3079 Lesbian, Gay, Bisexual, and Transgender (LGBT) Health CHAPTER 400

are at greater risk of suicide and homelessness, whereas elderly LGBT

individuals face barriers to health because of isolation and fewer family

supports), necessitating a longitudinal approach to examining LGBT

health issues. There are more limited data on the health of LGBT

individuals outside the United States and Europe. However, studies

demonstrate that problems are greatest when people cannot be open

about their sexual orientation and gender identity. Encouraging greater

LGBT acceptance and access to health care will be critical to improving

outcomes and experiences for LGBT communities.

■ CREATING POSITIVE HEALTH EXPERIENCES

FOR LGBT PATIENTS

Understanding Gender Identity and Sexual Orientation

Addressing health disparities and creating positive health care experiences require an understanding of the diversity of cultural expression

and lives of LGBT persons. First, providers must be able to distinguish

gender identity from sexual orientation. Gender identity is a person’s

internal sense of their gender. It should not be confused with sex

assigned at birth, which is based on anatomy and biology. Gender

TABLE 400-1 Common LGBT Terminology and Definitions

TERM DEFINITION

Agender Identifying as having no gender.

Asexual Experiencing little or no sexual attraction to others.

Assigned sex at birth The sex (male or female) assigned to a child at birth, most often based on the child’s external anatomy. Also referred to as birth sex,

natal sex, biological sex, or sex.

Bisexual A sexual orientation that describes a person who is emotionally and sexually attracted to people of their own gender and people of

other genders.

Cisgender A person whose gender identity and assigned sex at birth correspond (i.e., a person who is not transgender).

Gay A sexual orientation that describes a person who is emotionally and sexually attracted to people of their own gender. It can be used

regardless of gender identity, but it is more commonly used to describe men.

Gender dysphoria Distress experienced by some individuals whose gender identity does not correspond with their assigned sex at birth. Manifests as

clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Gender expression The way a person acts, dresses, speaks, and behaves (i.e., feminine, masculine, androgynous). Gender expression does not

necessarily correspond to assigned sex at birth or gender identity.

Gender identity A person’s internal sense of being a man/male, woman/female, both, neither, or another gender.

Gender nonconforming Expressing a gender that differs from a given society’s norms for males and females.

Heterosexual A sexual orientation that describes women who are emotionally and sexually attracted to men, and men who are emotionally and

sexually attracted to women.

Intersex (disorders of sexual

development)

A group of rare conditions where the reproductive organs and genitals do not develop as expected.

Lesbian A sexual orientation that describes a woman who is emotionally and sexually attracted to other women.

Men who have sex with men

(MSM)/women who have sex

with women (WSW)

Categories used in research and public health to describe those who engage in same-sex sexual behavior, regardless of their

sexual orientation. Individuals rarely use the terms MSM or WSW to describe themselves.

Pangender Describes a person whose gender identity comprises many genders.

Pansexual A sexual orientation that describes a person who is emotionally and sexually attracted to people regardless of gender.

Queer An umbrella term used by some to describe people who think of their sexual orientation or gender identity as outside of societal

norms. Some people view the term as more fluid and inclusive than traditional categories for sexual orientation and gender identity.

Due to its history as a derogatory term, it is not embraced or used by all members of the LGBT community.

Questioning Describes an individual who is unsure about or is exploring their own sexual orientation and/or gender identity.

Same-sex attraction Describes the experience of a person who is emotionally and/or sexually attracted to people of the same gender. Use of this term is

not indicative of a person’s sexual behavior.

Sexual orientation Describes how a person characterizes their physical and emotional attraction to others. Sexual orientation is distinct from sex,

gender identity, and gender expression.

Trans man/transgender man/

female-to-male (FTM)

A transgender person whose gender identity is male may use these terms to describe themselves. Some will just use the term man.

Trans woman/transgender

woman/male-to-female (MTF)

A transgender person whose gender identity is female may use these terms to describe themselves. Some will just use the term

woman.

Transgender Describes a person whose gender identity and assigned sex at birth do not correspond. Also used as an umbrella term to include

gender identities outside of male and female.

Transition/affirmation For transgender persons, the process of coming to recognize, accept, and express one’s gender identity. Most often, this refers to

the period when a person makes social, legal, and/or medical changes, such as changing their clothing, name, and sex designation,

as well as using medical interventions.

Note: It is important to note that definitions vary across communities, that they change over time, and that not all LGBT people agree with all these definitions.

identity expands beyond the binary male and female and includes

persons who think of their gender as containing elements of both or

neither. Many individuals who do not identify with the gender that correlates with their sex assigned at birth often use the terms transgender

or trans-male or trans-female to identify themselves. Sexual orientation

refers to how one thinks of their physical or emotional attraction to

others. Sexual orientation has three dimensions: attraction, behavior,

and identity. Attraction refers to one’s desire to be with someone,

regardless of one’s behavior or stated identity. For example, a woman

may be attracted to another woman, but this attraction may never be

acted upon and may not form part of her sexual identity. Behavior

refers to a person’s sexual and romantic partners. Although sexual

identity often aligns with behavior, some individuals who identify as

heterosexual may have same-gender partners and some individuals

who identify as lesbian or gay may have different-gender partners.

Lastly, identity refers to how a person defines their own sexuality. Common terms for sexual identity include gay, lesbian, bisexual, straight,

heterosexual, homosexual, and asexual (Table 400-1). As individuals go

through the process of understanding their sexuality and self-identity

over time, they may change how they define their sexual identity.

3080 PART 12 Endocrinology and Metabolism

The creation of a welcoming environment requires not making any

assumptions about an individual’s gender identity or sexual orientation. Both front-line staff and clinicians should be cognizant of patient

communication. For example:

• Instead of saying “How may I help you, sir?”, say “How may I help

you?”

• Instead of saying “She is here for her appointment,” say “The patient

is here in the waiting room.”

• Instead of saying “Do you have a wife?”, say “Are you in a relationship?

• Instead of saying “What are your mother’s and father’s names?”, say

“What are your parents’ names?”

Developing Comfort and Competency in Sexual Health

Developing comfort discussing sexual health and intimacy is critical to

providing appropriate care. After inquiring about healthy relationships

and relationship status, a good starting place is to ask if a patient is

sexually active and, if so, with whom, how often, and what types of

physical interactions and types of sex they have with their partner(s).

These discussions can allow clinicians to focus subsequent conversations on issues most relevant to a patient’s health. For example, a

gay man with multiple sexual partners who engages in receptive anal

sex without condoms is at high risk for HIV and sexually transmitted

infections (STIs). It will be important to recommend more frequent

screenings for STIs and discuss use of preexposure prophylaxis (PrEP)

and condoms to prevent HIV and STIs. Additionally, if you are seeing

a transgender man, it will be important to know if he still has natal

female genitalia to ensure appropriate cancer screening, desire for

having biologic children, and contraceptive needs. Notably, many if not

most transgender people have not had gender affirmation surgery and

retain their natal sex organs.

Creating a Welcoming and Safe Health Care Environment

Hospitals and clinics can take a number of steps to create a welcoming and safe space for LGBT patients. This starts by establishing and

communicating a nondiscrimination policy that clearly includes

gender identity, gender expression, and sexual orientation protections.

Additionally, hospitals and clinics can develop and implement an

equal visitation policy to ensure equal visitation for LGBT patients

from same-sex partners, parents, and other family and friends.

Staff training in LGBT patient-centered care also is a key component of

creating inclusive health environments. This includes covering LGBT

cultural competency, caring for LGBT patients, creating an inclusive

environment for LGBT patients and staff, and other topics important

for LGBT health.

As hospitals and clinics continue to adopt electronic health records,

collecting sexual orientation and gender identity information becomes

increasingly important to delivering personalized care to LGBT individuals. It allows providers to monitor quality of care and track population-based outcomes. This information can be captured by three

questions:

• How do you think of yourself? As straight or heterosexual; lesbian,

gay, or homosexual; bisexual; something else; don’t know; choose

not to disclose.

• What is your current gender identity? Male; female; transgender

male/trans man/female-to-male (FTM); transgender female/trans

woman/male-to-female (MTF); genderqueer, neither exclusively

male nor female; additional category, please specify; choose not to

disclose.

• What sex were you assigned at birth on your original birth certificate?

Male; female; choose not to disclose.

The physical environment of a hospital or clinic is important, but

the majority of clinical spaces do not signal that they are safe spaces

for LGBT patients. Most health care posters, pamphlets, and materials

feature heterosexual individuals or couples; adding LGBT-friendly

images and text can help signal that the hospital or clinic is a safe

space for sexual and gender minorities. In addition, easily identifying LGBT-competent providers by using websites, buttons, and pins

can help patients select providers and feel at ease when attending

appointments. Lastly, designating all-gender bathrooms is important

to creating welcoming spaces, particularly for transgender and gender-nonconforming individuals.

■ FUTURE DIRECTION IN LGBT HEALTH

While social and cultural acceptance of the LGBT community has

improved in certain parts of the world, many LGBT individuals continue to experience discrimination, stigmatization, and violence. Inequitable health care policies and practices, lack of awareness of LGBT

health issues, and limited understanding of the unique health needs of

LGBT individuals contribute to decreased access to care and disparities

in health outcomes for LGBT individuals. Addressing these barriers

will require improved data collection on the LGBT population; understanding of the intersectionality of gender identity, sexual orientation,

race/ethnicity, and other sociocultural determinants of health; and

outcomes-focused research across the life course. In striving to deliver

high-quality care experiences for all patients, hospitals, clinics, and

providers need to focus on meeting the needs of the LGBT community.

■ FURTHER READING

Centers for Disease Control and Prevention: Lesbian, Gay,

Bisexual, and Transgender Health. 2018. Available at www.cdc.gov/

lgbthealth/. Accessed December 10, 2019.

Fenway Health: Glossary of LGBT Terms for Health Care Teams.

March 2018. Available at www.lgbthealtheducation.org/wp-content/

uploads/LGBT-Glossary_March2016.pdf. Accessed December 10,

2019.

Institute of Medicine: The Health of Lesbian, Gay, Bisexual, and

Transgender (LGBT) People: Building a Foundation for Better

Understanding. 2011. Available at www.nap.edu/catalog.php?record_

id=13128. Accessed December 10, 2019.

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-sexual-orientation-and-gender-identity-data-in-electronic-health-records.

Accessed December 10, 2019.

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. Accessed December 10, 2019.

National Center for Transgender Equality: The Report of the

2015 U.S. Transgender Survey. 2015. Available at http://www.ustranssurvey.org/reports#USTS. Accessed December 10, 2019.

Safer JD, Tangpricha V: Care of transgender persons. N Engl J Med

381:2451, 2019.

Substance Abuse and Mental Health Services Administration:

Top Health Issues for LGBT Populations Information & Resource

Kit. 2012. Available at https://store.samhsa.gov/product/top-healthissues-lgbt-populations/sma12-4684. Accessed December 10, 2019.

Section 3 Obesity, Diabetes Mellitus,

and Metabolic Syndrome

401 Pathobiology of Obesity

Stephen O’Rahilly, I. Sadaf Farooqi

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.

3081Pathobiology of Obesity CHAPTER 401

highest prevalence 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 overweight 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 reasonable

proxy for fat mass. Using age- and sex-specific BMI cutoffs (overweight

≥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 information is integrated to control hunger, satiety, and the expenditure of

energy. The key locus for the integration of these signals is the hypothalamus, an area of the brain at least partially outside the blood-brain

barrier that facilitates its ability to receive hormonal signals and combine these with sensory, cognitive, and other neural inputs.

The hypothalamus receives two broad types of hormonal signals

relevant to energy balance (Fig. 401-2). 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 disappearance of fat. Humans born without functional

leptin or leptin receptors, although normal weight at birth, become

severely obese from an early age, largely as a result of an intense insatiable appetite. 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 dieting. The hypothalamus also receives hormonal signals that are

more 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, produced by the pancreas in response to carbohydrate and protein-rich meals, also has effects on the hypothalamic

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. 401-3). These neurons are responsive 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.

Underweight

<18.5

Normal weight

18.5–24.9

Body Mass Index

(weight in kg/height in meters squared)

Overweight

25–29.9

Obese

>30.0

FIGURE 401-1 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.

However, in environments where food is abundant and when individuals tend to be sedentary, the chronic excess of energy intake over

expenditure leads to obesity. The risks of becoming obese 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 measure, the body mass index (BMI), is generally used. This is calculated as

weight/height2

 (in kg/m2

) (Fig. 401-1). 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 populations,

and there is growing evidence that the relationship between BMI and

adverse outcomes may be 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

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 how obese a person is, 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

were obese 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

represent 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

3082 PART 12 Endocrinology and Metabolism

Hypothalamus

Adipose

tissue

Leptin

Insulin

Amylin

PYY

OXM

Ghrelin

Pancreas

Brainstem

Vagus nerve

GLP1

CCK

FIGURE 401-2 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. 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.

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), neuropeptide Y (NPY), and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). AGRP actively switches off melanocortin receptors.

Leptin, which suppress 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.

■ THE PHYSIOLOGY OF NUTRIENT STORAGE IN

ADIPOSE TISSUE

When energy intake exceeds energy expenditure, 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 triacylglycerol (triglyceride).

This fat is more efficient because, unlike glycogen, it does not need

accompanying water, and when metabolized, it generates almost three

times more energy per gram than does carbohydrate. Adipocytes (fat

cells) have evolved to contain a highly specialized organelle, the unilocular fat droplet, which holds the triglyceride within a single-layer of

phospholipid that contains all the components needed for enzymes

that make and breakdown triglycerides 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. Some

new fat cells can be made in adulthood when

~10% of our fat cell population turns over

every year.

■ THE CAUSES OF OBESITY: AN

INTERACTION OF GENES AND

ENVIRONMENT

For a person to become obese, 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 tissue. 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,

obese people 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

tellingly 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 is obese the amount of

energy they expend in the resting state is more, not less, than a nonobese person. However, if an obese person loses weight by dieting,

there is some evidence that they tend to be more “energy efficient”

than a person who has never been obese, particularly in terms of how

many calories they burn during a defined bout of muscular activity.

However, the effects are subtle. It seems very likely that there are some

individuals who are predominantly predisposed 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.

■ 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 infrequently leads to the belief

3083Pathobiology of Obesity CHAPTER 401

Leptin Adipose

tissue

Ventromedial

nucleus

BDNF

POMC AGRP

α/β-MSH AGRP

MC4R

SIM1

Paraventricular

nucleus

Reduced food

intake

Increased energy

expenditure

Arcuate

nucleus

LEPR LEPR

Hypothalamus

Hypothalamus

FIGURE 401-3 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.

that the principal cause of obesity must be either the obese 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 obese people. 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 increasingly 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 physical 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 populace

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 factors 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. 402). 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. 483). 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 gastrointestinal health (Chap. 471). At present, it is

premature to ascribe any significant role

to the human microbiome in obesity or its

adverse consequences.

■ 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 becoming obese? 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 progressively 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 neurologic

conditions and identifying genetic conditions so that appropriate

3084 PART 12 Endocrinology and Metabolism

genetic counseling and, in some cases, treatment can be started. Clinically, it remains useful to categorize the genetic obesity syndromes

as those with dysmorphism and/or developmental delay and those

without these features (Tables 401-1 and 401-2). Although individually these monogenic disorders are rare, cumulatively, up to 20% of

children 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 management (many such patients find it very difficult to lose

weight through diet and exercise) and can inform clinical decisionmaking regarding the use of bariatric surgery (feasible in some; high

risk in others) (Chap. 402). 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 or the leptin receptor. It is also being explored for the treatment

of other genetic obesity syndromes affecting the melanocortin pathway.

■ 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 neurodevelopmental 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. 466).

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, features 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 suggested 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)

(Chap. 412). Maternal transmission of GNAS1 mutations leads to

AHO (characterized by short stature, obesity, and skeletal defects) plus

resistance to several hormones (e.g., parathyroid hormone), whereas

paternal transmission leads only to the AHO phenotype. The clinical

spectrum is very broad, and some patients may present with obesity

alone.

Bardet-Biedl syndrome is a rare autosomal recessive disease characterized by obesity, developmental delay, polydactyly, retinal dystrophy

or pigmentary retinopathy, hypogonadism, and renal abnormalities.

The same clinical features can arise from mutations in >20 genes,

which disrupt signaling in primary cilia. Overlapping clinical features

are seen in a number of other genetic obesity syndromes (Table 401-1).

■ 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 homozygous 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 401-2). Normal pubertal development rarely occurs in adults

with leptin or leptin receptor deficiency, with biochemical evidence

of hypogonadotropic hypogonadism. However, there is some evidence

TABLE 401-1 Classical Genetic Obesity Syndromes

SYNDROME INHERITANCE ADDITIONAL CLINICAL FEATURES

Prader-Willi Autosomal

dominant

Hypotonia, failure to thrive in infancy,

developmental delay, short stature,

hypogonadotropic hypogonadism,

sleep disturbance, obsessive behavior

Albright’s hereditary

osteodystrophy

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

TABLE 401-2 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

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.

3085Pathobiology of Obesity CHAPTER 401

for the delayed but spontaneous onset of menses in a small number of

leptin- and leptin receptor–deficient adults. Leptin treatment permits

progression of pubertal development, suggesting that leptin is a permissive factor for the development of puberty.

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 hypopigmentation

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 early-onset

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; homozygous carriers are severely obese. Patients are often hyperphagic from

early childhood and hyperinsulinemic and have increased lean mass

and increased linear growth.

■ 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 abnormalities that overlap with autism-like features that could be related to

reduced oxytocin signaling (Table 401-2). 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 common variant in BDNF (V66M), found in heterozygous form in

~20% of the population, is associated with a number of traits and neuropsychiatric 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 become obese, 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. 383). 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 help to distinguish true endogenous hypercortisolism 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. 386). Occasionally, in severely obese

patients, 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 necessary 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 craniopharyngiomas), inflammatory masses, or after a severe head injury

(Chap. 379). 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 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. 408). Some of these consequences are related, at least in part, to

the direct mechanical or gravitational effects of the expanded fat mass

itself (Fig. 401-4). However, the principal mechanisms behind many of

the complications 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.

As people become obese, 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 obesity, 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 predisposition of obese people to develop certain cancers.

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?

Dementia

Stroke

Sleep apnea

Gallstones

Esophagitis

Type 2

diabetes

NAFLD

PCOS

Hypertension

Hypertriglyceridemia

Ischemic heart disease

Heart failure

Cancer of esophagus,

colon, endometrium,

pancreas, kidney

Arthritis

Gout

FIGURE 401-4 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.