Obesity
Obesity is a chronic, multifactorial disease characterized by excessive accumulation of adipose tissue resulting from an imbalance between caloric intake and energy expenditure. The pathogenesis of obesity involves complex interactions among genetic, environmental, behavioral, and metabolic factors. Genetic predisposition interacts with environmental influences such as high-calorie diets, sedentary lifestyles, and psychosocial factors to promote positive energy balance and fat storage. Neuroendocrine mechanisms, including dysregulation of appetite-controlling hormones and signaling pathways in the hypothalamus, contribute to increased food intake and reduced satiety. Insulin resistance, chronic inflammation, and alterations in adipokine secretion further exacerbate metabolic disturbances. Obesity is associated with significant health impacts, including increased risk of type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidemia, certain cancers, obstructive sleep apnea, osteoarthritis, and reduced quality of life. It also imposes substantial psychosocial burdens, healthcare costs, and decreases life expectancy.
Primary obesity, also known as essential obesity, is the most prevalent form and arises from the interplay of genetic, behavioral, and environmental factors without an identifiable secondary cause. It is frequently associated with excessive caloric intake, physical inactivity, and often develops gradually over time. Primary obesity can present in both childhood and adulthood and is influenced by familial trends and lifestyle habits.
Secondary obesity results from identifiable medical conditions or pharmacological treatments that disrupt normal metabolism or energy balance. Common etiologies include endocrine disorders such as Cushing's syndrome, hypothyroidism, polycystic ovary syndrome (PCOS), and hypothalamic injury. Certain medications, including glucocorticoids, antipsychotics, and some antidepressants, can also induce secondary obesity.
Monogenic obesity is a rare form caused by single-gene mutations affecting pathways that regulate hunger, satiety, and energy expenditure. Examples include mutations in the leptin gene, leptin receptor, pro-opiomelanocortin (POMC), or melanocortin 4 receptor (MC4R). Individuals with monogenic obesity often present with severe, early-onset obesity and may have additional endocrine or developmental abnormalities.
Syndromic obesity occurs as part of complex genetic syndromes that include obesity as one of multiple clinical features. Notable examples include Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. These conditions are often associated with neurodevelopmental delays, dysmorphic features, and organ system involvement in addition to obesity.
Childhood obesity refers to excessive adiposity in individuals under 18 years of age. It is particularly concerning due to its association with early onset of comorbidities, persistence into adulthood, and increased risk of severe obesity later in life. Contributing factors include genetic susceptibility, parental influences, dietary patterns, reduced physical activity, and socio-environmental determinants.
Obesity has reached epidemic proportions globally, with the World Health Organization estimating that in 2016, more than 1.9 billion adults were overweight, of whom over 650 million were classified as obese. The prevalence of obesity has nearly tripled since 1975. In the United States, recent data indicate that approximately 42% of adults and 19% of children and adolescents are obese. The burden of obesity displays marked geographic, socioeconomic, and ethnic disparities, with higher rates observed in urbanized and high-income settings, as well as among certain ethnic minorities. The incidence of severe obesity, defined as a body mass index (BMI) ≥40 kg/m², is also rising, particularly among women and younger populations. Obesity significantly contributes to global morbidity and mortality, accounting for an estimated 4 million deaths annually and substantial disability-adjusted life years (DALYs) lost.
The diagnosis of obesity is primarily based on anthropometric measurements, with body mass index (BMI) being the most widely used criterion. BMI is calculated as weight in kilograms divided by height in meters squared (kg/m²). In adults, a BMI of 30 kg/m² or greater is classified as obese, with further subclassification into class I (30.0–34.9 kg/m²), class II (35.0–39.9 kg/m²), and class III (≥40 kg/m²) obesity. In children and adolescents, obesity is defined as a BMI at or above the 95th percentile for age and sex-specific growth charts. Additional assessments include waist circumference, which provides an estimate of central adiposity and associated cardiometabolic risk, with thresholds of >102 cm in men and >88 cm in women indicating increased risk. Comprehensive evaluation also involves detailed medical history, assessment of comorbidities, physical examination, and laboratory investigations to identify secondary causes, metabolic complications, and cardiovascular risk factors. Diagnostic workup may include fasting glucose, lipid profile, liver function tests, thyroid function tests, and, when indicated, hormonal assays or genetic testing. Clinical staging systems, such as the Edmonton Obesity Staging System, may be employed to stratify risk and guide management.
Multiple pharmacological and device-based interventions are available for the management of obesity. Mazdutide is a therapeutic agent indicated for weight management, administered to support significant reductions in body weight. Tirzepatide is used in the treatment of obesity, acting as a dual agonist to facilitate weight loss in affected individuals. Semaglutide is prescribed for chronic weight management, functioning as a glucagon-like peptide-1 receptor agonist to promote satiety and reduce caloric intake. The combination of bupropion and naltrexone is utilized to aid weight loss by modulating central appetite pathways and reward mechanisms. Lorcaserin hydrochloride is indicated for obesity treatment, acting as a selective serotonin 2C receptor agonist to enhance feelings of fullness and decrease food consumption. Phentermine/topiramate is a combination therapy approved for weight management, combining a sympathomimetic agent with an anticonvulsant to suppress appetite and increase energy expenditure. Liraglutide, including its depot formulation, is used in obesity management as a glucagon-like peptide-1 receptor agonist, enhancing satiety and facilitating weight reduction. The implantable gastric stimulator is a device-based intervention designed to modulate gastric motility and neurohormonal signaling, thereby promoting weight loss in selected patients. Orlistat, also known as orlipastat or tetrahydrolipstatin, is a gastrointestinal lipase inhibitor that reduces dietary fat absorption and is indicated for long-term obesity management.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | mazdutide (USAN) | 2259884-03-0 | C210 H322 N46 O67 | 4563.072 |
 | tirzepatide (Rec INN; USAN) | 2023788-19-2 | C225 H348 N48 O68 | 4813.451 |
 | semaglutide (USAN) | 910463-68-2 | C187 H291 N45 O59 | 4113.578 |
| Bupropion/naltrexone | ||||
 | lorcaserin hydrochloride (USAN) | 616202-92-7 (free base); 846589-98-8 | C11 H14 Cl N . Cl H | 232.15 |
| phentermine/topiramate | ||||
 | liraglutide (Rec INN; USAN); liraglutide Depot | 204656-20-2 | C172 H265 N43 O51 | 3751.202 |
| implantable gastric stimulator | ||||
 | orlipastat; orlistat (Rec INN; USAN); tetrahydrolipstatin | 96829-58-2 | C29 H53 N O5 | 495.735 |
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