# 29 - 413 Pathobiology of Obesity

### 413 Pathobiology of Obesity

Fenway Health: Glossary of LGBT terms for health care teams. 
February 2024. Available at https://www.lgbtqiahealtheducation.org/
publication/lgbtqia-glossary-of-terms-for-health-care-teams/.
Institute of Medicine: The health of lesbian, gay, bisexual, and trans­
gender (LGBT) people: Building a foundation for better understand­
ing. 2011. Available at www.nap.edu/catalog.php?record_id=13128.
Institute of Medicine: Collecting sexual orientation and gender 
identity data in electronic health records: Workshop summary. 2013. 
Available at https://www.nap.edu/catalog/18260/collecting-sexualorientation-and-gender-identity-data-in-electronic-health-records.
Joint Commission: Advancing effective communication, cultural 
competence, patient- and family-centered care for the lesbian, gay, 
bisexual, and transgender community: A field guide. 2011. Available 
at www.jointcommission.org/lgbt.
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2015 U.S. Transgender Survey. 2015. Available at https://transequality.
org/sites/default/files/docs/usts/USTS-Full-Report-Dec17.pdf.
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Section 3	 Obesity, Diabetes Mellitus, 
and Metabolic Syndrome
Stephen O’Rahilly, I. Sadaf Farooqi

Pathobiology of Obesity
Adipose tissue evolved as a solution to the challenge of the intermittent 
availability of food. At times when food is plentiful, excess calories are 
converted to triglycerides and efficiently stored in the unilocular lipid 
droplets that occupy most of the volume of fat cells. When needed, 
the triglyceride is rapidly broken down to free fatty acids and glycerol, 
which provide an energy source to other sites throughout the body. 
However, in environments where food is abundant and when indi­
viduals tend to be sedentary, the chronic excess of energy intake over 
expenditure leads to obesity. The risks of developing obesity under 
those circumstances and of developing the illnesses associated with 
obesity vary greatly between individuals, with that variation having a 
strong genetic basis.
■
■DEFINITION OF OBESITY AND OVERWEIGHT
Obesity is defined as a state of excess adipose tissue mass that adversely 
affects health. The direct measurement of fat mass is not something 
that is readily undertaken in routine clinical practice, so a proxy mea­
sure, the body mass index (BMI), is generally used. This is calculated 
as weight/height2 (in kg/m2) (Fig. 413-1). BMI-based definitions of 
obesity and overweight have been established based on associations 
with certain morbidities and excess mortality. These definitions have 
been based largely on studies of predominantly white, Western popula­
tions, and there is growing evidence that the relationship between BMI 
and adverse outcomes is different in people from other ethnic groups, 
usually in the direction of worse health outcomes being seen at lower 
levels of BMI. The World Health Organization (WHO) defines a BMI 
of 30 kg/m2 as the cutoff point for obesity, while individuals with values 
between 25 and 30 kg/m2 are classified as overweight. For individuals 
with a very muscular body habitus, the BMI may overestimate the 

Body Mass Index
(weight in kg/height in meters squared)
Pathobiology of Obesity
CHAPTER 413
Underweight
<18.5
Normal weight
18.5–24.9
Overweight
25–29.9
Obese
>30.0
FIGURE 413-1  Definitions of overweight and obesity. The World Health Organization 
defines obesity based on body mass index (BMI), which is calculated as weight in 
kilograms divided by the height in meters squared.
amount of body fat. For any given BMI, women will generally have a 
higher percentage of body fat than men.
The extent to which different adipose depots expand in response 
to chronic overnutrition varies markedly between people. In general, 
females store more fat in subcutaneous tissues, especially on buttocks, 
thighs, and upper arms, whereas men are more prone to store fat in 
intraabdominal and truncal subcutaneous sites. A simple measure of 
fat distribution is provided by a measurement of the waist-to-hip ratio. 
Independent of the degree of obesity, a waist-to-hip ratio >0.9 in women 
and >1.0 in men is associated with adverse health outcomes such as 
type 2 diabetes and dyslipidemia.
■
■EPIDEMIOLOGY
The annual National Health and Nutrition Examination Survey 
(NHANES) provides an ongoing record of the prevalence of obesity in 
the United States. In 2017–2018, 42.4% of U.S. adults aged ≥20 years old 
had obesity with no significant differences in prevalence by age group. 
Non-Hispanic black people had the highest prevalence of obesity at 
49.6%, followed by Hispanic (44.8%), non-Hispanic white (42.2%), and 
non-Hispanic Asian (17.4%) people. In the United States, Asians repre­
sent a highly heterogeneous group encompassing both East and South 
Asia as well as a substantial Filipino community. The risks of obesity 
and its complications may differ greatly between people from different 
parts of Asia; in general, the prevalence of obesity is somewhat higher 
in women than in men, with black women having the highest preva­
lence at 56.9%. There has been a marked increase in the prevalence of 
obesity over time. For example, between 1976 and 1980, the NHANES 
survey reported a prevalence of 14.5%, indicating a near threefold 
increase over the past 40 years.
This trend is seen globally. According to the WHO, obesity has 
nearly tripled worldwide since 1975. In 2016, >1.9 billion adults aged 
≥18 years old were overweight. Of these, >650 million were obese; 39% 
of adults aged ≥18 years old were overweight in 2016, and 13% were 
obese. Most of the world’s population lives in countries where over­
weight and obesity kills more people than underweight.
During this time, one of the most striking changes has been in the 
prevalence of obesity in children. In children, the relationship between 
BMI and body fat varies considerably with age and with pubertal 
maturation; however, when adjusted for age and sex, BMI is a reason­
able proxy for fat mass. Using age- and sex-specific BMI cutoffs (over­
weight ≥91st percentile; obesity ≥99th percentile), in 2019, the WHO 
estimated that 38 million children under the age of 5 were overweight 
or obese, and in 2016, they reported that 340 million children and 
adolescents aged 5–19 were overweight or obese.
■
■PHYSIOLOGIC REGULATION OF ENERGY 
BALANCE
Discussions about obesity so frequently focus on the issues of personal 
choice or the obesogenic environment that it can be easy to forget that

the amount of stored energy in our bodies is subject to homeostatic 
control by fundamental physiologic processes essential to our survival. 
In the 1940s, it was demonstrated that rodents defend their level of 
body fat; once returned to ad libitum diets after a short period of 
enforced caloric restriction or excess, animals either overconsumed or 
underconsumed calories until they returned to their previous status. 
Since that time, research has progressively dissected the signals that 
sense nutrient stores and the contents of our diets and how this infor­
mation is integrated to control hunger, satiety, and the expenditure of 
energy. The key locus for the integration of these signals is the hypo­
thalamus, an area of the brain at least partially outside the blood-brain 
barrier that facilitates its ability to receive hormonal signals and com­
bine these with sensory, cognitive, and other neural inputs.

PART 12
Endocrinology and Metabolism
The hypothalamus receives multiple hormonal signals relevant to 
energy balance (Fig. 413-2). The circulating concentration of leptin, a 
peptide hormone produced by fat cells, increases as fat stores increase 
and declines as fat stores are depleted. Importantly, under conditions 
of caloric restriction, circulating leptin levels fall faster than the dis­
appearance of fat. Humans born without functional leptin or leptin 
receptors, although normal weight at birth, develop severe obesity 
from an early age, largely as a result of an intense drive to eat (hyper­
phagia). Clearly, a reduction of leptin below normal level is a powerful 
stimulus to food intake and largely explains the rebound overeating 
and weight regain that occurs after a period of starvation or diet­
ing. The hypothalamus also receives hormonal signals that are more 
Hypothalamus
Leptin
Ghrelin
Adipose
tissue
GLP1
CCK
Insulin
Amylin
PYY
OXM
Pancreas
FIGURE 413-2  The homeostatic regulation of body weight. In most people, body weight remains stable over long 
periods of time despite fluctuations in the amount of food we eat and the amount of activity we undertake. This 
homeostatic regulation of body weight is controlled by the neurons in the hypothalamus, which receive hormonal 
signals from adipose tissue such as leptin and neural and hormonal signals from the gut in response to meals. 
Glucagon-like peptide 1 (GLP1) and cholecystokinin (CCK) from enteroendocrine cells of the small intestine and 
peptide YY (PYY) and oxyntomodulin (OXM) from the large intestine are secreted in response to eating a meal 
and/or the presence of nutrients in the intestinal lumen. Their release, together with neural signals from the 
vagus nerve and the enteric nervous system, contributes to satiety, acting on the hypothalamus via projections 
from the brainstem. Insulin, produced by the pancreas in response to carbohydrate- and protein-rich meals and 
potentiated by the action of some of the gut hormones, also has effects on the hypothalamic neurons controlling 
energy balance, whereas amylin acts predominantly via the brainstem. The release of the hormone ghrelin from 
the stomach increases in the unfed state and induces appetite by acting on hypothalamic neurons as well as on 
receptors in the brainstem.

immediately related to the amount and type of food that has been 
ingested. Peripheral hormones such as cholecystokinin (CCK) from 
the stomach, glucagon-like peptide 1 (GLP-1) and gastric inhibitory 
polypeptide (GIP) from enteroendocrine cells of the small intestine, 
and peptide YY (PYY) and oxyntomodulin from the large intestine are 
secreted in response to eating a meal and/or the presence of nutrients 
in the intestinal lumen. Their release together with neural signals from 
the vagus nerve and the enteric nervous system contributes to satiety, 
often indirectly acting on the hypothalamus via projections from the 
brainstem. Insulin and amylin, produced by the pancreas in response 
to carbohydrate and protein-rich meals, also have effects on neurons 
controlling energy balance.
The propeptide pro-opiomelanocortin (POMC) is expressed in 
a highly restricted population of hypothalamic neurons that project 
widely throughout the brain (Fig. 413-3). These neurons are respon­
sive to the endocrine signals described above and are critical to the 
regulation of energy balance. The POMC-derived peptides α- and 
β-melanocyte-stimulating hormone (MSH) act on the melanocortin 
4 receptor (MC4R) to regulate both food intake and aspects of energy 
expenditure that are influenced by the sympathetic nervous system. 
γ-MSH, acting mostly through the MC3 receptor, appears to play more 
of a role in controlling linear growth and the disposition of nutrients 
into lean versus fat tissues. Signaling through both these melanocortin 
receptors is also subject to negative control by a different population of 
neurons, which make and release agouti-related peptide (AGRP), neu­
ropeptide Y (NPY), and the inhibitory neu­
rotransmitter γ-aminobutyric acid (GABA). 
AGRP actively switches off melanocortin 
receptors. Leptin, which suppresses food 
intake, simultaneously stimulates POMC 
neurons and inhibits NPY/AGRP neurons. 
Human energy balance is highly sensitive 
to signaling through this system as people 
who have a genetic defect in just one of the 
two copies of the MC4R gene are very prone 
to overeat (hyperphagia) and to gain weight.
Brainstem
Vagus nerve
■
■THE PHYSIOLOGY OF 
NUTRIENT STORAGE IN 
ADIPOSE TISSUE
When energy intake exceeds energy expen­
diture, a small amount of that excess energy 
is stored as glycogen in liver and skeletal 
muscle. But if the imbalance is greater, then 
our bodies are designed to store that excess 
energy in a more efficient way as triacylglyc­
erol (triglyceride). This fat is more efficient 
because, unlike glycogen, it does not need 
accompanying water, and when metabo­
lized, it generates more than twice as much 
energy per gram than does carbohydrate. 
Adipocytes (fat cells) have evolved to contain 
a highly specialized organelle, the unilocu­
lar fat droplet, which holds the triglycer­
ide within a single-layer of phospholipid 
that contains all the components needed for 
enzymes that make and breakdown triglyc­
erides in a manner that is rapidly responsive 
to metabolic requirements. No other type of 
cell is specifically designed to store fat safely 
in this manner, and many of the adverse 
consequences of obesity are likely caused 
not by having too much fat in adipocytes 
but by “nonprofessional” cells being forced 
to take up and store fat. During weight gain, 
the amount of lipid in each fat cell increases. 
Some new fat cells can also be made in adult­
hood when ~10% of our fat cell population 
turns over every year.

Paraventricular
nucleus
Ventromedial
nucleus
BDNF
MC4R
α/β-MSH
AGRP
Arcuate
nucleus
POMC
AGRP
Hypothalamus
LEPR
LEPR
Hypothalamus
Leptin
Adipose
tissue
FIGURE 413-3  Hypothalamic pathways regulating body weight. Neurons in the hypothalamus regulate energy intake 
and expenditure in response to leptin and other hormones. In the fed state, leptin stimulates primary neurons in the 
arcuate nucleus of the hypothalamus that express pro-opiomelanocortin (POMC). The POMC-derived peptides α- and 
β-melanocyte-stimulating hormone (MSH) act on the melanocortin 4 receptor (MC4R) expressed on neurons in the 
paraventricular nucleus to reduce energy intake and increase energy expenditure. At the same time, leptin inhibits 
neurons expressing agouti-related peptide (AGRP), which switches off melanocortin receptors. When these and 
other key molecules, such as brain-derived neurotrophic factor (BDNF) and single minded-1 (SIM1), are disrupted by 
inherited mutations, affected individuals have hyperphagia and severe obesity.
■
■THE CAUSES OF OBESITY: AN INTERACTION OF 
GENES AND ENVIRONMENT
For a person to develop obesity, energy intake must exceed energy 
expenditure in a manner that is sufficiently sustained to result in 
the accumulation of a large excess of triglyceride in adipose tis­
sue. As obesity is a cumulative pathology, if energy intake exceeds 
energy expenditure by even a small amount (as little as 7 kcal/d), 
this is sufficient to develop obesity over a matter of years or decades. 
Even where obesity is common, there are many people who are not 
overweight. Economic and social factors are likely to play a role as 
there are more normal-weight people in wealthier and more socially 
advantaged groups, at least in Western societies. It is also true, 
however, that because of discrimination, people with obesity may 
become socially and economically disadvantaged, which complicates 
interpretation of that data. We can, however, state with considerable 
certainty that genetic factors play a major role in predisposing people 
to a range of adiposity. We know this from a large number of studies 
comparing identical and nonidentical twins. It is particularly telling 
that the degree of adiposity in adult life of identical twins brought 
up in different families is very similar between the twins but is not 
at all correlated with that of the adoptive siblings with whom they 
were raised.

■
■THE RELATIVE ROLES OF 
EXCESS INTAKE AND LOWER 
ENERGY EXPENDITURE IN 
CONFERRING BIOLOGIC 
PREDISPOSITION
Do these heritable factors influence 
energy intake, energy expenditure, or 
both? It is clear that by the time a person 
develops obesity the amount of energy 
they expend in the resting state is more, 
not less, than a normal weight person. 
However, if a person with obesity loses 
weight by dieting, there is some evidence 
that they tend to be more “energy effi­
cient” than a person who has never been 
obese, particularly in terms of how many 
calories they burn during a defined bout 
of activity. However, the effects are subtle. 
It seems very likely that there are some 
individuals who are predominantly pre­
disposed to develop obesity by virtue of 
a lower metabolic rate, but thus far, apart 
from severe hypothyroidism, concrete 
examples are scarce. In contrast, a much 
more consistent and compelling body 
of evidence supports the idea that the 
genetic predisposition to obesity is largely 
mediated through the brain’s control of 
food intake. When studied in controlled 
settings, individuals who carry genetic 
variants that predispose to obesity tend to 
eat more and be less readily satiated. This 
is very readily demonstrable when the 
mutation has a major effect on obesity 
predisposition, but similar data are now 
emerging in the case of common genetic 
variants with smaller effects.

Reduced food
intake
Increased energy
expenditure
Pathobiology of Obesity
CHAPTER 413
SIM1
■
■ENVIRONMENTAL FACTORS 
PREDISPOSING TO OBESITY
Obesity cannot exist in the absence of 
sufficient food to lay down and maintain 
excess fat stores. That fact not infre­
quently leads to the belief that the prin­
cipal cause of obesity must be either a 
person’s ignorance of the role of excess 
caloric intake or their conscious choice to 
prioritize the immediate pleasures of eating over the long-term health 
harms associated with obesity. Taken to extremes, these views can 
engender serious social, economic, and medical discrimination against 
people with obesity. It is clear that genetic factors, however important 
they are in an individual’s predisposition to obesity, cannot explain the 
marked increase in obesity prevalence that has occurred in the past few 
decades. We have to look to an environment that has become increas­
ingly obesogenic to explain that phenomenon. In most developed and 
developing countries, energy-dense and highly palatable food and 
beverages have been aggressively marketed, made cheaper than ever 
before, provided in larger portions, and made available ubiquitously 
and continuously. This has been combined with the reduction in physi­
cal activity in work and domestic life due to mechanization and the 
change in the nature of employment. Even the control of our external 
temperature by artificial heating and cooling has meant less energy 
expended on thermoregulation. Taken together, these are likely to be 
the major factors driving the recent increase in obesity. It is important 
to remember, however, that a substantial proportion of the population 
remains normal weight under these circumstances and a large part of 
that is attributable to their genetic good fortune.
There is much current investigation into other environmental fac­
tors that might influence the development of obesity. Heated debates

continue about the optimal balance of macronutrients in the diet 
to maintain normal weight and good health. Much of this revolves 
around the potential benefits of reducing the relative proportion of 
carbohydrates in the diet (Chap. 414). There seems to be reasonable 
consensus that, in the short term, diets that are rich in protein and fat 
and lower in carbohydrates more readily result in quick weight loss. 
This may be because the appetite-suppressing gut hormones discussed 
above increase more in response to protein than to carbohydrate, 
thus inducing earlier satiation. However, longer-term studies to date 
are less compelling, and the long-term increases in protein and fat 
intake are not without at least theoretical risks. A growing body of 
evidence suggests that exposures early in life, either in utero or in early 
postnatal life, might “program” individuals to develop obesity and/
or cardiometabolic disease through effects that are often attributed 
to “epigenetics” (Chap. 497). This is an attractive idea, and if true, it 
would mean that time-limited and affordable interventions early in 
life might have lifelong benefits. Inevitably, it will take time to see if 
the promise of such interventions will be fulfilled. Much excitement 
has been generated by the increasing recognition of the diversity of 
our intestinal microbiome, which clearly has relevance to gastroin­
testinal health (Chap. 484). At present, it is premature to ascribe any 
significant role to the human microbiome in obesity or its adverse 
consequences.

PART 12
Endocrinology and Metabolism
■
■WHY DOESN’T LEPTIN PREVENT OBESITY?
Leptin is known to suppress food intake, and its levels rise as fat stores 
expand. So why does this not prevent us from developing obesity? The 
most plausible explanation lies in the evolutionary history of leptin 
and the fact that it appears to defend strongly against the loss of body 
fat stores, with a fall in circulating leptin below a person’s habitual 
level being a powerful stimulus to food intake, whereas the response 
to rises in leptin above the normal level is less pronounced. At higher 
levels of leptin, administering extra amounts of the hormone may 
have no discernible effect at all—a phenomenon that has come to be 
called leptin resistance. It is important to remember that even though 
a person appears to be leptin resistant, some leptin action is occurring; 
otherwise, the person would become as insatiably hungry and progres­
sively obese as someone with congenital leptin deficiency (see below). 
It also seems likely that a subgroup of people may have relatively low 
leptin levels, which plays a role in the etiology of their obesity. There 
are likely other hormonal signals produced in severe obesity that, 
unlike leptin, continue to exert a suppressive effect on food intake and 
help to ensure that the expansion of adipose tissue does not become 
indefinitely cumulative.
■
■SINGLE-GENE DISORDERS LEADING TO OBESITY
The assessment of severely obese children and, indeed, adults should 
be directed at screening for potentially treatable endocrine and neuro­
logic conditions and identifying genetic conditions so that appropriate 
genetic counseling and, in some cases, treatment can be started. Clini­
cally, it remains useful to categorize the genetic obesity syndromes as 
those with dysmorphism and/or developmental delay and those with­
out these features (Tables 413-1 and 413-2). Although individually 
these monogenic disorders are rare, cumulatively, up to 20% of chil­
dren with severe obesity have rare chromosomal abnormalities and/or 
highly penetrant genetic mutations that drive their obesity. This figure 
is likely to increase with wider accessibility to genetic testing and as 
new genes are identified. A genetic diagnosis can inform manage­
ment (many such patients find it very difficult to lose weight through 
diet and exercise) and can inform clinical decision-making regarding 
the use of bariatric surgery (feasible in some; high risk in others) 
(Chap. 414). There are a number of drugs in clinical trials targeted 
specifically at patients with genetic obesity syndromes. Specifically, 
setmelanotide, a MC4R agonist, has been used effectively in phase 
2/3 clinical trials in children who are genetically deficient in POMC, 
PCSK1, and the leptin receptor. It is also being explored for the treat­
ment of other genetic obesity syndromes affecting the melanocortin 
pathway and in acquired hypothalamic obesity caused by tumors such 
as craniopharyngiomas.

TABLE 413-1  Classical Genetic Obesity Syndromes
ADDITIONAL CLINICAL 
FEATURES
SYNDROME
INHERITANCE
Prader-Willi
Autosomal 
dominant
Hypotonia, failure to thrive in 
infancy, developmental delay, 
short stature, hypogonadotropic 
hypogonadism, sleep 
disturbance, obsessive 
behavior
Albright’s hereditary 
osteodystrophy or 
pseudohypoparathyroidism
Autosomal 
dominant
Short stature in some, skeletal 
defects, developmental delay, 
shortened metacarpals; 
hormone resistance when 
mutation on maternally 
inherited allele
Bardet-Biedl
Autosomal 
recessive
Syndactyly/brachydactyly/
polydactyly, developmental 
delay, retinal dystrophy or 
pigmentary retinopathy, 
hypogonadism, renal 
abnormalities
Cohen’s
Autosomal 
recessive
Facial dysmorphism, 
microcephaly, hypotonia, 
developmental delay, 
retinopathy
Carpenter’s
Autosomal 
recessive
Acrocephaly, brachydactyly, 
developmental delay, 
congenital heart defects; 
growth retardation, 
hypogonadism
Alström’s
Autosomal 
recessive
Progressive cone-rod 
dystrophy, sensorineural 
hearing loss, hyperinsulinemia, 
early type 2 diabetes mellitus, 
dilated cardiomyopathy, 
pulmonary, hepatic and renal 
fibrosis
Tubby
Autosomal 
recessive
Progressive cone-rod 
dystrophy, hearing loss
■
■CLASSICAL SYNDROMIC DISORDERS
A number of syndromes were identified by clinicians long before 
their exact genetic cause was known. In these syndromes, obesity is 
associated with a stereotyped set of other anomalies, often neurode­
velopmental in type. The precise genetic basis for the majority of these 
syndromes is now known. Prader-Willi syndrome (PWS) is the most 
common syndromic cause of obesity, with an estimated prevalence of 
~1 in 25,000. It is an autosomal dominant disorder caused by deletion 
of an imprinted region on the paternal chromosome 15 (Chap. 479). 
The characteristic clinical features are hypotonia, feeding difficulties 
in infancy, developmental delay, hypogonadotropic hypogonadism, 
hyperphagia (increased food intake), and obesity. Children with PWS 
are short with reduced lean body mass and increased fat mass, fea­
tures resembling those seen in growth hormone (GH) deficiency; GH 
treatment decreases body fat and increases linear growth and muscle 
mass and is now standard of care in this condition. Low levels of brain 
expression of the neuropeptide oxytocin and the nerve growth factor 
brain-derived neurotrophic factor (BDNF) in PWS patients have sug­
gested new therapeutic opportunities for these patients.
Inherited or de novo (not found in either parent) mutations in 
another imprinted gene, GNAS1, which encodes Gsα protein, cause 
a syndrome known as Albright’s hereditary osteodystrophy (AHO) 
or pseudohypoparathyroidism (PHP) (Chap. 424). Maternal trans­
mission of GNAS1 mutations leads to short stature, obesity, and 
skeletal defects plus resistance to several hormones (e.g., parathyroid 
hormone), whereas paternal transmission leads only to the AHO phe­
notype. The clinical spectrum is very broad, and some patients may 
present with obesity alone.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive dis­
ease characterized by obesity, developmental delay, polydactyly, reti­
nal dystrophy or pigmentary retinopathy, hypogonadism, and renal

TABLE 413-2  Obesity Syndromes due to Mutations in Genes 
Controlling Energy Homeostasis Pathways
GENE AFFECTED
INHERITANCE
ADDITIONAL CLINICAL FEATURES
Leptin
Autosomal 
recessive
Severe hyperphagia, frequent 
infections, hypogonadotropic 
hypogonadism, mild hypothyroidism
Leptin receptor
Autosomal 
recessive
Severe hyperphagia, frequent 
infections, hypogonadotropic 
hypogonadism, mild hypothyroidism
Proopiomelanocortin
Autosomal 
recessive
Hyperphagia, cholestatic jaundice 
or adrenal crisis due to ACTH 
deficiency, pale skin and red hair
Prohormone 
convertase 1
Autosomal 
recessive
Small-bowel enteropathy, 
postprandial hypoglycemia, 
hypothyroidism, ACTH deficiency, 
hypogonadism, central diabetes 
insipidus
Carboxypeptidase E
Autosomal 
recessive
Severe insulin resistance
Melanocortin 4 
receptor
Autosomal 
dominant
Hyperphagia, accelerated linear 
growth
Single-minded 1
Autosomal 
dominant
Hyperphagia, accelerated linear 
growth, speech and language delay, 
autistic traits
BDNF
Autosomal 
dominant
Hyperphagia, developmental delay, 
hyperactivity, behavioral problems 
including aggression
TrkB
Autosomal 
dominant
Hyperphagia, speech and language 
delay, variable developmental delay, 
hyperactivity, behavioral problems 
including aggression
SH2B1
Autosomal 
dominant
Hyperphagia, disproportionate 
hyperinsulinemia, early type 2 
diabetes mellitus, behavioral 
problems including aggression
Abbreviations: ACTH, adrenocorticotropic hormone; BDNF, brain-derived 
neurotrophic factor; SH2B1, Src-homology-2 (SH2) B-adaptor protein-1 (SH2B1); 
TrkB, tropomyosin receptor kinase B.
abnormalities. The same clinical features can arise from mutations 
in >26 genes, which disrupt signaling in primary cilia. Melanocortin 
receptor agonists may be useful in treating hyperphagia and obesity in 
patients with BBS. Overlapping clinical features are seen in a number 
of other genetic obesity syndromes (Table 413-1).
■
■DISORDERS OF LEPTIN-MELANOCORTIN 
SIGNALING
Homozygous mutations that disrupt the production or action of leptin 
are rare but result in a disorder that is treatable. Children with homo­
zygous loss-of-function leptin mutations have rapid weight gain in the 
first few months of life, resulting in severe obesity due to an intense 
drive to eat (hyperphagia) and impaired satiety with food-seeking 
behavior soon after the end of a meal. Congenital leptin deficiency 
can be treated with subcutaneous injections of recombinant leptin, 
which reduce hunger, increase satiety, and lead to weight loss. Similar 
clinical features are seen in patients with homozygous mutations in the 
leptin receptor gene, but they are not responsive to leptin treatment 
(Table 413-2). Normal pubertal development rarely occurs in adults 
with leptin or leptin receptor deficiency, with biochemical evidence 
of hypogonadotropic hypogonadism. However, there is some evidence 
for the delayed but spontaneous onset of menses in a small number 
of leptin- and leptin receptor–deficient adults. Leptin treatment per­
mits progression of pubertal development, suggesting that leptin is a 
permissive factor for the development of puberty. An MC4R agonist 
(setmelanotide) is licensed for chronic weight management in leptin 
receptor deficiency.
Homozygous or compound heterozygous mutations in POMC 
lead to hyperphagia and early-onset obesity. As adrenocorticotropic 
hormone (ACTH) is produced in the pituitary gland by cleavage from 
POMC, patients also present with isolated ACTH deficiency (neonatal 

hypoglycemia and cholestatic jaundice). In the skin, POMC-derived 
melanocortin peptides act on melanocortin 1 receptors to induce 
pigmentation. For this reason, the lack of POMC-derived peptides 
in obese patients with POMC deficiency results in hypopigmenta­
tion of skin and hair, which is more noticeable in people of Caucasian 
ancestry who often have red hair. Prohormone convertase 1 (PCSK1) 
is an enzyme involved in the cleavage of POMC into ACTH, which is 
then further cleaved to make α-MSH by carboxypeptidase E. Impaired 
processing of POMC contributes to the hyperphagic severe early-onset 
obesity and ACTH deficiency in people lacking PCSK1 who also 
have hypogonadotropic hypogonadism, postprandial hypoglycemia 
(due to impaired processing of proinsulin to insulin), and a neonatal 
enteropathy in early childhood. Heterozygous mutations that impair 
the function of MC4R are found in 5–6% of patients with severe earlyonset obesity and at a frequency of ~1 in 300 in the general population, 
making this the most common gene in which variants contribute to 
obesity. MC4R mutations are inherited in a co-dominant manner, with 
variable penetrance and expression in heterozygous carriers; homozy­
gous carriers are severely obese. Patients are often hyperphagic from 
early childhood and hyperinsulinemic and have increased lean mass 
and increased linear growth.

Pathobiology of Obesity
CHAPTER 413
■
■GENETIC SUBTYPES OF OBESITY ASSOCIATED 
WITH NEUROBEHAVIORAL ABNORMALITIES
Both PWS patients and patients with mutations in SIM1 (a gene that 
acts downstream of MC4R) exhibit a spectrum of behavioral abnor­
malities that overlap with autism-like features that could be related to 
reduced oxytocin signaling (Table 413-2). Mutations affecting BDNF 
and its receptor tropomyosin receptor kinase B (TrkB) cause speech and 
language delay, hyperphagia, and severe obesity, as well as hyperactivity, 
autistic traits, and impaired short-term memory. Interestingly, a com­
mon variant in BDNF (V66M), found in heterozygous form in ~20% of 
the population, is associated with a number of traits and neuropsychi­
atric disorders including anxiety and depression. Chromosomal deletion 
and mutations affecting Src-homology-2 (SH2) B-adaptor protein-1 
(SH2B1) are associated with dominantly inherited, severe, early-onset 
obesity, disproportionate insulin resistance, early-onset type 2 diabetes, 
and behavioral problems including aggressive behavior.
■
■OBESITY SECONDARY TO OTHER DISORDERS
Endocrine Disorders 
Patients with hypothyroidism may gain 
weight and develop obesity, although it is rarely the sole cause of severe 
obesity. It is nonetheless prudent always to measure thyroid function in 
a patient presenting with obesity. Measurement of thyroid-stimulating 
hormone (TSH) will detect significant primary disease of the thyroid, 
but for rare secondary hypothyroidism, additional measurement of 
free thyroxine levels is needed (Chap. 395). Weight gain can also be a 
presenting feature of Cushing’s syndrome. Clinically, the presence of 
spontaneous bruising, livid striae, myopathy, and marked centripetal 
distribution of body fat helps to distinguish true endogenous hyper­
cortisolism from common obesity. This condition is usually reasonably 
straightforward to diagnose based on tests that approximate cortisol 
production rates (24-h urine free cortisol) or the suppression of serum 
cortisol by dexamethasone (Chap. 398). Occasionally, in patients with 
severe obesity, effects of adiposity on glucocorticoid metabolism can 
make it difficult to interpret results, and more sophisticated tests, 
including those measuring diurnal rhythm of cortisol, may be neces­
sary to establish or exclude the diagnosis with confidence. Weight 
gain can also be a presenting feature of patients with insulinoma, 
driven largely by the need to eat more frequently than normal to avoid 
hypoglycemia.
Hypothalamic Damage 
The hypothalamic regions that control 
energy balance can be disrupted by tumors (such as craniopharyngio­
mas), inflammatory masses, or after a severe head injury (Chap. 391). In 
such cases, there is often some accompanying evidence of disruption of 
the hormonal functions of the anterior or posterior pituitary, although 
it may be subtle and the history of hyperphagia and weight gain is often 
short. It is worth noting that in common obesity, GH levels in response

Dementia 
Stroke
Sleep apnea
Hypertension 
Hypertriglyceridemia 
Ischemic heart disease 
Heart failure
Gallstones 
Esophagitis
Cancer of esophagus,
colon, endometrium,
pancreas, kidney
Type 2
diabetes 
NAFLD
PART 12
Endocrinology and Metabolism
PCOS
Arthritis 
Gout 
FIGURE 413-4  Obesity-related complications. The expanded fat mass that 
characterizes obesity predisposes to certain obesity-related complications (e.g., 
osteoarthritis of knees, reflux esophagitis, and obstructive sleep apnea) directly 
through its mass and/or volume. However, in the case of the metabolic, endocrine, 
and cardiovascular complications, the link is less clear. Further research is needed 
to establish whether some features of the expanded fat mass influence the 
development of these complications or whether other aspects of the chronically 
overnourished state, such as excess fat outside the fat depot, are more relevant. 
NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovarian syndrome.
to provocative testing may be somewhat lower than normal, but this 
does not necessarily suggest the presence of a structural lesion.
■
■ADVERSE CONSEQUENCES OF 
OBESITY
Mechanistic Considerations 
Obesity is 
associated with a wide range of pathologies that 
can adversely impact morbidity and mortality 
(Chap. 420). Some of these consequences are 
related, at least in part, to the direct mechani­
cal or gravitational effects of the expanded fat 
mass itself (Fig. 413-4). However, the principal 
mechanisms behind many of the complica­
tions of obesity are less likely to be due to the 
expanded fat mass itself but more closely related 
to the chronic state of overnutrition itself and its 
effects on tissues throughout the body.
Adipose tissue 
Inflammation
As people develop obesity, one of the first and 
most prominent biochemical abnormalities that 
develops is the need for increased circulating 
concentrations of insulin to maintain glucose 
homeostasis. This state of insulin resistance 
generally worsens with a greater degree of obe­
sity, but there is a high degree of interindividual 
variability. It is more prominent when fat is 
distributed more centrally. Insulin resistance/
hyperinsulinemia is likely to play a major role in 
the predisposition to metabolic endocrine and 
cardiovascular diseases seen more frequently in 
obesity and may even play a role in the predispo­
sition of people with obesity to develop certain 
cancers.
FIGURE 413-5  How does obesity cause metabolic disease? Insulin resistance is one of the earliest 
complications of obesity and underlies and precedes many of its adverse health consequences. The disposal 
and production of glucose by the most important tissues, muscle and liver, respectively, become less sensitive 
to insulin, and this results in a compensatory increase in insulin secretion from the pancreas. There are two 
main theories for the association of obesity with insulin resistance. In the first, products of macrophages and 
other inflammatory cells that are more abundant in obese adipose tissue can, through paracrine or endocrine 
routes, disturb insulin’s action in muscle and liver cells. In the second, as adipose storage deposits fill up, they 
become less able to take on excessive calories, which end up being stored as ectopic lipid in tissues such as 
muscle and liver, which are not primarily designed to store nutrients of this type. The evidence in humans is 
stronger for the latter hypothesis.
The main sites of insulin action in the body 
are the liver and skeletal muscle. Thus, for 
insulin resistance to be discernible at the level 

of the whole body, the action of insulin must be disturbed in one or 
both of these tissues. It seems unlikely that an expanded fat cell mass 
would do that directly. How then does obesity lead to a state of insulin 
resistance? One hypothesis suggests a leading role for the inflammation 
that occurs in the adipose tissue in obesity (Fig. 413-5). This undoubt­
edly happens, as there are more macrophages in obese than nonobese 
adipose tissues, and this is associated with higher levels of inflamma­
tory markers in the circulation of people with obesity. The majority of 
macrophages in obese adipose tissue are found in clusters around dead 
or dying adipocytes, so it appears that these cells are clearing debris 
after cell death. Studies in animal models provide strong support for 
the notion that this inflammatory state is mechanistically linked to 
insulin resistance, but evidence from humans for this is not as strong.
An alternative hypothesis is that as individuals develop obesity they 
become less able to safely store nutrients in their adipose tissue and 
begin to redirect macronutrients to other tissues that are not designed 
for fat storage and may be damaged by the nutrient excess. This cer­
tainly happens to people who are born with a lack of adipose tissue 
(lipodystrophy) who, early in life, develop severe versions of all the 
metabolic complications that are seen in obesity as they have no safe 
depot in which to store excess nutrients. There are stronger human 
data from both genetic and pharmacologic studies for the existence 
of the latter mechanism. How ectopic fat leads to insulin resistance 
and other damaging effects is still a puzzle, but it is very likely a major 
driver of pathology associated with obesity.
Metabolic Complications 
• 
DYSLIPIDEMIA  The insulin resis­
tance of obesity is frequently associated with dyslipidemia character­
ized by high circulating triglycerides and low high-density lipoprotein 
cholesterol (Chap. 419). Occasionally, the hypertriglyceridemia may 
be severe enough to put the patient at risk of pancreatitis. Although 
there is a relationship between obesity and raised circulating levels of 
low-density lipoprotein cholesterol (which is the major risk factor for 
coronary artery disease), genetic factors independent of obesity and 
the type of dietary fat consumed probably have an even greater impact.
Chronic imbalance of energy intake > Energy expenditure
Expansion of adipose tissue depots
Limited fat cell capacity
for continuing storage
Inflammatory 
cytokines
Storage of lipid in
nonadipose tissue
Defective glucose handling 
in liver and muscle
Insulin resistance/compensatory hyperinsulinemia