Obesity

Heritability of BMI is high across different age groups, ranging from 40 to 60% (1, 2). With few exceptions, obesity does not follow a simple Mendelian pattern of inheritance but is rather a complex interplay of multiple loci. Genetic factors may affect the many signaling molecules and receptors used by parts of the hypothalamus and gastrointestinal tract to regulate food intake (see sidebar Pathways Regulating Food Intake). Genome studies have helped define signaling pathways implicated in the predisposition to obesity. Differences in expression of signaling molecules within the leptin-melanocortin pathway (eg, the melanocortrin-4 receptor) have been particularly associated with central control of appetite. Genetic factors can be inherited or result from conditions in utero (called genetic imprinting). Environmental conditions such as nutrition, sleep patterns, and alcohol consumption alter gene expression in various metabolic pathways epigenetically; this effect suggests possible reversibility of environmental factors and refinement of therapeutic targets.

Genetic factors also regulate energy expenditure, including basal metabolic rate, diet-induced thermogenesis, and nonvoluntary activity–associated thermogenesis. Genetic factors may have a greater effect on the distribution of body fat, particularly abdominal fat (which increases the risk of metabolic syndrome), than on the amount of body fat.

Weight is gained when caloric intake exceeds energy needs. Important determinants of energy intake include

• Portion sizes

• The energy density of the food

Systemic drivers of lifestyle and behavioral factors are rooted in community culture and economic systems. Communities which do not have access to fresh fruits and vegetables and which do not consume water as the main fluid consumed tend to have higher rates of obesity. High-calorie, energy-dense foods (eg, processed foods), diets high in refined carbohydrates, and consumption of soft drinks, fruit juices, and alcohol promote weight gain.

Access to safe recreational spaces (eg, pedestrian and biking infrastructure, parks) and availability of public transportation can encourage physical activity and help protect against obesity.

Prenatal maternal obesity, prenatal maternal smoking, excessive weight gain during pregnancy (see table Guidelines for Weight Gain During Pregnancy), and intrauterine growth restriction can disturb weight regulation and contribute to weight gain during childhood and later. Obesity that persists beyond early childhood makes weight loss in later life more difficult.

The composition of the gut microbiome also appears to be an important factor; early use of antibiotics and other factors that alter the composition of the gut microbiome may promote weight gain and obesity later in life (3).

Early exposure to obesogens, a type of endocrine-disrupting chemical (eg, cigarette smoke, bisphenol A, air pollution, flame retardants, phthalates, polychlorinated biphenyls) can alter metabolic set points through epigenetics or nuclear activation, increasing the propensity of developing obesity (4).

Adverse childhood events or abuse in early childhood increase risk of several disorders, including obesity. The Centers for Disease Control and Prevention's adverse childhood events study demonstrated that childhood history of verbal, physical, or sexual abuse predicted an increase of 8% in risk of a BMI ≥ 30 and 17.3% in risk of a BMI ≥ 40. Certain types of abuse carried the strongest risk. For example, frequent verbal abuse had the largest increase in risk (88%) of a BMI > 40. Being often hit and injured increased the risk of BMI > 30 by 71% (5). Cited mechanisms for the association between abuse and obesity include neurobiologic and epigenetic phenomena (6).

Insufficient sleep (usually considered < 6 to 8 hours/night) can result in weight gain by changing the levels of satiety hormones that promote hunger. In the Wisconsin Sleep Cohort Study involving 1024 healthy adults, a decrease in sleep was proportional to an increase in BMI. In adults, BMI increased by 3.6% when average sleep time decreased from 8 hours to 5 hours (7)

Smoking cessation is associated with weight gain and can deter patients from quitting smoking.

Uncommonly, weight gain is caused by one of the following disorders:

• Alternations in brain structure and function caused by a tumor (especially a craniopharyngioma) or an infection (particularly those affecting the hypothalamus), which can stimulate consumption of excess calories

• Hyperinsulinism due to pancreatic tumors

• Hypercortisolism due to Cushing syndrome, which causes predominantly abdominal obesity

• Hypothyroidism (rarely a cause of substantial weight gain)

• Hypogonadism

At least 2 pathologic eating patterns may be associated with obesity:

• Binge eating disorder is consumption of large amounts of food quickly with a subjective sense of loss of control during the binge and distress after it. This disorder does not include compensatory behaviors, such as vomiting. Binge eating disorder occurs in about 3.5% of women and 2% of men during their lifetime and in about 10 to 20% of people entering weight reduction programs. Obesity is usually severe, large amounts of weight are frequently gained or lost, and pronounced psychologic disturbances are present.

• Night-eating syndrome

Similar but less extreme patterns probably contribute to excess weight gain in more people. For example, eating after the evening meal contributes to excess weight gain in many people who do not have night-eating syndrome.

1. 1. Mahmoud AM: An overview of epigenetics in obesity: The role of lifestyle and therapeutic interventions. Int J Mol Sci 23 (3):1341. 2022. doi: 10.3390/ijms23031341

2. 2. Nan C, Guo B, Claire Warner C, et al: Heritability of body mass index in pre-adolescence, young adulthood and late adulthood. Eur J Epidemiol 27 (4):247–253, 2012. doi: 10.1007/s10654-012-9678-6 Epub 2012 Mar 18.

3. 3. Ajslev TA, Andersen CS, Gamborg M, et al: Childhood overweight after establishment of the gut microbiota: The role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes 35 (4): 522–529, 2011. doi: 10.1038/ijo.2011.27

4. 4. Heindel JJ, Newbold R, Schug TT: Endocrine disruptors and obesity. Nat Rev Endocrinol 11 (11):653–661, 2015. doi: 10.1038/nrendo.2015.163

5. 5. Williamson DF, Thompson TJ, Anda RF, et al: Body weight and obesity in adults and self-reported abuse in childhood. Int J Obes Relat Metab Disord  26 (8):1075–1082, 2002. doi: 10.1038/sj.ijo.0802038

6. 6. Anda RF, Felitti VJ, Bremner JD, et al: The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci 256 (3):174–186, 2006. doi: 10.1007/s00406-005-0624-4

7. 7. Taheri S, Lin L, Austin D, et al: Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 1 (3):e62, 2004. doi: 10.1371/journal.pmed.0010062 Epub 2004 Dec 7.

Body composition—the percentage of body fat and muscle—is also considered when obesity is diagnosed. Although probably unnecessary in routine clinical practice, body composition analysis can be helpful if clinicians question whether elevated BMI is due to muscle or excessive fat.

Men are considered to have obesity when body fat levels are > 25%. In women, the cutoff is > 32%.

The percentage of body fat can be estimated by measuring skinfold thickness (usually over the triceps) or determining mid upper arm muscle area.

Bioelectrical impedance analysis (BIA) can estimate percentage of body fat simply and noninvasively. BIA estimates percentage of total body water directly; percentage of body fat is derived indirectly. BIA is most reliable in healthy people and in people with only a few chronic disorders that do not change the percentage of total body water (eg, moderate obesity, diabetes mellitus). Whether measuring BIA poses risks in people with implanted defibrillators is unclear.

Underwater (hydrostatic) weighing is the most accurate method for measuring percentage of body fat. Costly and time-consuming, it is used more often in research than in clinical care. To be weighed accurately while submerged, people must fully exhale beforehand.

Imaging procedures, including CT, MRI, and dual-energy x-ray absorptiometry (DXA), can also estimate the percentage and distribution of body fat but are usually used only for research.

Patients with obesity should be screened for common comorbid disorders, such as obstructive sleep apnea, diabetes, dyslipidemia, hypertension, steatotic liver disease, and depression. Screening tools can help; for example, for obstructive sleep apnea, clinicians can use an instrument such as the STOP-BANG questionnaire (see table STOP-BANG Risk Score for Obstructive Sleep Apnea) and often the apnea-hypopnea index (total number of apnea or hypopnea episodes occurring per hour of sleep). Obstructive sleep apnea is often underdiagnosed, and obesity increases the risk.

1. 1. WHO Expert Consultation: Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 363 (9403):157–163, 2004. doi: 10.1016/S0140-6736(03)15268-3 Erratum in Lancet 363 (9412):902, 2004.

2. 3. Ross R, Neeland IJ, Yamashita S, et al: Waist circumference as a vital sign in clinical practice: A Consensus Statement from the IAS [International Atherosclerosis Society] and ICCR [International Chair on Cardiometabolic Risk] Working Group on Visceral Obesity. Nat Rev Endocrinol16 (3):177–189, 2020. doi: 10.1038/s41574-019-0310-7 Epub 2020 Feb 4.

3. 3. Luo J,  Hendryx M, Laddu D, et al: Racial and ethnic differences in anthropometric measures as risk factors for diabetes. Diabetes Care 2019 42 (1):126–133. 2019. doi: 10.2337/dc18-1413 Epub 2018 Oct 23.

Balanced eating is important for weight loss and maintenance.

Strategies include

• Eating small meals and avoiding or carefully choosing snacks

• Substituting fresh fruits and vegetables and salads for refined carbohydrates and processed food

• Substituting water for soft drinks or juices

• Limiting alcohol consumption to moderate levels

• Including no- or low-fat dairy products, which are part of a healthy diet and help provide an adequate amount of vitamin D

Low-calorie, high-fiber diets that modestly restrict calories (by 600 kcal/day) and that incorporate lean protein appear to have the best long-term outcome. Foods with a low glycemic index (see table Glycemic Index of Some Foods) and marine fish oils or monounsaturated fats derived from plants (eg, olive oil) reduce the risk of cardiovascular disorders and diabetes.

Use of meal replacements can help with weight loss and maintenance; these products can be used regularly or intermittently.

Diets that are overly restrictive are unlikely to be maintained or to result in long-term weight loss. Diets that limit caloric intake to < 50% of basal energy expenditure (BEE), described as very low calorie diets, can have as few as 800 kcal/day.

Energy expenditure and metabolic rate vary with diet and activity. Restrictive dieting may produce short-term modest weight loss; however, levels of hormones such as leptin, insulin, gastric inhibitory polypeptide (GIP), and ghrelin change to favor weight regain. In a long-term analysis of low-calorie diets, between one- third and two thirds of dieters regained more weight than they lost initially (2).

Exercise increases energy expenditure, basal metabolic rate, and diet-induced thermogenesis. Exercise also seems to regulate appetite to more closely match caloric needs. Other benefits associated with physical activity include

• Increased insulin sensitivity

• Improved lipid profile

• Lower blood pressure

• Better aerobic fitness

• Improved psychologic well-being

• Decreased risk of breast and colon cancer

• Increased life expectancy

Exercise, including strengthening (resistance) exercises, increases muscle mass. Because muscle tissue burns more calories at rest than does fat tissue, increasing muscle mass produces lasting increases in basal metabolic rate. Exercise that is interesting and enjoyable is more likely to be sustained. A combination of aerobic and resistance exercise is better than either alone. Guidelines suggest physical activity of 150 minutes/week for health benefits and 300 to 360 minutes/week for weight loss and maintenance. Developing a more physically active lifestyle can help with weight loss and maintenance.

Clinicians can recommend various behavioral interventions to help patients lose weight (3). They include

• Support

• Self-monitoring

• Stress management

• Contingency management

• Problem solving

• Stimulus control

Support may come from a group, friends or family members. Participation in a support group can improve adherence to lifestyle changes and thus increase weight loss. The more frequently people attend group meetings, the greater the support, motivation, and supervision they receive and the greater their accountability, resulting in greater weight loss. Patients can get support by using social media to connect with each other and clinicians.

Self-monitoring may include keeping a food log (including the number of calories in foods), weighing regularly, and observing and recording behavioral patterns. Other useful information to record includes time and location of food consumption, the presence or absence of other people, and mood. Clinicians can provide feedback about how patients may improve their eating habits.

Stress management involves teaching patients to identify stressful situations and to develop strategies to manage stress that do not involve eating (eg, going for a walk, meditating, deep breathing).

Contingency management involves providing tangible rewards for positive behaviors (eg, for increasing time spent walking or reducing consumption of certain foods). Rewards may be given by other people (eg, from members of a support group or a health care practitioner) or by the person (eg, purchase of new clothing or tickets to a concert). Verbal rewards (praise) may also be useful.

Problem solving involves identifying and planning ahead for situations that increase the risk of unhealthy eating (eg, travelling, going out to dinner) or that reduce the opportunity for physical activity (eg, driving across country).

Stimulus control involves identifying obstacles to healthy eating and an active lifestyle and developing strategies to overcome them. For example, people may avoid going by a fast food restaurant or not keep sweets in the house. For a more active lifestyle, they may take up an active hobby (eg, gardening), enroll in scheduled group activities (eg, exercise classes, sports teams), walk more, make a habit of taking the stairs instead of elevators, and park at the far end of parking lots (resulting in a longer walk).

Technology-based resources such as applications for mobile devices, and other technological devices may also help with adherence to lifestyle changes and weight loss. Applications can help patients set a weight-loss goal, monitor their progress, track food consumption, and record physical activity.

Pharmacotherapy to treat obesity should be considered for people with a BMI of > 27 kg/m2 plus comorbidities or 30 kg/m2 without comorbidities (4). Before prescribing medications, clinicians must identify comorbidities that may be affected by medications (eg. diabetes, seizure disorders, opioid use disorder), and concomitant medications that may promote weight gain.

Most anti-obesity medications are in one of the following classes:

• glucagon-like peptide 1 [GLP-1] agonists)

Weight loss, effects on comorbidities, and adverse effect profiles differ widely among medications.

Patients must be warned that stopping long-term anti-obesity medications may result in weight regain.

Specific medications include:

inhibits pancreatic lipase, decreasing intestinal absorption of fat and improving blood glucose and lipids. Because orlistatorlistat difficult to tolerate. Orlistat is available over-the-counter.

The combination of (used to treat seizure disorders and migraines) is approved for long-term use. This combination medication results in weight loss for up to 2 years. Because birth defects are a risk, the combination should be given to women of reproductive age only if they are using contraception and are tested monthly for pregnancy. Other potential adverse effects include sleep problems, cognitive impairment, and increased heart rate. Long-term cardiovascular effects are unknown, and postmarketing studies are ongoing (5).

lorcaserin compared with those taking placebo. The most common adverse effects in patients without diabetes are headache, nausea, dizziness, fatigue, dry mouth, and constipation; these effects are usually self-limited. Lorcaserinserotonin syndrome is a risk. Lorcaserin was withdrawn from the United States market after an increased cancer risk was identified in a postmarketing trial (6).

bupropion include nausea, vomiting, headache, and mild increases in systolic and diastolic blood pressure. Contraindications to bupropion include uncontrolled hypertension and a history of or risk factors for seizures because bupropion reduces the seizure threshold.

7insulin release from the pancreas to induce glycemic control; liraglutide also stimulates satiety and reduces food intake. Liraglutide is injected daily, and dose is titrated up over the course of 5 weeks. Adverse effects include nausea and vomiting; liraglutide has warnings that include acute pancreatitis and risk of thyroid C-cell tumors.

insulin release and reduces appetite and energy intake via effects on appetite centers in the hypothalamus. Semaglutide 2.4 mg subcutaneously has resulted in a mean body weight loss of 14.9% at 68 weeks versus 2.4% in patients treated with placebo (8). Patients taking semaglutide also had greater improvements in cardiovascular risk factors as well as patient-reported physical functioning. Like liraglutide, the most common adverse effects of semaglutide include nausea and diarrhea, which are usually transient and mild to moderate in severity. Warnings for semaglutide include thyroid tumors and pancreatitis.

is a novel gastric inhibitory polypeptide (GIP) and GLP-1 agonist used to treat type 2 diabetes. In a phase 3 trial, it resulted in substantial and sustained reductions in body weight in patients who did not have diabetes. Improvements in cardiometabolic disease were also observed. It can cause pancreatitis, hypoglycemia, and C-cell tumors of the thyroid and is contraindicated in patients with multiple endocrine neoplasia syndrome type 2 (9).

All GLP-1 agonists are associated with adverse effects such as nausea, vomiting, and delayed gastric emptying, which can increase the risk of aspiration. The American Society of Anesthesiologists Task Force on Preoperative Fasting recommends holding daily-dosed GLP-1 agonists the day of surgery and weekly-dosed medications 1 week before surgery (10).

Studies have shown that anti-obesity medications can be safe and effective for weight loss after bariatric surgery if weight is regained. Investigation into the use of anti-obesity medications (eg, GLP-1 receptor agonists) as a bridge t therapy to metabolic and bariatric surgery is ongoing (11).

Anti-obesity medications should be stopped or changed if patients do not have documented weight loss after 12 weeks of treatment.

Bariatric surgery is the most effective treatment for patients with severe obesity.

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5. 5. Jordan J, Astrup A, Engeli S, et alJ Hypertens 32 (6): 1178–1188, 2014. doi: 10.1097/HJH.0000000000000145 Published online 2014 Apr 30.

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Obesity in children is defined as BMI greater than the 95th percentile. For children with obesity, complications are more likely to develop because the duration of the disorder is longer. More than 25% of children and adolescents meet overweight or obesity criteria. (See also Obesity in Adolescents.) Similar to adults, complications related to obesity in children include hypertension, dyslipidemia, diabetes and joint problems.

Overview of Childhood Nutritio...

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Risk factors for obesity in infants are low birth weight (1) and maternal weight, diabetes, and smoking.

After puberty, food intake increases; in boys, the extra calories are used to increase protein deposition, but in girls, fat storage is increased.

For children with obesity, psychologic complications (eg, poor self-esteem, social difficulties, depression) and musculoskeletal complications can develop early. Some musculoskeletal complications, such as slipped capital femoral epiphyses, are specific to children. Other early complications may include obstructive sleep apnea, , hyperlipidemia, and nonalcoholic steatohepatitis. Risk of cardiovascular, respiratory, metabolic, hepatic, and other obesity-related complications increases when these children become adults.

Risk of obesity persisting into adulthood depends partly on when obesity first develops. In a meta-analysis of several large cohort studies, 55% of children with obesity continued to have obesity in adolescence, and 70% continued to have obesity over the age of 30 (2).

Treatment of obesity in children and adolescents involves lifestyle modifications and, for children with severe obesity, metabolic and bariatric surgery.. Participating in physical activities during childhood may promote a lifelong physically active lifestyle. Limiting sedentary activities (eg, watching TV, using the computer or handheld devices) can also help. Medications and surgery are avoided but, if complications of obesity are life threatening, may be warranted.

Measures that control weight and prevent obesity in children may have the largest public health benefits. Such measures should be implemented in the family, schools, and primary care. However, lifestyle modifications often do not result in permanent weight loss.

The 2023 updated guidelines from the American Academy of Pediatrics (AAP) recommend that children and adolescents who have severe obesity (defined as BMI ≥ 40 or BMI > 35 with significant health complications related to obesity) should be treated with metabolic and bariatric surgery, and treatment should involve a multidisciplinary team. The major metabolic and bariatric surgical societies have similar recommendations; however, metabolic and bariatric surgery is not often used in children and adolescents. Barriers include stigma against bariatric surgery in this population and lack of available centers and clinicians trained to take care of children and adolescents with obesity (3).

In the United States, the percentage of older people with obesity has been increasing.

With age, body fat increases and is redistributed to the abdomen, and muscle mass is lost, largely because of physical inactivity, but decreased androgens and growth hormone (which are anabolic) and inflammatory cytokines produced in obesity may also play a role.

Risk of complications depends on

• Body fat distribution (increasing with a predominantly abdominal distribution)

• Duration and severity of obesity

• Associated sarcopenia

Increased waist circumference, suggesting abdominal fat distribution, predicts morbidity (eg, hypertension, diabetes mellitus, coronary artery disease) and mortality risk better in older adults than does BMI. With aging, fat tends to accumulate more in the waist.

For older adults, physicians may recommend that caloric intake be reduced and physical activity be increased. However, if older patients wish to substantially reduce their caloric intake, their diet should be supervised by a physician. Physical activity also improves muscle strength, endurance, and overall well-being and reduces the risk of developing chronic disorders such as diabetes. Activity should include strengthening and endurance exercises.

Metabolic and bariatric surgery has historically been used less frequently in older patients. In a large retrospective study comparing outcomes in patients < 65 with those of patients ≥ 65 having sleeve gastrectomy or gastric bypass, complication rates between the groups were similar. Although older patients tended to have higher American Society of Anesthesiologists (ASA) scores and more comorbidities at baseline, morbidity and mortality after surgery did not differ between groups. In the ≥ 65 group, the positive effect of bariatric surgery on weight loss and obesity-related comorbidities was present but less pronounced than in the < 65 group. Overall, the data suggest that age alone should not be considered a contraindication to metabolic and bariatric surgery (4).

1. 1. Jornayvaz FR, Vollenweider P, Bochud M, et al: Low birth weight leads to obesity, diabetes and increased leptin levels in adults: The CoLaus study. Cardiovasc Diabetol 15:73, 2016. doi: 10.1186/s12933-016-0389-2

2. 2. Simmonds M, Llewellyn A, Owen ACG, Woolacott N: Predicting adult obesity from childhood obesity: A systematic review and meta-analysis. Obes Rev 17 (2):95–107, 2016. doi: 10.1111/obr.12334 Epub 2015 Dec 23.

3. 3. Elkhoury D, Elkhoury C, Gorantla VR. Improving access to child and adolescent weight loss surgery: A review of updated National and International Practice Guidelines. Cureus 15 (4):e38117, 2023. doi: 10.7759/cureus.38117

4. 4. Iranmanesh P, Boudreau V, Ramji K, et al: Outcomes of bariatric surgery in elderly patients: A registry-based cohort study with 3-year follow-up. Int J Obes (Lond) 46 (3), 574–580 2022. https://doi.org/10.1038/s41366-021-01031-]]