurodegenerative disorder that is
caused by genetic abnormalities of the long arm of chromosome 15
(q11-13). The majority of patients have a deletion of paternal DNA in
this region; most of the remainder have two copies of maternal
chromosome 15 (uniparental disomy).
• Bardet-Biedl syndrome — It is an autosomal recessive disorder
characterized by obesity and several other abnormalities, including
microorchidism in men, intellectual disability (mental retardation),
retinal dystrophy, polydactyly, renal malformations (particularly
calyceal abnormalities), and polyuria and polydipsia.
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38. GENETIC FACTORS IN PEOPLE WITH OBESITY
Common obesity
• Obesity is a heritable trait, but the genes that contribute to the more
common forms of obesity have been difficult to identify.
• However, genome wide association studies in large populations
have identified polymorphisms in genes that are associated with
obesity risk.
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40. GENETIC FACTORS IN PEOPLE WITH OBESITY
Common obesity
• A variant in the FTO gene (fat mass and obesity associated) on
chromosome 16 predisposes to type 2 diabetes through an effect on
BMI.
• In a genome-wide association study of 16,000 individuals (and
confirmed in additional populations), common variants near MC4R
were associated with increasing body mass index in both children
and adults.
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41. GENETIC FACTORS IN PEOPLE WITH OBESITY
Common obesity
• Mutations in PCSK1 (prohormone convertase 1/3) gene are
associated with monogenic obesity, but may also contribute to
polygenic obesity.
• Brain-derived neurotrophic factor (BDNF) may play a role in energy
balance; BDNF haploinsufficiency is associated with childhood-
onset obesity.
• The gene for peroxisome-proliferator-activated receptor (PPAR)
gamma 2, a transcription factor that has a key role in adipocyte
differentiation.
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42. PREDICTORS OF OBESITY
Several factors associated with a high risk of obesity have been
identified.
Some are metabolic and others are socioeconomic.
• Among the former are a low metabolic rate, increased carbohydrate
oxidation, insulin resistance, and low sympathetic activity.
• Among the latter are lower socioeconomic class, lower education
level, and cessation of smoking.
• Weight gain is very common when people stop smoking. This is
thought to be mediated at least in part by nicotine withdrawal. The
average weight gain is 4 to 5 kg in four to six months, but it can be
much greater.
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43. PHYSIOLOGIC BASIS FOR OBESITY
• An increase in body fat (both visceral and nonvisceral
[subcutaneous]) requires that energy intake be increased over
energy expenditure.
• However, the truth and simplicity of this statement of the first law of
thermodynamics fail to include the modulating effect of other
variables such as intrauterine growth, growth hormone and
reproductive hormone secretion, and the feedback between energy
intake and expenditure.
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44. PHYSIOLOGIC BASIS FOR OBESITY
Determinants of energy expenditure
• Low energy expenditure is one factor that can promote weight gain.
• Approximately 70 percent of energy expenditure is utilized for basal
or resting metabolic processes.
• These include the energy involved in maintaining body temperature
and ion gradients across cell membranes, cardiac and respiratory
muscle function, gastrointestinal motility and secretion, and other
metabolic storage and mobilization processes.
• Another 10 percent of energy expenditure is dissipated through the
thermic responses to food.
• The final component of energy expenditure is activity and exercise.
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45. PHYSIOLOGIC BASIS FOR OBESITY
Brown adipose tissue and body temperature
• Brown adipose tissue (BAT) regulates energy expenditure in small
mammals and newborn infants.
• Through a process called adaptive thermogenesis, uncoupling
protein 1 (UCP1), a marker gene for BAT, allows mitochondria to
generate heat instead of ATP, thereby maintaining normal body
temperature.
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46. PHYSIOLOGIC BASIS FOR OBESITY
Food
• The macronutrient composition of food affects energy expenditure,
but not fat storage. In a randomized trial designed to determine
whether the level of dietary protein affects body composition, weight
gain, and energy expenditure, 28 individuals were randomly
assigned to overfeeding with diets containing 5, 15, or 25 percent of
energy from protein.
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47. PHYSIOLOGIC BASIS FOR OBESITY
Food
• Overconsumption of a diet with normal (15 percent of energy) or
high (25 percent) compared with low (5 percent) protein increased
resting energy expenditure and lean body mass. Although overall
weight gain was less with a low protein diet (approximately 3 versus
6 kg), body fat accumulation was similar and was related to excess
calories consumed rather than the protein composition of the diet.
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48. PHYSIOLOGIC BASIS FOR OBESITY
Activity
• The final component of energy expenditure is activity and exercise,
known as activity thermogenesis, which includes both exercise and
nonexercise activity thermogenesis (NEAT). An often overlooked
component is spontaneous physical activity (fidgeting), which can
account for the expenditure of 100 to 800 kcal/day and, along with
genetic factors, is responsible for much of the variance in energy
expenditure among individuals that is not explained by differences in
fat-free mass.
• A sedentary lifestyle is an important factor in the development of
obesity, and for children this has been associated with many hours
watching television, an effect that may persist into adulthood.
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49. THE CONTROL SYSTEM
• The feedback control system consists of the cellular processes for
energy expenditure and for digestion, absorption, transport, and
storage of nutrients and their subsequent mobilization and utilization
as fuels.
• The central nervous system controller receives afferent signals from
the periphery about deficits or surpluses of foods or alterations in the
rate of fuel utilization.
• The controller processes this information and initiates metabolic and
cognitive responses according to whether food is needed and if so,
when and where to get it. The controller also initiates signals that
alter metabolism of nutrients and the cognitive processes for food
seeking.
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50. THE CONTROL SYSTEM
Afferent signals from fat and the gastrointestinal tract
• The afferent signals that carry messages about surpluses or deficits
of nutrients include neural circuits, circulating hormones, and
nutrients themselves. Among them, leptin is one of the most potent.
Leptin production is closely correlated with body fat mass, and leptin
can reduce food intake and increase the activity of the sympathetic
nervous system.
• Gastric distention and gastric contractions serve as signals for
satiety and hunger, respectively. Nutrient absorption (or its lack)
may also serve as signals leading to satiety (or hunger).
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51. THE CONTROL SYSTEM
Ghrelin
• Several gut hormones may be involved in regulation of food intake.
Glucagon-like peptide-1 (GLP-1), cholecystokinin, enterostatin, and
polypeptide Y 3-36 reduce food intake.
• Ghrelin, a 28 amino acid peptide produced in the stomach and
duodenum, is an endogenous ligand for the growth hormone (GH)
secretagogue receptor. This peptide has two major effects: it
stimulates GH secretion and increases food intake in rodents and
humans.
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52. THE CONTROL SYSTEM
Central controller
• Messages from the periphery reach the brain via the circulation
(leptin, glucose) or the autonomic nervous system (vagal afferents).
Information from the gastrointestinal tract and oropharynx is neurally
transmitted to the hindbrain and processed in the nucleus of the
tractus solitarius.
• Leptin and possibly glucose and amino acids reach the brain by
transport across the blood-brain barrier or directly in those regions of
the brain in which this barrier is absent.
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53. THE CONTROL SYSTEM
Central controller
Within the brain, several regions are important in processing
information about food and relating it to body weight. They are:
• The nucleus of the tractus solitarius, the hindbrain area in which
vagal and other neural inputs are integrated.
• The arcuate nucleus at the base of the hypothalamus integrates
leptin signals by reciprocally changing the production and release of
pairs of peptides (neuropeptide Y and agouti-related peptide) that
increase food intake, and other pairs (cocaine-amphetamine-related
transcript and proopiomelanocortin) that decrease food intake.
• The paraventricular nucleus (PVN) plays a central role in regulation
of food intake. It receives a rich supply of signals from the peptides
in the arcuate nucleus.
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54. THE CONTROL SYSTEM
Central controller
Within the brain, several regions are important in processing
information about food and relating it to body weight. They are:
• The ventromedial hypothalamus, the destruction of which reduces
activity of the sympathetic nervous system and leads to increased
food intake and profound obesity.
• The lateral hypothalamus which, if damaged, may decrease feeding
and lower body weight.
• Selected regions of the amygdala, which may modulate feeding,
either through connections to the ventromedial hypothalamus or
elsewhere.
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55. THE CONTROL SYSTEM
Stimulators of food intake
• As noted above, neuropeptide Y is one of the most potent
stimulators of food intake known.
• Ghrelin, melanin-concentrating hormone, growth hormone-releasing
hormone, norepinephrine, and orexin-A and orexin-B (also called
hypocretin) also stimulate food intake. Two of these hormones,
norepinephrine and neuropeptide Y, appear to stimulate
predominantly carbohydrate intake.
• The importance of melanocyte-stimulating hormone has been
demonstrated by the observations that disruption of the
melanocortin-4 receptor in the hypothalamus leads to massive
obesity, the identification of an agouti-related peptide which may
compete with the hormone, and the description of obesity caused by
proopiomelanocortin mutations.
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56. THE CONTROL SYSTEM
Inhibitors of food intake
A number of hormones inhibit food intake. However, it is often difficult
to separate effects on decreasing food intake from other effects such as
aversion to food.
• Cholecystokinin decreases food intake when administered either
centrally or peripherally.
• Enterostatin is a penta peptide derived from a proenzyme in the
gastrointestinal tract called procolipase. It reduces food intake, in
particular fat intake, when given peripherally or into the brain.
• Infusion of the gut hormones GLP-1, pancreatic polypeptide,
oxyntomodulin, or peptide YY 3-36 suppresses food intake in both
lean and obese subjects.
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57. THE CONTROL SYSTEM
Efferent mediators
• The sympathetic nervous system has a tonic role in maintaining
energy expenditure and blood pressure. In addition, the activity of
the peripheral sympathetic nerves supplying thermogenic tissues
and food intake are inversely related. These nerves activate
thermogenic tissues via beta-3-adrenergic receptors, resulting in a
reduction in food intake. Animals lacking beta-3-receptors in adipose
tissue do not reduce food intake in response to beta-3-agonist
stimulation.
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58. THE CONTROL SYSTEM
Efferent mediators
• Glucocorticoids are a second key component of the efferent system,
acting to increase food intake. In the absence of glucocorticoid,
leptin deficiency or lesions of the ventromedial hypothalamus do not
cause obesity. The permissive effect of glucocorticoids may be
mediated via inhibition of sympathetic nervous system activity.
Stimulation of food intake contributes to the weight gain in patients
with Cushing's syndrome or those treated with exogenous
glucocorticoids.
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59. FOOD INTAKE
• The modulation of food intake from meal to meal is normally
integrated to maintain a constant weight status, and defective
integration produces obesity or leanness. This modulation occurs in
the face of a 25 percent coefficient of variation in day-to-day food
intake. Food intake increases in early life to reach a peak in the
second decade after which it declines. Men consistently eat more
than women in concert with their higher fat-free mass. The age-
related decline in caloric intake in men and women is associated
with a slow decline in their energy expenditure. The fact that both
men and women become more obese in middle age implies that the
decline in energy expenditure is faster than the decline in food
intake.
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60. SUMMARY
• Animal models of obesity have played an important role in
understanding the molecular mechanisms of obesity.
• Genetic factors play a permissive role and interact with
environmental factors to produce obesity. Studies suggest that
heritable factors are responsible for 30 to 70 percent of the variation
in adiposity. There are nearly 50 genes with polymorphisms related
to obesity that have been identified by genome-wide scans.
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65. SUMMARY
• An increase in body fat (both visceral and nonvisceral
[subcutaneous]) requires that energy intake be increased over
energy expenditure over an extended period of time. However, there
is a feedback mechanism between energy intake and expenditure, a
mechanism that tends to maintain body weight. Weight gain is
associated with an increase in energy expenditure which retards
further weight gain, whereas weight loss is associated with a
decrease in total and resting energy expenditure, a change that
retards further weight loss.
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