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Chapter 413 | Part 12: Endocrinology and Metabolism

Pathobiology of Obesity · Part 12 – Endocrinology & Metabolism

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Obesity is defined as excess adipose tissue mass adversely affecting health; BMI is the standard proxy (weight/height^2).
  2. WHO defines obesity as BMI >30 kg/m2; overweight is BMI 25–30 kg/m2.
  3. Waist-to-hip ratio >0.9 in women or >1.0 in men indicates central adiposity associated with adverse outcomes.
  4. Leptin resistance explains why elevated leptin levels in obesity do not prevent weight gain; leptin defends against fat loss but not gain.
  5. Genetic factors play a major role in predisposition, but environmental factors (obesogenic environment) drive the recent increase in prevalence.
  6. Insulin resistance is a hallmark of obesity, driven by inflammation in adipose tissue and ectopic fat storage in non-adipose tissues.
  7. Classical genetic syndromes (e.g., Prader-Willi, Bardet-Biedl) present with obesity plus specific dysmorphic or developmental features.
  8. Monogenic obesity (e.g., MC4R mutations) is the most common genetic cause of severe early-onset obesity (~5–6% of severe cases).
  9. Treatment for congenital leptin deficiency involves recombinant leptin; MC4R agonists (setmelanotide) are used for specific genetic defects.
  10. Obesity-related complications include mechanical (osteoarthritis, sleep apnea) and metabolic (dyslipidemia, type 2 diabetes, NAFLD).

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Hypothalamic pathways regulating body weight
2 🖼 Figure of Obesity FIGURE 413-1 Definitions of overweight and obesity
3 🖼 Figure Obesity-related complications
4 🖼 Figure The homeostatic regulation of body weight
5 🖼 Figure The homeostatic regulation of body weight

1. DEFINITION & OVERVIEW

Obesity is defined as a state of excess adipose tissue mass that adversely affects health. The direct measurement of fat mass is not readily undertaken in routine clinical practice, so a proxy measure, the body mass index (BMI), is generally used. This is calculated as weight/height^2 (in kg/m^2). 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 is different in people from other ethnic groups, usually in the direction of worse health outcomes being seen at lower levels of BMI.

1.1 Definitions of Overweight and Obesity

The World Health Organization (WHO) defines a BMI of 30 kg/m^2 as the cutoff point for obesity, while individuals with values between 25 and 30 kg/m^2 are classified as overweight. For individuals with a very muscular body habitus, the BMI may overestimate the amount of body fat. 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.

1.2 Physiologic Regulation of Energy Balance

Human energy balance is highly sensitive to signaling through the hypothalamic system. The hypothalamus receives multiple hormonal signals relevant to energy balance. The circulating concentration of leptin, a peptide hormone produced by fat cells, increases as fat stores increase and declines as fat stores are depleted. Under conditions of caloric restriction, circulating leptin levels fall faster than the 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 (hyperphagia). 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. 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. 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), neuuropeptide Y (NPY), and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). AGRP actively switches off melanocortin receptors. Leptin, which suppresses food intake, simultaneously stimulates POMC neurons and inhibits NPY/AGRP neurons.

2. 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 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 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.

2.1 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 that the principal 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 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 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 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. 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”. This is an attractive idea, and if true, it would mean that time-limited and affordable interventions early in life might have lifelong benefits. Much excitement has been generated by the increasing recognition of the diversity of our intestinal microbiome, which clearly has relevance to gastrointestinal health. At present, it is premature to ascribe any significant role to the human microbiome in obesity or its adverse consequences.

3. ETIOLOGY & PATHOPHYSIOLOGY

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 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, 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 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 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. 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 decision-making regarding the use of bariatric surgery (feasible in some; high risk in others) or pharmacologic therapy.

3.1 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 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. 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 decision-making regarding the use of bariatric surgery (feasible in some; high risk in others) or pharmacologic therapy. 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 treatment of other genetic obesity syndromes affecting the melanocortin pathway and in acquired hypothalamic obesity caused by tumors such as craniopharyngiomas. 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.

Table 1 — Table 413-1 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
Bardet-Biedl Autosomal recessive Syndactyly/brachydactyly/polydactyly, developmental delay, retinal dystrophy or pigmentary retinopathy, hypogonadism, renal abnormalities
Carpenter’s Autosomal recessive Acrocephaly, brachydactyly, developmental delay, congenital heart defects; growth retardation, hypogonadism
Tubby Autosomal recessive Progressive cone-rod dystrophy, hearing loss

Table 2 — 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
Carboxypeptidase E Autosomal recessive Severe insulin resistance
Melanocortin 4 receptor Autosomal dominant Hyperphagia, accelerated linear growth, hyperinsulinemia, early type 2 diabetes mellitus, behavioral problems including aggression
Single-minded 1 Autosomal dominant Hyperphagia, accelerated linear growth, speech and language delay, autistic traits
TrkB Autosomal dominant Hyperphagia, speech and language delay, variable developmental delay, hyperactivity, behavioral problems including aggression
BDNF Autosomal dominant Hyperphagia, developmental delay, hyperactivity, behavioral problems including aggression
SH2B1 Autosomal dominant Hyperphagia, disproportionate hyperinsulinemia, early type 2 diabetes mellitus, behavioral problems including aggression

3.2 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 progressively obese as someone with congenital leptin deficiency. 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.

3.3 Obesity Secondary to Other 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. 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 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. 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 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. In these 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.

4. CLINICAL FEATURES

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/height^2 (in kg/m^2). 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 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/m^2 as the cutoff point for obesity, while individuals with values between 25 and 30 kg/m^2 are classified as overweight. For individuals with a very muscular body habitus, the BMI may overestimate the amount of body fat. 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.

4.1 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. 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) pseudohypoparathyroidism. Maternal transmission 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 phenotype. The clinical spectrum is very broad, and some patients may present with obesity alone. Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disease characterized by obesity, developmental delay, polydactyly, retinal dystrophy or pigmentary retinopathy, hypogonadism, and renal abnormalities. Overlapping clinical features are seen in a number of other genetic obesity syndromes. 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. 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. 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.

4.2 Adverse Consequences of Obesity

Obesity is associated with a wide range of pathologies that can adversely impact morbidity and mortality. Some of these consequences are related, at least in part, to the direct mechanical or gravitational effects of the expanded fat mass itself. 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 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 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 people with obesity to develop certain other cancers. The main sites of insulin action in the body are the liver and skeletal muscle. Thus, for muscle and liver, 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. This undoubtedly happens, as there are more macrophages in obese than nonobese adipose tissues, and this is associated with higher levels of inflammatory 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 certainly 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.

5. DIFFERENTIAL DIAGNOSIS

The differential diagnosis of obesity primarily distinguishes between primary (common) obesity and secondary obesity due to specific endocrine or genetic disorders. Primary obesity is characterized by excess adipose tissue mass without specific syndromic features. Secondary obesity may be caused by hypothyroidism, Cushing’s syndrome, insulinoma, or hypothalamic damage. Genetic obesity syndromes are distinguished by the presence of dysmorphism and/or developmental delay (e.g., Prader-Willi, Bardet-Biedl) or by specific gene mutations (e.g., MC4R, Leptin). The presence of specific features such as hypotonia, failure to thrive in infancy, or specific dysmorphic features should prompt evaluation for syndromic causes. Measurement of thyroid function (TSH, free thyroxine) is prudent in all patients presenting with obesity to exclude hypothyroidism. Measurement of cortisol production rates or suppression tests is indicated if clinical features of Cushing’s syndrome are present (spontaneous bruising, livid striae, myopathy, marked centripetal distribution of body fat). Genetic testing is indicated for severe early-onset obesity, especially if there is a family history or specific syndromic features.

5.1 Primary vs Secondary Obesity

Primary obesity is the most common form, driven by energy imbalance and genetic predisposition. Secondary obesity is less common and requires specific investigation. Hypothyroidism is a common cause of weight gain but rarely the sole cause of severe obesity. Cushing’s syndrome presents with specific clinical features (bruising, striae, myopathy). Insulinoma presents with weight gain driven by the need to eat frequently to avoid hypoglycemia. Hypothalamic damage presents with short history of hyperphagia and weight gain, often with pituitary dysfunction.

6. INVESTIGATIONS & DIAGNOSIS

The diagnosis of obesity is primarily based on BMI calculation and waist-to-hip ratio measurement. BMI is calculated as weight/height^2 (in kg/m^2). Waist-to-hip ratio >0.9 in women and >1.0 in men indicates central adiposity. Genetic testing is indicated for severe early-onset obesity, especially if there is a family history or specific syndromic features. Thyroid function tests (TSH, free thyroxine) are indicated to exclude hypothyroidism. Cortisol production rates or suppression tests are indicated if clinical features of Cushing’s syndrome are present. Genetic testing for specific obesity syndromes (e.g., MC4R, Leptin, POMC) is available and can inform management.

6.1 Diagnostic Criteria and Workup

BMI cutoffs: Overweight (25–30 kg/m^2), Obesity (>30 kg/m^2). Waist-to-hip ratio: >0.9 in women, >1.0 in men. Genetic testing: Indicated for severe early-onset obesity, syndromic features, or family history. Thyroid function: TSH and free thyroxine. Cortisol: 24-h urine free cortisol or suppression tests. Imaging: MRI/CT for hypothalamic lesions if indicated.

7. MANAGEMENT & TREATMENT

Management of obesity includes lifestyle modifications, pharmacologic therapy, and surgical intervention. Lifestyle modifications include diet and exercise. Pharmacologic therapy includes leptin for congenital leptin deficiency and MC4R agonists (setmelanotide) for specific genetic defects. Bariatric surgery is feasible in some genetic cases but high risk in others. Treatment for Prader-Willi syndrome includes GH treatment. Treatment for Bardet-Biedl syndrome includes melanocortin receptor agonists. Treatment for common obesity includes weight loss diets and behavioral therapy.

7.1 Pharmacologic Therapy

Leptin: Subcutaneous injections for congenital leptin deficiency. MC4R agonists (setmelanotide): Licensed for chronic weight management in leptin receptor deficiency and other genetic obesity syndromes. Metformin: Not explicitly detailed in this chapter but standard for metabolic syndrome. GLP-1 agonists: Not explicitly detailed in this chapter but standard for metabolic syndrome.

7.2 Surgical Intervention

Bariatric surgery: Feasible in some genetic cases, high risk in others. Indications include severe obesity with comorbidities. Contraindications include severe psychiatric comorbidities.

8. PROGNOSIS & COMPLICATIONS

Obesity is associated with a wide range of pathologies that can adversely impact morbidity and mortality. Some of these consequences are related, at least in part, to the direct mechanical or gravitational effects of the expanded fat mass itself. 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 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 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 people with obesity to develop certain other cancers. The main sites of insulin action in the body are the liver and skeletal muscle. Thus, for muscle and liver, 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. This undoubtedly happens, as there are more macrophages in obese than nonobese adipose tissues, and this is associated with higher levels of inflammatory 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 certainly 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.

8.1 Metabolic Complications

Dyslipidemia: High circulating triglycerides and low high-density lipoprotein cholesterol. Hypertriglyceridemia may be severe enough to put the patient at risk of pancreatitis. Insulin resistance: Generally worsens with a greater degree of obesity. Cardiovascular diseases: Predisposition to coronary artery disease. Cancers: Predisposition to certain cancers.

8.2 Mechanical Complications

Osteoarthritis: Of knees and other weight-bearing joints. Reflux esophagitis: Due to increased intra-abdominal pressure. Obstructive sleep apnea: Due to upper airway obstruction.

9. SPECIAL CONSIDERATIONS

Ethnic variations: 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 highest prevalence at 56.9%. Pregnancy: Leptin is a permissive factor for the development of puberty. Pediatric obesity: 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.

9.1 Ethnic Variations

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 highest prevalence at 56.9%.

9.2 Pediatric Obesity

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.

10. KEY PEARLS & CLINICAL TRAPS

Leptin resistance: 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. Ectopic fat: 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. Genetic testing: A genetic diagnosis can inform management (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).

10.1 Clinical Pearls

Leptin resistance explains why elevated leptin levels in obesity do not prevent weight gain. Insulin resistance is a hallmark of obesity. Genetic factors play a major role in predisposition, but environmental factors drive the recent increase in prevalence. Obesity cannot exist in the absence of sufficient food to lay down and maintain excess fat stores.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Hypothalamic pathways regulating body weight

Caption: FIGURE 413-3 Hypothalamic pathways regulating body weight. Neurons in the and expenditure in response to leptin and other hormones. In the fed state, leptin arcuate nucleus of the hypothalamus that express pro-opiomelanocortin (POMC). The β-melanocyte-stimulating hormone (MSH) act on the melanocortin 4 receptor (MC4R) paraventricular nucleus to reduce energy intake and increase energy expenditure. At neurons expressing agouti-related peptide (AGRP), which switches off melanocortin other key molecules, such as brain-derived neurotrophic factor (BDNF) and single inherited mutations, affected individuals have hyperphagia and severe obesity. — Figure 413-1: Definitions of overweight and obesity based on Body Mass Index (BMI) cutoffs. Underweight (30.0).

Figure 2

of Obesity FIGURE 413-1 Definitions of overweight and obesity

Caption: of Obesity 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, — Figure 413-2: The homeostatic regulation of body weight. Diagram showing signals from adipose tissue (leptin), gut hormones (CCK, GLP-1, PYY, OXM), pancreas (insulin, amylin), and stomach (ghrelin) acting on the hypothalamus and brainstem to control energy balance.

Figure 3

Obesity-related complications

Caption: FIGURE 413-4 Obesity-related complications. The expanded fat mass that characterizes obesity predisposes to certain obesity-related complications (e.g., Metabolic Complications • DYSLIPIDEMIA osteoarthritis of knees, reflux esophagitis, and obstructive sleep apnea) directly tance of obesity is frequently associated with through its mass and/or volume. However, in the case of the metabolic, endocrine, ized by high circulating triglycerides and low and cardiovascular complications, the link is less clear. Further research is needed cholesterol (Chap. 419). Occasionally, the to establish whether some features of the expanded fat mass influence the be severe enough to put the patient at risk of development of these complications or whether other aspects of the chronically overnourished state, such as excess fat outside the fat depot, are more relevant. there is a relationship between obesity and raised NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovarian syndrome. low-density lipoprotein cholesterol (which is the coronary artery disease), genetic factors — Figure 413-3: Hypothalamic pathways regulating body weight. Illustration of arcuate nucleus neurons expressing pro-opiomelanocortin (POMC) and agouti-related peptide (AGRP), their regulation by leptin, and downstream effects on energy intake and expenditure.

Figure 4

The homeostatic regulation of body weight

Caption: FIGURE 413-2 The homeostatic regulation of body weight. In most people, body weight periods of time despite fluctuations in the amount of food we eat and the amount of homeostatic regulation of body weight is controlled by the neurons in the hypothalamus, signals from adipose tissue such as leptin and neural and hormonal signals from the Glucagon-like peptide 1 (GLP1) and cholecystokinin (CCK) from enteroendocrine cells peptide YY (PYY) and oxyntomodulin (OXM) from the large intestine are secreted in and/or the presence of nutrients in the intestinal lumen. Their release, together with vagus nerve and the enteric nervous system, contributes to satiety, acting on the from the brainstem. Insulin, produced by the pancreas in response to carbohydrate- potentiated by the action of some of the gut hormones, also has effects on the energy balance, whereas amylin acts predominantly via the brainstem. The release of — Figure 413-4: Obesity-related complications. Visual representation of mechanical effects (osteoarthritis of knees, reflux esophagitis, obstructive sleep apnea) and metabolic/endocrine complications (dyslipidemia, hypertension, type 2 diabetes, NAFLD, PCOS, cancer).

Figure 5

The homeostatic regulation of body weight

Caption: FIGURE 413-2 The homeostatic regulation of body weight. In most people, body weight periods of time despite fluctuations in the amount of food we eat and the amount of homeostatic regulation of body weight is controlled by the neurons in the hypothalamus, signals from adipose tissue such as leptin and neural and hormonal signals from the Glucagon-like peptide 1 (GLP1) and cholecystokinin (CCK) from enteroendocrine cells peptide YY (PYY) and oxyntomodulin (OXM) from the large intestine are secreted in and/or the presence of nutrients in the intestinal lumen. Their release, together with vagus nerve and the enteric nervous system, contributes to satiety, acting on the from the brainstem. Insulin, produced by the pancreas in response to carbohydrate- potentiated by the action of some of the gut hormones, also has effects on the energy balance, whereas amylin acts predominantly via the brainstem. The release of — Figure 413-5: Mechanisms of how obesity causes metabolic disease. Diagram illustrating insulin resistance via inflammation (macrophages in adipose tissue) and ectopic lipid storage in liver and muscle, leading to compensatory hyperinsulinemia and metabolic complications.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.