Obesity

Introduction

Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, is increased to a point where it is associated with certain health conditions or increased mortality. Although obesity is an individual clinical condition, it is increasingly viewed as a serious and growing public health problem: excessive body weight has been shown to predispose to various diseases, particularly cardiovascular diseases, diabetes mellitus type 2, sleep apnea and osteoarthritis. Obesity is characterized as a state of excess adipose mass with abnormal increase of fat on the subcutaneous connective tissue. Obesity is generally gauged by the Body Mass Index(BMI). A high BMI is associated with a higher risk for potentially lethal medical problems.

Associated Anatomy

Obesity is a disease and its pathology lies in the increased size and number of fat cells. An anatomic classification of obesity from which a pathologic classification arises is based on the number of adipocytes, on the regional distribution of body fat, or on the characteristics of localized fat deposits.

Obesity can contribute to a multitude of health effects and body anatomical changes, including:

• Respiratory system and sleep (sleep apnea; asthma; breathlessness)
• Digestive system (GERD; gallbladder disease & gallstones; eating disorders)
• Reproductive system (menstrual problems; pregnancy complications; infertility; impotence; birth defects; PCOS-polycystic ovary syndrome)
• Endocrine system (pancreatitis; fatty pancreas)
• Cardiovascular system (heart attack; elevated cholesterol/atherosclerosis; abnormal heart rhythms; hypertension; peripheral vascular disease; stroke)
• Mental health (depression)
• Liver (nonalcoholic fatty liver disease-NALD; nonalcoholic steatohepatitis-NASH)
• Kidneys (kidney stones; chronic kidney disease-CKD)
• Musculoskeletal system (osteoarthritis in the back, hips, knees; gout)
• Immune system (inflammation; lowered immunity)

Causes

Obesity results from a combination of factors, including the reduced opportunity for physical activity, the increased availability of high-calorie foods, and the presence of genes that make obesity more likely. But ultimately, obesity results from consuming more calories than the body needs over a long period of time.

Excess calories are stored in the body as fat (adipose tissue). The number of calories needed varies from person to person, depending on age, sex, activity level, and metabolic rate. A person’s resting (basal) metabolic rate—the amount of calories the body burns while at rest is determined by the amount of muscle (lean) tissue a person has and the person’s total body weight. The more muscle people have, the higher their metabolic rate.

Changes in the bacteria that are normally present in the digestive system (called gut flora) may increase the risk of obesity. Normally, these bacteria help the body by helping it digest food among other things. Changes in the number and types of bacteria in the digestive system may change how the body processes food.

Obesogens are chemical compounds that disrupt normal development and metabolism (eg cigarette smoke, bisphenol A, air pollution, flame retardants, phthalates, polychlorinated biphenyls). Being exposed to obesogens early in life can increase the risk of developing obesity.

Physical inactivity

In developed countries, lack of physical activity is common and contributes to the increase in obesity. Opportunities for physical activity have been engineered away by technological advances, such as elevators, cars, and remote controls. More time is spent doing sedentary activities, such as using the computer, watching television, and playing video games. Also, people’s jobs have become more sedentary as office or desk jobs have replaced manual labor. Sedentary people use fewer calories than more active people and thus require fewer calories in the diet. If caloric intake is not reduced accordingly, people gain weight.

Diet

The diet in developed countries is energy dense. That is, it consists of foods that have a large number of calories in a relatively small amount (volume). Most of these foods contain more processed carbohydrates, more fat, and less fiber. Fats, by nature, are energy dense. Fat has 9 calories per gram, but carbohydrates and proteins have 4 calories per gram.

Convenience foods, such as energy-dense snacks offered at vending machines and fast food restaurants, contribute to the increase in obesity. High-calorie beverages, including soda, juices, many coffee drinks, and alcohol, also contribute significantly. For example, a 12-ounce soda or bottle of beer has 150 calories, and a 12-ounce coffee beverage (containing dairy and sugar) or fruit smoothie can have 500 or more calories. High-fructose corn syrup (used to sweeten many bottled beverages) is often singled out as being particularly likely to cause obesity. However, recent studies show that it is no more likely to cause obesity than other foods with a similar number of calories in sugar.

Larger portion sizes at restaurants and in packaged foods and beverages encourage people to overeat. Also, restaurant and packaged foods are often prepared in ways that add calories. As a result, people may consume more calories than they realize.

Genes

Obesity tends to run in families. However, families share not only genes but also environment, and separating the two influences is difficult. Genes can affect how quickly the body burns calories at rest and during exercise. They can also affect appetite and thus how much food is consumed. Genes may have a greater effect on where body fat accumulates, particularly fat around the waist and in the abdomen, than on how much body fat accumulates.

Many genes influence weight, but each gene has only a very small effect. Obesity rarely results when only one gene is abnormal.

Rarely, mutations in the following genes result in obesity:

The gene for the melanocortin 4 receptor: Receptors are structures on the surface of cells that inhibit or produce an action in the cell when certain substances (such as chemical messengers) bind with them. Melanocortin 4 receptors are located mainly in the brain. They help the body regulate its use of energy. A mutation in this gene may account for obesity in 1 to 4% of children.

The ob gene: This gene controls the production of leptin, a hormone made by fat cells. Leptin travels to the brain and interacts with receptors in the hypothalamus (the part of the brain that helps regulate appetite). The message carried by leptin is to decrease food intake and increase the amount of calories (energy) burned. A mutation in the ob gene prevents leptin production and results in severe obesity in a very small number of children. In these cases, administration of leptin reduces weight to a normal amount.

Background 

Certain characteristics can increase the risk of becoming overweight or obese. They include the following:

• Certain racial and ethnic backgrounds, such as black, Hispanic, and Pacific Islander
• A lower education level
• Obesity during childhood, which tends to persist into adulthood

Pregnancy and menopause

Gaining weight during pregnancy is normal and necessary. However, pregnancy can be the beginning of weight problems if women do not return to their prepregnancy weight. About 15% of women permanently gain 20 pounds or more with each pregnancy. Having several children close together may compound the problem. Breastfeeding can help women return to their prepregnancy weight.

If a pregnant woman is obese or smokes, weight regulation in the child may be disturbed, contributing to weight gain during childhood and later.

After menopause, many women gain weight. This weight gain may result from reduced activity. Hormonal changes may cause fat to be redistributed and accumulate around the waist. Fat in this location increases the risk of health problems (such as metabolic syndrome).

Aging

Obesity becomes more common as people age. As people age, body composition may change as muscle tissue decreases. The result is a higher percentage of body fat and a lower basal metabolic rate (because muscle burns more calories).

Lifestyle

Sleep deprivation or lack of sleep (usually considered less than 6 to 8 hours per night) can result in weight gain. Sleeplessness results in hormonal changes that increase appetite and cravings for energy-dense foods.

Stopping smoking usually results in weight gain. Nicotine decreases appetite and increases the metabolic rate. When nicotine is stopped, people may eat more food, and their metabolic rate decreases, so that fewer calories are burned. As a result, body weight may increase by 5 to 10%.

Hormones

Hormonal disorders rarely cause obesity. The following are among the most common:

Cushing syndrome is caused by excessive levels of cortisol in the body. The syndrome can result from a benign tumor in the pituitary gland (pituitary adenoma) or from a tumor in the adrenal gland or elsewhere, such as in the lungs. Cushing syndrome typically causes fat to accumulate in the face, making it look full (called moon face), and behind the neck (called a buffalo hump).

Polycystic ovary syndrome affects about 5 to 10% of women. Affected women tend to be overweight or obese. Levels of testosterone and other male hormones are increased, causing fat to accumulate in the waist and abdomen, which is more harmful than the fat that is distributed throughout the body.

Eating disorders

Binge eating disorder is characterized by bingeing—eating large amounts of food during a short amount of time and usually by feeling guilty, remorseful, or out of control. Most affected people do not purge (for example, by vomiting or using laxatives or diuretics). Binge eating disorder is diagnosed when bingeing episodes occur at least twice a week for 6 or more months.

Night-eating syndrome involves not eating much during the day, consuming a lot of food or calories in the evening, and awakening to eat in the middle of the night. Rarely, taking a sleeping pill, zolpidem, can cause similar problems.

Drugs

Many drugs used to treat common disorders promote weight gain. These drugs include some drugs used to treat psychiatric disorders including depression, some drugs used to treat seizures, some drugs used to treat high blood pressure (antihypertensives, such as beta-blockers), corticosteroids, and some drugs used to treat diabetes mellitus.

Differential Diagnosis

Mesomorphic body states, as seen in body builders and people in related occupations (eg, professional wrestling), may be associated with elevated BMIs, but as a result of increased muscle mass rather than excess adiposity. In addition, anasarca may be mistaken for obesity if not carefully evaluated clinically. Other conditions to consider while examining for obesity include the following:

• Depression
• Type 2 diabetes mellitus
• Fatty liver
• Gastroesophageal reflux disease (GERD)
• Hirsutism
• Polygenic hypercholesterolemia
• Hypothyroidism
• Insulinoma
• Kallmann syndrome and idiopathic hypogonadotropic hypogonadism
• Generalized lipodystrophy
• Polycystic ovarian disease (Stein-Leventhal syndrome)
• Cushing syndrome
• Adiposa dolorosa (Dercum disease)
• Partial lipodystrophies associated with localized lipohypertrophy

Drugs

Few medications are available for the management of obesity. Generally, the medications approved by the US Food and Drug Administration (FDA) for obesity are intended for patients with a BMI of 30 or above (obese) or of 27 or above (overweight) with a weight-related risk factor (eg, diabetes, hypertension). All are indicated as adjuncts to caloric restriction, increased physical activity, and behavior modification.

Orlistat (Xenical, Alli)

Orlistat is a gastrointestinal and pancreatic lipase inhibitor that induces weight loss by inhibiting dietary fat absorption. Orlistat should be taken during or up to 1 hour after a meal containing fat. Its effectiveness in producing weight loss does not depend on systemic absorption. Orlistat is available over the counter (Alli) in a half-strength dose and as a prescription drug (Xenical) as a full-strength dose.

Orlistat may reduce absorption of some fat-soluble vitamins (A, D, E, K) and beta carotene. Administer a multivitamin supplement containing fat-soluble vitamins orally daily, 2 hours before or 1 hour after a meal. Orlistat may also affect the absorption of some medications. In particular, patients on warfarin need closer monitoring because of the potential for malabsorption of vitamin K.

At the full dose of 120 mg 3 times daily, Xenical is frequently associated with such adverse GI events as flatulence, oily stool, diarrhea, and stool incontinence. Frequently, these adverse events result from the common misconception that because orlistat blocks fat absorption, people can consume more fat. It is important to advise patients to reduce total fat intake while on orlistat to reduce the frequency and severity of adverse events.

Doses of the over-the-counter form of orlistat, Alli (60 mg), are associated with fewer adverse events. However, this dosage is less effective for weight loss.

Lorcaserin (Belviq, Belviq XR)

Lorcaserin is indicated as an adjunct to a reduced-calorie diet and exercise for long-term weight management in patients with an initial BMI of ≥30 (obese) or in those with a BMI of ≥27 (overweight) who have at least 1 weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus).

The exact mechanism of action of lorcaserin is unknown, but this agent is thought to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus.

Phentermine/topiramate (Qsymia)

This low-dose combination of phentermine, a sympathomimetic amine anorectic, and extended-release topiramate, an antiepileptic drug that possibly suppresses appetite and enhances satiety. The drug combination is indicated as an adjunct to a reduced-calorie diet and increased physical activity for long-term weight management in adults.

Phentermine (Adipex P, Lomaira)

Phentermine is a sympathomimetic amine that increases the release and reuptake of norepinephrine and dopamine. Its anorexiant effect occurs as a result of satiety-center stimulation in hypothalamic and limbic areas of the brain.

As a pharmacologic component of a comprehensive weight-reduction program (including behavioral modification, caloric restriction, and exercise), phentermine is intended for patients with an initial BMI of ≥30 (obese). It is also appropriate for patients with a BMI of ≥27 (overweight) who have other risk factors (eg, diabetes, hyperlipidemia, hypertension).

Phentermine is indicated for patients aged ≥16 y. It is available in capsules, tablets, and orally disintegrating tablets. This medication is contraindicated for use in pregnant women.

Diethylpropion (Generic)

Diethylpropion is indicated for use as a short-term adjunct in the management of obesity. It is a sympathomimetic amine that reduces appetite, an effect that appears to be secondary to CNS effects. It is available in a 24-hour controlled-release formulation that should be taken at midmorning. It is indicated for patients aged ≥16 y.

Phendimetrazine (Bontril PDM)

Phendimetrazine is indicated for use as a short-term adjunct in the management of obesity in patients aged ≥17 y. It is a sympathomimetic amine that reduces appetite, an effect that appears to be secondary to CNS effects.

This agent is available in a 24-hour slow-release 105 mg capsule, which should be taken in the morning 30-60 minutes before breakfast. It is also available in 17.5-35 mg tablets, which should be taken 2 or 3 times daily and an hour before a meal. The maximum recommended dose is 70 mg TID. Phendimetrazine is contraindicated during pregnancy.

Benzphetamine (Regimex)

Benzphetamine is a sympathomimetic amine that reduces appetite, an effect that appears to be secondary to CNS effects. It is used as a short-term adjunct to caloric restriction in exogenous obesity. It is indicated for use in patients aged ≥12 y; the maximum dose is 50 mg TID. This medication is contraindicated during pregnancy.

Epidemiology

The prevalence of obesity worldwide is increasing, particularly in the industrialized nations of the Northern hemisphere, such as the United States, Canada, and most countries of Europe. Available data from the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project suggest that at least 15% of men and 22% of women in Europe are obese. 

Similar data are being reported in other parts of the world, including from many developing nations. Reports from countries such as Malaysia, Japan, Australia, New Zealand, and China have detailed an epidemic of obesity in the past 2-3 decades. Data from the Middle Eastern countries of Bahrain, Saudi Arabia, Egypt, Jordan, Tunisia, and Lebanon, among others, indicate this same disturbing trend, with levels of obesity often exceeding 40%.

Internationally, rates of obesity are higher in women than in men. A somewhat higher rate would be expected, given the biologically higher percentage of body fat in women.

Information from the Caribbean and from South America highlights similar trends. Although data from Africa are scant, a clear and distinct secular trend of profoundly increased BMIs is observed when people from Africa emigrate to the northwestern regions of the world. Comparisons of these indices among Nigerians and Ghanaians residing in their native countries with indices in recent immigrants to the United States show this trend poignantly.

In 2016, a study by the NCD Risk Factor Collaboration indicated, 124 million children and adolescents worldwide were obese, compared with 11 million in 1975. According to the study, 73% of this change resulted from an increased prevalence of obesity (as opposed to other factors, such as population growth). The study also reported that between 1975 and 2016, the number of obese adults worldwide rose from 100 million to 671 million. Figures for children/adolescents and adults who were overweight, but not obese, were 213 million and 1.3 billion, respectively, in 2016. 

Although socioeconomic class and the prevalence of obesity are negatively correlated in most industrialized countries, including the United States, this correlation is distinctly reversed in many relatively undeveloped areas, including China, Malaysia, parts of South America, and sub-Saharan Africa.

Race-related demographics

Obesity is a cosmopolitan disease that affects all races worldwide. However, certain ethnic and racial groups appear to be particularly predisposed. The Pima Indians of Arizona and other ethnic groups native to North America have a particularly high prevalence of obesity. In addition, Pacific islanders (eg, Polynesians, Micronesians, Maoris), African Americans, and Hispanic populations (either Mexican or Puerto Rican in origin) in North America also have particularly high predispositions to the development of obesity.

Secular trends clearly emphasize the importance of environmental factors (particularly dietary issues) in the development of obesity. In many genetically similar cohorts of high-risk ethnic and racial groups, the prevalence of obesity in their countries of origin is low but rises considerably when members of these groups emigrate to the affluent countries of the Northern Hemisphere, where they alter their dietary habits and activities. These findings form the core concept of the thrifty gene hypothesis espoused by Neel and colleagues. 

The thrifty gene hypothesis posits that human evolution favored individuals who were more efficient at storing energy during times of food shortage and that this historic evolutionary advantage is now a disadvantage during a time of abundant food availability.

Age-related demographics

Children, particularly adolescents, who are obese have a high probability of becoming adults who are obese; hence, the bimodal distribution of obesity portends a large-scale obesity epidemic in the next few decades. Taller children generally tend to be more obese than shorter peers, are more insulin-resistant, and have increased leptin levels. 

Adolescent obesity poses a serious risk for severe obesity during early adulthood, particularly in non-Hispanic black women. This calls for a stronger emphasis on weight reduction during early adolescence, specifically targeting groups at greater risk.

Prognosis

Data from insurance databases and large, prospective cohorts, such as findings from the Framingham and National Health and Nutrition Examination Survey (NHANES) studies, clearly indicate that obesity is associated with a substantial increase in morbidity and mortality rates.

Obesity on its own is associated with increased cardiovascular morbidity and mortality and greater all-cause mortality. For a person with a BMI of 25-28.9 kg/m², the relative risk for coronary heart disease is 1.72. The risk progressively increases with an increasing BMI; with BMIs greater than 33 kg/m², the relative risk is 3.44. Similar trends have been demonstrated in the relationship between obesity and stroke or chronic heart failure.

Overall, obesity is estimated to increase the cardiovascular mortality rate 4-fold and the cancer-related mortality rate 2-fold. As a group, people who are severely obese have a 6- to 12-fold increase in the all-cause mortality rate. Although the exact magnitude of the attributable excess in mortality associated with obesity (about 112,000-365,000 excess deaths annually) has been disputed, obesity is indisputably the greatest preventable health-related cause of mortality after cigarette smoking.

For persons with severe obesity (BMI ≥40), life expectancy is reduced by as much as 20 years in men and by about 5 years in women. The greater reduction in life expectancy for men is consistent with the higher prevalence of android (ie, predominantly abdominal) obesity and the biologically higher percent body fat in women. The risk of premature mortality is even greater in obese persons who smoke.

Some evidence suggests that, if unchecked, trends in obesity in the United States may be associated with overall reduced longevity of the population in the near future. Data also show that obesity is associated with an increased risk and duration of lifetime disability. Furthermore, obesity in middle age is associated with poor indices of quality of life in old age.

The mortality data appear to have a U – or J -shaped conformation in relation to weight distribution.  Underweight was associated with substantially high risk of death in a study of Asian populations, and a high BMI is also associated with an increased risk of death, except in Indians and Bangladeshis. A study in whites found that all-cause mortality is generally lowest with a BMI of 20-24.9 and reinforced that overweight and underweight lead to an increased risk of death. ^[71]

The degree of obesity (generally indicated by the BMI) at which mortality discernibly increases in African Americans and Hispanic Americans is greater than in white Americans; this observation suggests a notable racial spectrum and difference in this effect. The optimal BMI in terms of life expectancy is about 23-25 for whites and 23-30 for blacks. Emerging data suggest that the ideal BMI for Asians is substantially lower than that for whites. 

Stated another way, individuals who have abdominal obesity (elevated waist circumference) are at risk for obesity-related health complications. Most individuals with a BMI of over 25 and essentially all persons with a BMI of more than 30 have abdominal obesity.

Factors that modulate the morbidity and mortality associated with obesity include the following:

• Age of onset and duration of obesity
• Severity of obesity
• Amount of central adiposity
• Comorbidities
• Gender
• level of cardiorespiratory fitness
• Race

A study by Jung et al found a correlation between abdominal obesity and high-volume benign prostatic hyperplasia (BPH), ie, a prostate volume of 40 mL or greater. The report, which involved 571 participants, also found a positive association between serum leptin levels and high-volume BPH and a negative association between serum adiponectin and high-volume BPH. 

Natural Progression

At the initial phase, behavioral and environmental factors play a key role in the constitution of adipose tissue excess. Progressively biological alterations of adipose tissue metabolism lead to some degree of irreversibility of the disease and contribute to the development of its metabolic and cardio-vascular complications.

Pathophysiology

Different factors are in involved in the pathophysiology of obesity which may include:

Lifestyle

Most researchers have concluded that the combination of an excessive nutrient intake and a sedentary lifestyle are the main cause for the rapid acceleration of obesity in Western society in the last quarter of the 20th century.

Despite the widespread availability of nutritional information in schools, doctors’ offices, on the internet and on groceries, it is evident that overeating remains a substantial problem. For instance, reliance on energy-dense fast-food meals tripled between 1977 and 1995, and calorie intake quadrupled over the same period.

However, dietary intake in itself is insufficient to explain the phenomenal rise in levels of obesity in much of the industrialized world during recent years. An increasingly sedentary lifestyle also has a significant role to play. More and more research into child obesity, for example, links such things as the school run, with the current high levels of this disease.

Less well established life style issues which may influence obesity include a stressful mentality and insufficient sleep.

Genetics

As with many medical conditions, the calorific imbalance that results in obesity often develops from a combination of genetic and environmental factors. Polymorphisms in various genes controlling appetite, metabolism, and adipokine release predispose to obesity, but the condition requires availability of sufficient calories, and possibly other factors, to develop fully. Various genetic conditions that feature obesity have been identified (such as Prader-Willi syndrome, Bardet-Biedl syndrome, MOMO syndrome, leptin receptor mutations and melanocortin receptor mutations), but known single-locus mutations have been found in only about 5% of obese individuals. While it is thought that a large proportion of the causative genes are still to be identified, much obesity is likely the result of interactions between multiple genes, and non-genetic factors are likely also important.

A 2007 study identified fairly common mutations in the FTO gene; heterozygotes had a 30% increased risk of obesity, while homozygotes faced a 70% increased risk. On a population level, the thrifty gene hypothesis postulates that certain ethnic groups may be more prone to obesity than others, and the ability to take advantage of rare periods of abundance and use such abundance by storing energy efficiently may have been an evolutionary advantage in times when food was scarce. Individuals with greater adipose reserves were more likely to survive famine. This tendency to store fat is likely maladaptive in a society with stable food supplies.

Medical Illness

Certain physical and mental illnesses and particular pharmaceutical substances may predispose to obesity. Apart from the fact that correcting these situations may improve the obesity, the presence of increased body weight may complicate the management of others.

Medical illnesses that increase obesity risk include several rare congenital syndromes (listed above), hypothyroidism, Cushing’s syndrome, growth hormone deficiency. Smoking cessation is a known cause for moderate weight gain, as nicotine suppresses appetite. Certain medications (e.g. steroids, atypical antipsychotics, some fertility medication) may cause weight gain.

Mental illnesses may also increase obesity risk, specifically some eating disorders such as bulimia nervosa, binge eating disorder, and compulsive overeating (also known as food addiction).

Neurobiological Mechanisms

Scientists investigating the mechanisms and treatment of obesity may use animal models such as mice to conduct experiments.

Flier et al. summarizes the many possible pathophysiological mechanisms involved in the development and maintenance of obesity. This field of research had been almost unapproached until leptin was discovered in 1994. Since this discovery, many other hormonal mechanisms have been elucidated that participate in the regulation of appetite and food intake, storage patterns of adipose tissue, and development of insulin resistance. Since leptin’s discovery, ghrelin, orexin, PYY 3-36, cholecystokinin, adiponectin, and many other mediators have been studied. The adipokines are mediators produced by adipose tissue; their action is thought to modify many obesity-related diseases.

Leptin and ghrelin are considered to be complementary in their influence on appetite, with ghrelin produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched). Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high). Although administration of leptin may be effective in a small subset of obese individuals who are leptin deficient, many more obese individuals are thought to be leptin resistant. This resistance is thought to explain in part why administration of leptin has not been shown to be effective in suppressing appetite in most obese subjects.

While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood. The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain’s feeding and satiety centers, respectively.

The arcuate nucleus contains two distinct groups of neurons. The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity.

Microbiological Aspects

The role of bacteria colonizing the digestive tract in the development of obesity has recently become the subject of investigation. Bacteria participate in digestion (especially of fatty acids and polysaccharides), and alterations in the proportion of particular strains of bacteria may explain why certain people are more prone to weight gain than others. Human digestive tract are generally either members of the phyla of bacteroidetes or of firmicutes. In obese people, there is a relative abundance of firmicutes (which cause relatively high energy absorption), which is restored by weight loss. From these results it cannot yet be concluded whether this imbalance is the cause of obesity or an effect.

Social Determinants

Some obesity co-factors are resistant to the theory that the “epidemic” is a new phenomenon. In particular, a class co-factor consistently appears across many studies. Comparing net worth with BMI scores, a 2004 study found obese American subjects approximately half as wealthy as thin ones. When income differentials were factored out, the inequity persisted, thin subjects were inheriting more wealth than fat ones. A higher rate of a lower level of education and tendencies to rely on cheaper fast foods is seen as a reason why these results are so dissimilar. Another study finds women who married into higher status are predictably thinner than women who married into lower status.

A 2007 study of more than 32,500 children of the original Framingham Heart Study cohort followed for 32 years indicated that BMI change in friends, siblings or spouse predicted BMI change in subjects irrespective of geographical distance. The association was strongest among mutual friends and lower among siblings and spouses (although these differences were not statistically significant). The authors concluded from the results that acceptance of body mass plays an important role in changes in body size.

Environmental Factors

While it may often appear obvious why a certain individual gets fat, it is far more difficult to understand why the average weight of certain societies have recently been growing. While genetic causes are central to understanding obesity, they cannot fully explain why one culture grows fatter than another.

This is most notable in the United States. In the years from just after the Second World War until 1960 the average person’s weight increased, but few were obese. In the two and a half decades since 1980 the growth in the rate of obesity has accelerated markedly and is increasingly becoming a public health concern.

There are a number of theories as to the cause of this change since 1980. Most believe it is a combination of various factors.

Lack of activity: obese people are less active in general than lean people, and not just because of their obesity. A controlled increase in calorie intake of lean people did not make them less active; correspondingly when obese people lost weight they did not become more active. Weight change does not affect activity levels, but the converse seems to be the case.

Lower relative cost of foodstuffs: massive changes in agricultural policy in the United States and Europe have led to food prices for consumers being lower than at any point in history. This can raise costs for consumers in some areas but greatly lower it in others. Current debates into trade policy highlight disagreements on the effects of subsidies. In the United States, production of corn, soy, wheat and rice is subsidized through the U.S. farm bill. Corn and soy, which are main sources of the sugars and fats in processed food, are thus cheap compared to fruits and vegetables.

Increased marketing has also played a role. In the early 1980s in America the Reagan administration lifted most regulations pertaining to sweets and fast food advertising to children. As a result, the number of advertisements seen by the average child increased greatly, and a large proportion of these were for fast food and sweets.

The changing workforce as each year a greater percent of the population spends their entire workday behind a desk or computer, seeing virtually no exercise. In the kitchen the microwave oven has seen sales of calorie-dense frozen convenience foods skyrocket and has encouraged more elaborate snacking.

A social cause that is believed by many to play a role is the increasing number of two income households in which one parent no longer remains home to look after the house. This increases the number of restaurant and take-out meals.

Urban sprawl may be a factor: obesity rates increase as urban sprawl increases, possibly due to less walking and less time for cooking.

Since 1980 fast food restaurants have seen dramatic growth in terms of the number of outlets and customers served. Low food costs, and intense competition for market share, led to increased portion sizes—for example, McDonalds french fries portions rose from 200 calories (840 kilojoules) in 1960 to over 600 calories (2,500 kJ) today.

Possible Complications

People with obesity are more likely to develop a number of potentially serious health problems, including:

• Heart disease and strokes. Obesity makes you more likely to have high blood pressure and abnormal cholesterol levels, which are risk factors for heart disease and strokes.
• Type 2 diabetes. Obesity can affect the way your body uses insulin to control blood sugar levels. This raises your risk of insulin resistance and diabetes.
• Certain cancers. Obesity may increase your risk of cancer of the uterus, cervix, endometrium, ovary, breast, colon, rectum, esophagus, liver, gallbladder, pancreas, kidney and prostate.
• Digestive problems. Obesity increases the likelihood that you’ll develop heartburn, gallbladder disease and liver problems.
• Gynecological and sexual problems. Obesity may cause infertility and irregular periods in women. Obesity also can cause erectile dysfunction in men.
• Sleep apnea. People with obesity are more likely to have sleep apnea, a potentially serious disorder in which breathing repeatedly stops and starts during sleep.
• Osteoarthritis. Obesity increases the stress placed on weight-bearing joints, in addition to promoting inflammation within the body. These factors may lead to complications such as osteoarthritis.

Possible Treatment

Treatment of obesity starts with comprehensive lifestyle management (ie, diet, physical activity, behavior modification), which should include the following:

• Self-monitoring of caloric intake and physical activity
• Goal setting
• Stimulus control
• Nonfood rewards
• Relapse prevention

As with all chronic medical conditions, effective management of obesity must be based on a partnership between a highly motivated patient and a committed team of health professionals. This team may include the physician, a psychologist or psychiatrist, physical and exercise therapists, dietitians, and other subspecialists, depending on the comorbidities of the individual patient. Scientific evidence indicates that multidisciplinary programs reliably produce and sustain modest weight loss between 5% and 10% for the long-term. 

In January, 2015, the Endocrine Society released new guidelines on the treatment of obesity to include the following: 

• Diet, exercise, and behavioral modification should be included in all obesity management approaches for body mass index (BMI) of 25 kg/m² or higher. Other tools, such as pharmacotherapy for BMI of 27 kg/m² or higher with comorbidity or BMI over 30 kg/m2 and bariatric surgery for BMI of 35 kg/m² with comorbidity or BMI over 40 kg/m², should be used as adjuncts to behavioral modification to reduce food intake and increase physical activity when this is possible.
• Drugs may amplify adherence to behavior change and may improve physical functioning such that increased physical activity is easier in those who cannot exercise initially. Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications.
• To promote long-term weight maintenance, the use of approved weight loss medication (over no pharmacological therapy) is suggested to ameliorate comorbidities and amplify adherence to behavior changes, which may improve physical functioning and allow for greater physical activity in individuals with a BMI of 30 kg/m² or higher or in individuals with a BME of 27 kg/m² and at least one associated comorbid medical condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus, and obstructive sleep apnea).
• If a patient’s response to a weight loss medication is deemed effective (weight loss of 5% or more of body weight at 3 mo) and safe, it is recommended that the medication be continued. If deemed ineffective (weight loss less than 5% at 3 mo) or if there are safety or tolerability issues at any time, it is recommended that the medication be discontinued and alternative medications or referral for alternative treatment approaches be considered.
• In patients with type 2 diabetes mellitus who are overweight or obese, antidiabetic medications that have additional actions to promote weight loss (such as glucagon-like peptide-1 [GLP-1] analogs or sodium-glucose-linked transporter-2 [SGLT-2] inhibitors) are suggested, in addition to the first-line agent for type 2 diabetes mellitus and obesity, metformin.
• In obese patients with type 2 diabetes mellitus who require insulin therapy, at least one of the following is suggested: metformin, pramlintide, or GLP-1 agonists to mitigate associated weight gain due to insulin. The first-line insulin for this type of patient should be basal insulin. This is preferable to using either insulin alone or insulin with sulfonylurea.
• Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers, rather than beta-adrenergic blockers, should be considered as first-line therapy for hypertension in patients with type 2 diabetes mellitus who are obese.
• In women with a BMI of 27 kg/m² or more with comorbidities or a BMI of 30 kg/m² or more, seeking contraception, oral contraceptives are suggested over injectable medications because of weight gain with injectables, provided that women are well informed about the risks and benefits (ie, oral contraceptives are not contraindicated).

Weight-loss programs

The 3 major phases of any successful weight-loss program are as follows:

• Preinclusion screening phase
• Weight-loss phase
• Maintenance phase – This can conceivably last for the rest of the patient’s life but ideally lasts for at least 1 year after the weight-loss program has been completed

Evidence supports the use of commercial weight-loss programs. A 12-week randomized, controlled trial found that commercially available weight-loss programs are more successful and more affordable than primary care practice–based programs led by specially trained staff.

Pharmacologic therapy

Few drugs are available for the treatment of obesity, and their effectiveness is limited to palliation (ie, production and maintenance of weight loss) rather than cure, with benefits fading when the drugs are stopped. Because all medications inherently have more risks than diet and exercise do, pharmacologic therapy should be used only in patients in whom the benefit justifies the risk. 

Surgery

In patients with morbid obesity associated with comorbidities, bariatric surgery is the only available therapeutic modality associated with clinically significant and relatively sustained weight loss. Well-performed bariatric surgery, in carefully selected patients and with a good multidisciplinary support team, substantially ameliorates the morbidities associated with severe obesity.

Primary Prevention

Public health and policy responses to obesity seek to understand and correct the environmental factors responsible for shifts in the prevalence of overweight and obesity in a population. Obesity and overweight are, currently, primarily policy problems in the United States. Policy and public health solutions look to change the environmental factors that promote calorie dense, low nutrient food consumption and that inhibit physical activity.

In the United States, policy has focused primarily on controlling childhood obesity which has the most serious long-term public health implication. Efforts have been underway to target schools. There are efforts underway to reform federally-reimbursed meal programs, limit food marketing to children, and ban or limit access to sugar sweetened beverages. In Europe, policy has focused on limiting marketing to children. There has been international focus on sugar policy and the role of agriculture policy in producing food environments that produce overweight and obesity in a population. To confront physical activity, efforts have examined zoning and access parks and safe routes in cities.

In the United Kingdom, a 2004 report by the Royal College of Physicians, the Faculty of Public Health and the Royal College of Paediatrics and Child Health, titled “Storing up Problems” was followed by a report by the British House of Commons Health Select Committee – the “the most comprehensive inquiry” ever by that body – on the impact of obesity on health and society in the UK and possible approaches to the problem. In 2006, the National Institute for Health and Clinical Excellence (NICE) issued a guideline on the diagnosis and management of obesity, as well as policy implications for non-healthcare organizations such as local councils. A 2007 report produced by Sir Derek Wanless for the King’s Fund warned that unless further action was taken, obesity had the capacity to cripple the National Health Service financially.

Whether you’re at risk of obesity, currently overweight or at a healthy weight, you can take steps to prevent unhealthy weight gain and related health problems. Not surprisingly, the steps to prevent weight gain are the same as the steps to lose weight: daily exercise, a healthy diet, and a long-term commitment to watch what you eat and drink.

• Exercise regularly. You need to get 150 to 300 minutes of moderate-intensity activity a week to prevent weight gain. Moderately intense physical activities include fast walking and swimming.
• Follow a healthy-eating plan. Focus on low-calorie, nutrient-dense foods, such as fruits, vegetables and whole grains. Avoid saturated fat and limit sweets and alcohol. Eat three regular meals a day with limited snacking. You can still enjoy small amounts of high-fat, high-calorie foods as an infrequent treat. Just be sure to choose foods that promote a healthy weight and good health most of the time.
• Know and avoid the food traps that cause you to eat. Identify situations that trigger out-of-control eating. Try keeping a journal and write down what you eat, how much you eat, when you eat, how you’re feeling and how hungry you are. After a while, you should see patterns emerge. You can plan ahead and develop strategies for handling these types of situations and stay in control of your eating behaviors.
• Monitor your weight regularly. People who weigh themselves at least once a week are more successful in keeping off excess pounds. Monitoring your weight can tell you whether your efforts are working and can help you detect small weight gains before they become big problems.
• Be consistent. Sticking to your healthy-weight plan during the week, on the weekends, and amidst vacation and holidays as much as possible increases your chances of long-term success.

Secondary Prevention

A meta-analysis of randomized controlled trials concluded that compared with usual care, dietary counseling interventions produce modest weight losses that diminish over time.

Risk factors

The presence of risk factors and diseases associated with obesity are also used to establish a clinical diagnosis. Possible life-threatening risk factors that would indicate clinical treatment of obesity

• Coronary heart disease
• Type 2 diabetes
• Sleep apnea

Other risk factors:

• Smoking
• Hypertension
• Age
• Family history

Signs or Symptom

Obesity can cause day-to-day health problems such as:

• breathlessness
• increased sweating
• snoring
• inability to cope with sudden physical activity
• feeling very tired every day
• back and joint pains
• low confidence and self esteem
• feeling isolated

Obesity can also cause changes you may not notice, but that can seriously harm your health, such as high blood pressure (hypertension) and high cholesterol levels (fatty deposits blocking your arteries). Both conditions significantly increase your risk of developing a cardiovascular disease, such as:

• coronary heart disease, which may lead to a heart attack
• stroke, which can cause significant disability and can be fatal

Another long-term problem that can affect obese people is type 2 diabetes. It is estimated that just under half of all cases of diabetes are linked to obesity. The main symptoms of diabetes are:

• feeling very thirsty
• going to the toilet a lot, especially at night
• extreme tiredness

Obesity can contribute to many other chronic conditions, including some cancers, some asthma, back problems, chronic kidney disease, dementia, gallbladder disease, gout, and osteoarthritis. Being overweight or obese is also associated with dying prematurely.

In addition to the day-to-day health problems, many people may also experience psychological problems.

These can affect relationships with family members and friends and may lead to depression.

Stage

BMI, or body mass index, is a simple and widely used method for estimating body fat. BMI was developed by the Belgian statistician and anthropometrist Adolphe Quetelet. It is calculated by dividing the subject’s weight by the square of his/her height, typically expressed either in metric or US “Customary” units:

Metric: BMI = kg/m^2

Where kg is the subject’s weight in kilograms and m is the subject’s height in metres.

US/Customary: BMI=lb*703/in^2

Where lb is the subject’s weight in pounds and in is the subject’s height in inches.

According to the BMI, obesity can be classified as:

• A BMI less than 18.5 is underweight
• A BMI of 18.5–24.9 is normal weight
• A BMI of 25.0–29.9 is overweight
• A BMI of 30.0–39.9 is obese
• A BMI of 40.0 or higher is severely (or morbidly) obese
• A BMI of 35.0 or higher in the presence of at least one other significant comorbidityis also classified by some bodies as morbid obesity

Studies

Active Not Recruiting

Number of studies: 506

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Completed

Number of studies: 4, 768

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Enrolling by Invitation

Number of studies: 92

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Not Yet Recruiting

Number of studies: 254

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Recruiting

Number of studies: 1, 231

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Results Available

Number of studies: 617

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Results Not available

Number of studies: 7, 489

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Suspended

Number of studies: 16

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Terminated

Number of studies: 280

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Withdrawn

Number of studies: 138

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Typical Test

Physical Examination

In the clinical examination, measure anthropometric parameters and perform the standard, detailed examination required in evaluating patients with any chronic, multisystem disorder, such as obesity.

Waist and hip circumference are useful surrogates in estimating visceral fat; serial tracking of these measurements helps in estimating the clinical risk over time. Neck circumference is predictive of a risk of sleep apnea, and its serial measurement in the individual patient is clinically useful for risk stratification. 

Examination of organ systems should include the following:

• Cutaneous – Search for intertriginous rashes from skin-on-skin friction; also search for hirsutism in women, acanthosis nigricans, and skin tags, which are common with insulin resistance secondary to obesity
• Cardiac and respiratory – Exclude cardiomegaly and respiratory insufficiency
• Abdominal – Attempt to exclude tender hepatomegaly, which may suggest hepatic fatty infiltration or NASH, and distinguish the striae distensae from the pink and broad striae that suggest cortisol excess

When examining the extremities, search for joint deformities (eg, coxa vara), evidence of osteoarthritis, and any pressure ulcerations. Localized and lipodystrophic fat distribution should also be identified, because of their common association with insulin resistance.

Laboratory tests

Standard laboratory studies in the evaluation of obesity should include the following:

• Fasting lipid panel
• Liver function studies
• Thyroid function tests
• Fasting glucose and hemoglobin A1c (HbA1c)

Other tests are performed as indicated by clinical findings. For example, the 24-hour urinary free-cortisol test is needed only when Cushing syndrome or other hypercortisolemic states are clinically suspected. However, approximately 4% of patients with Cushing syndrome have normal urinary free-cortisol values.

Lipid panel

At minimum, test fasting cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) levels. These levels may be normal, or the typical dyslipidemia associated with cardiometabolic syndrome may be found. This dyslipidemia is characterized by reduced HDL-C and elevated fasting triglyceride concentrations; however, increased low-density lipoprotein cholesterol (LDL-C) and normal to marginally increased total cholesterol are not uncommon among obese individuals.

Liver and thyroid function tests

Liver function tests yield normal results in most obese patients. However, elevated transaminase levels may indicate nonalcoholic steatohepatitis (NASH) or fatty infiltration of the liver).

Thyroid function test results are also typically normal, but checking them to detect primary hypothyroidism (characterized by increased serum thyrotropin and normal or reduced thyroxine and/or triiodothyronine levels) is worthwhile. Screening with a serum thyrotropin level is usually sufficient. Of importance, hypothyroidism itself rarely causes more than mild obesity.

Glucose and insulin tests

Obesity is associated with insulin resistance and increased serum levels of fasting insulin and C-peptide serum levels. However, insulin levels are normal in many persons who are obese.

All patients with obesity should be screened for diabetes. Additional information is gained by using glucose and HbA1c tests together if the patient is fasting. The American Diabetes Association currently recommends using the HbA1c test not only to screen for diabetes, but also to follow patients who already have the diagnosis. In contrast, the American Association of Clinical Endocrinologists recommends that HbA1c be considered an additional, optional diagnostic criterion. 

Prediabetes is indicated by impaired fasting glucose (fasting plasma glucose levels of 100-125 mg/dL [5.6-6.9 mmol/L]) or impaired glucose tolerance (2-h oral glucose tolerance test values of 140-199 mg/dL [7.8-11.0 mmol/L]). Patients with these findings are at relatively high risk for the future development of diabetes. Type 2 diabetes is diagnosed when the fasting glucose is 126 mg/dL or greater or HbA1c is 6.5% or higher.

Evaluation of Degree of Fat

Body mass index (BMI) calculation, waist circumference, and waist/hip ratio are the common measures of the degree of body fat used in routine clinical practice. Other procedures that are used in few clinical centers include the following:

• Caliper-derived measurements of skin-fold thickness
• Dual-energy radiographic absorptiometry (DEXA)
• Bioelectrical impedance analysis
• Ultrasonography to determine fat thickness
• Underwater weighing

The standard techniques for measuring visceral fat are magnetic resonance imaging (MRI) and computed tomography (CT) scanning. Less expensive techniques for direct measurement of visceral fat include abdominal ultrasonography and abdominal bioelectrical impedance.