Epidemiologic and Etiologic Considerations of Obesity

Issues of Concern

Historically, malnourishment was considered the most pressing medical problem in society. Fortunately, social programs, charitable organizations, improved technology, and increased availability of prepackaged foods in resource-rich societies have made nutrition readily accessible. Notwithstanding, the relative improvement of availability has ushered in a fundamental shift in population health, replacing caloric deficit with caloric excess.[12] Currently, increased body mass index, expanding waistlines, and an increasing prevalence of comorbid chronic medical conditions led by obesity are observed. Obesity is considered a multifactorial, progressive, and chronic systemic medical problem that can often be complex and relatively difficult to treat.

From a clinical perspective, patients know their need to lose weight and have likely been told by previous clinicians to "take charge" of their weight loss. Unfortunately, few nonsurgical strategies have been established to ensure successful and sustainable weight loss. Emerging research has reinforced that the simplest way to ensure successful weight loss over the long term is a graded caloric restriction strategy and physical exercise deployed over several months using monitored compliance, as fundamentally, humans are "creatures of habit." Therefore, breaking the reward-feedback loop associated with eating is paramount to controlling dietary habits.[13] Achieving this control requires understanding the complex behavioral elements of obesity. Clinicians must first begin at the molecular level by discussing how food becomes storable energy and how storable energy in excess becomes fat.

Molecular and Physiological Processes Associated With Fat Storage and Energy Utilization

Food consumption must undergo a rigorous and elaborate digestion process to break down into nutrients used for essential bodily functions. At its core, the fundamental building blocks for all cells in our body rely on fats, carbohydrates, and proteins, which we collectively call macronutrients (ie, macros). Simplistically, digestion has 3 phases: the cephalic, gastric, and intestinal. These phases have complex stimulatory/activating and inhibitory hormones that work together to achieve proper food degradation.

In the cephalic phase, sight, smell, and the mere thought of food activate an innate biological reflex. The oral cavity is the location for food's mechanical and early enzymatic breakdown. The cephalic phase activates salivary glands to produce saliva, which contains lingual lipase and amylase, beginning the process of digestion. This reflex response is triggered by the cerebral cortex acting on the hypothalamus and medulla oblongata, sending signals to the vagus nerve to stimulate gastric juices. This signaling action will activate and prime the gastrointestinal tract in preparation for the meal. The gastric phase begins upon entry of masticated food into the stomach.

A feedback loop is activated when stretch receptors within the stomach activate a vasovagal reflex to trigger the vagus nerve, further stimulating gastric secretory activity. The gastric lumen is an intricate set of epithelial cells with specific secretory activity. These cells protect the stomach lining and assist in secreting enzymes to aid digestion. The intestinal phase arrives when partially digested foods mixed with gastric juices enter the small intestine, where the systemic absorption of macronutrients begins.[14][15][16] 

The outlined digestion process breaks down carbohydrates, starting in the mouth and moving to their absorbable form, monosaccharides, in the small intestine. Fats become reduced to fatty acid chains and monoglycerides by bile salts secreted from the liver and lipase from the pancreas. Finally, protein is broken down into amino acids by pepsin released from the stomach and various other protein-degrading enzymes released from the pancreas.[17]

The fate of monosaccharides, fatty acids, and amino acids depends on the person's energy requirements; if an individual is in the fed state, the metabolic pathway shifts towards energy storage. Conversely, the metabolic pathway shifts towards oxidizing macronutrients for immediate energy consumption if fasting. Through differing metabolic pathways, monosaccharides, fatty acids, and amino acids can produce acetyl-coenzyme A, which can enter the Kreb cycle and eventually generate energy through oxidative phosphorylation via the electron transport chain of adenosine triphosphate.

Glycogen, primarily stored in the liver, can readily raise serum glucose through glycogenolysis. However, glycogen stores are depleted within 12 to 18 hours while fasting. Due to this limitation, the liver possesses the tools to convert noncarbohydrate precursors into glucose, which is called gluconeogenesis. This process can occur in the liver or renal cortex and can use precursors, eg, glycerol from fatty acids, lactate from anaerobic metabolism, and glutamine/alanine.[18] 

The entire process outlined above works through a delicate balance of hormone regulation. Leptin is a hormone stored in fat cells, and ghrelin is stored in the enteroendocrine cells of the gastrointestinal tract. Leptin suppresses food intake and is considered anorexigenic. Ghrelin stimulates the hunger reflex centrally at the level of the hypothalamus and is deemed to be orexigenic. Ghrelin is believed to be the primary hormone responsible for ushering in the cephalic phase of digestion.

However, existing research has only begun to understand the complex role of these hormones in obesity. For example, subjects with obesity tend to have elevated leptin levels and reduced levels of ghrelin, which is paradoxical to our understanding of the function of these 2 hormones. However, similar to type 2 diabetes and insulin, it is postulated that patients with obesity are leptin-resistant, but the precise mechanism of obesity induction is yet to be fully elucidated.[19] An intricate understanding of the above molecular and physiological responses is essential to treat this chronic disease properly.

Genetic Factors of Obesity

The induction of obesity is multifactorial, drawing from genetic, environmental, behavioral, physiological, social, and cultural factors. The possibility of hereditary variables in persons with obesity has been shown by studies comparing adiposity in twins, adoptees, and their parents (biological versus adoptive) and within families. Study results imply that 40% to 70% of an adult's body mass index (BMI) is inherited.[5][20] Adolescents with 1 obese parent have a 3- to 4-fold higher chance of becoming obese.[21] The risk of obesity is more than 10 times higher if you have 2 obese biological parents. Unfortunately, even with the extensive composite data of obesity-related gene loci, clinical testing based solely on variations in gene loci currently cannot accurately predict obesity using genes alone.[5]

The single nucleotide polymorphisms in the fat mass and obesity-associated FTO gene located on chromosome 16 contribute to the development of diabetes indirectly.[20] In another specific condition, genomic imprinting can produce de novo deletions in paternally derived 15q11-q13, a condition known as Prader-Willi syndrome. In addition to a characteristic physical appearance, patients with Prader-Willi syndrome have hyperphagia, which can lead to chronic energy intake/expenditure.[22] 

Another gene commonly implicated in monogenic childhood obesity is MC4R, which encodes the melanocortin-4 receptor. The MC4R gene is associated with hyperinsulinemia and increased weight gain in infancy.[23] Leptin, leptin receptor deficiencies, and proopiomelanocortin deficiency are the other genetic causes of obesity. Monogenetic obesity is often severe, manifests at a young age, and is frequently accompanied by other symptoms. 

Socioeconomic and Environmental Factors of Obesity

Epidemiological data has analyzed various geographical factors that may contribute to obesity. Social and cultural factors profoundly influence patients' dietary habits and behaviors. As a result, patients can often have an unhealthy understanding of a proper dietary regimen. 

Obesity prevalence is lowest among individuals with the highest income and education, irrespective of race and ethnicity. In urban locations throughout the United States, a diet built entirely on fast and prepackaged foods is not uncommon (see Image. Prevalence of Self-Reported Obesity). Much of the discrepancy can be due to the patient's lack of awareness of what foods contribute to chronic obesity.[24][25] 

In addition, healthy food options are often cost-prohibitive in urban locations. Due to recent global events, the cost of groceries has markedly increased, worsening this disparity in healthy food availability. Low- and middle-income families frequently turn to less costly, calorie-dense, and nutrient-poor options to make ends meet during difficult financial times. In combination with increased stress, socioeconomic factors will play a pivotal role in likely worsening the obesity pandemic across the globe. The worsening of obesity will exacerbate the high rate of chronic, obesity-related conditions, increasing the burden on our already stressed healthcare system. 

Advertising that promotes obesity-inducing foods targets specific racial and socioeconomic groups differently. An isolated example of this effect was observed with outdoor food and beverage advertisement density in Sacramento, Los Angeles, New Orleans, Philadelphia, Austin, and New York. Geographical areas with low-income Black and Latino populations were found to have a higher density of unhealthy food and beverage advertisements, placing those populations at a significant risk for developing obesity.[26][27][28][29] 

Another factor leading to the higher prevalence of obesity is the high cost of healthy food items. Thus, the prevalence of obesity differs across communities in the United States; Black adults had the greatest prevalence (50%) of obesity, and non-Hispanic Asian adults (17%) had the lowest prevalence.[30] This is probably tied to the social determinants of health, such as access to exercise, a wholesome diet, and general health information. 

Obesity hypoventilation syndrome (Pickwickian syndrome) results from diminished ventilatory drive and capacity related to obesity. This syndrome is defined as the presence of awake alveolar hypoventilation characterized by daytime hypercapnia (arterial carbon dioxide pressure level >45 mm Hg). The prevalence of obesity hypoventilation syndrome is largely unknown, but based on results from previous studies, it is estimated to be between 20% and 30% of patients who are obese.[31] Please see StatPearls' companion reference, "Obesity Hypoventilation Syndrome," for further discussion of this process.

Prenatal and Childhood Factors 

Childhood and infancy experiences may predispose patients to adult obesity. High maternal body mass index, high gestational weight gain, gestational diabetes, and maternal type 2 diabetes may all predispose to adult obesity and metabolic disorders in offspring. By modifying gene expression, maternal obesity may influence the brain regions involved in body weight regulation.[32] 

These epigenetic modifications, which may result from an increase in maternal nutrition supply to the developing fetus, promote increased hunger and fat accumulation in children. Children with obesity are 5 times more likely to be obese in adulthood.[33] This lends credibility to starting obesity-related prevention strategies earlier to reduce obesity prevalence in adulthood.

Another area for improvement is by adding healthier school lunch options. Results from a study using nonlinear regression models found that children who attended public schools had a higher BMI regardless of socioeconomic status. Furthermore, those children eligible for free or reduced-cost lunch and breakfast had a higher BMI.[34] Even though additional data is required to determine the impact of limiting the availability of nutrient-poor or high-sugar goods in schools on obesity, some study results have shown a net-positive result.[35][36][37]

Weight and Adulthood Factors of Obesity

Between the ages of 20 and 65, most adults acquire weight steadily. Therefore, the probability of becoming overweight (BMI 25 kg/m²) or obese (BMI 30 kg/m²) during one's lifetime is substantial. The energy imbalance responsible for the rise in obesity over the previous 30 years is estimated to be 100 kcal/day, illustrating that even a small daily positive energy balance may lead to clinically considerable weight gain over time. Weight rises until age 65. After that, the average weight loss is 0.65 kg/year.[38][39] This loss partly results from a loss in muscle mass (sarcopenia), whereas fat mass increases throughout old age, resulting in a reduced correlation between BMI and fat mass.[40] Aging reduces resting and active energy expenditure and may also affect taste and smell, thus reducing food intake.

Dietary Factors of Obesity

Over the last 70 years, a major shift in the global food environment has occurred, with more people having access to processed, high-calorie foods. The United States Department of Agriculture (USDA) statistics on dietary energy supply show that the average daily calorie consumption has risen from 2398 kcal/day/person in the 1970s to 2895 kcal/day/person in the 2000s. This increase in caloric consumption alone can explain the rise in obesity rates seen over this period. 

Additionally, the USDA statistics show that Americans consume less fruit, vegetables, and dairy than is advised while consuming more fat, sugar, meats, and grains. The "Western diet" is a colloquial term used to describe a diet high in processed foods, such as refined sugars and red meats, which may be excessively salty and sugary. This diet has been adopted primarily in the United States but has recently begun spreading into parts of Europe and Asia. In general, this diet type is associated with chronic inflammatory states, which are precursors to several chronic diseases such as diabetes, atherosclerosis, and chronic kidney disease.[41] Eaton et al described a "discordance hypothesis" that postulates that the Western diet is the primary driver of increasing BMIs due to a mismatch between calories consumed and burned.[42] Hunter-gatherers in our primitive human species would expend tremendous calories hunting, transporting, and preparing food. However, in our society, very little energy is expended procuring high-calorie foods, contributing to our natural tendency to store adipose tissue.

Physical Activity Factors of Obesity

Physical activity accounts for the greatest variation in total energy expenditure. Reduced regular physical activity and increased sedentary behavior have been linked to an increased risk of obesity.[43] The Amish community, with a low obesity rate, walks 14,000 to 18,000 steps per day, while the average American takes about 5000 to 6000 steps per day.[44] 

Furthermore, occupational and physical activity has decreased in the United States during the last half-century. Half of the American workforce was fairly active in 1960, but by 2010, over 70% were either sedentary or reported little physical activity. This decreased work-related energy expenditure by 140 kcal/day for men and 120 kcal/day for women, further explaining the increasing prevalence of obesity. Adults with physical or mental disabilities are more likely to be obese; those with reduced lower-extremity mobility are at the greatest risk.

Sleep Factors of Obesity 

Results from epidemiological studies demonstrate substantial and persistent relationships between reduced nocturnal sleep duration and night shift employment with the development of obesity and other metabolic disorders.[45][46] Night shift employees who spend more time sedentary and less time physically active have increased in numbers recently, resulting in decreased energy expenditure and an increase in the likelihood of obesity. Insufficient sleep also activates brain regions involved with food reward, increasing food consumption, particularly high-fat meals. Thus, adequate sleep and sleep patterns are crucial for lowering adiposity and several other metabolic ailments.

Medical Factors of Obesity

Multiple other comorbid conditions are associated with obesity. Hypothyroidism causes weight gain by reducing basal metabolic rate, thus leading to increased adiposity; however, the weight gain is usually modest and improves with treatment. Further, the increased levels of glucocorticoids in Cushing disease stimulate 11-beta-hydroxysteroid dehydrogenase type 1 in visceral fat and increase its lipogenic capability, leading to adiposity. Cushing disease is characterized by progressive central adiposity involving the trunk and abdomen, fat accumulation on the face and neck, and muscle wasting in the extremities. Cushing syndrome may result from the excess (iatrogenically or an overdose) intake of steroids over a long period.

The use of intensive insulin therapy and home glucose monitoring often manages diabetes. Tight control of blood glucose is critical in preventing the vascular complications of the condition. However, insulin therapy itself is associated with weight gain.[47][48] Some studies have suggested that metformin may result in weight loss in patients with type 2 diabetes. However, there is still little evidence to establish this association.[49]

Hypothalamic obesity is uncommon and may result from damage (eg, tumor, irradiation, surgery, or elevated intracranial pressure) to the ventromedial or paraventricular area of the hypothalamus or the amygdala, which regulates metabolic information about nutrient storage and food availability. Damage to the ventromedial hypothalamus results in hyperphagia and decreased energy expenditure, leading to obesity. Hypothalamic obesity can be associated with additional symptoms, including headache, nausea, or blurring of vision.[50]

Clinical Significance

Chronic obesity reverberates across many different areas of Western society. Since 1970, obesity incidence has nearly doubled in the United States, reflecting more than two-thirds of Americans now being overweight. In 2008, the estimated annual cost of obesity was approximately 147 billion dollars, representing almost 10% of healthcare-related spending.[51] 

In 2021, that number substantially increased to approximately 260.6 billion dollars.[52] We now know that truncal (abdominal) obesity and increased adipose stores are primary risk factors for developing atherosclerosis, which increases morbidity and mortality from cardiovascular complications. An international classification of obesity exists, with an associated likelihood of morbidity (see Table. Classification of Overweight and Obesity Based on Body Mass Index).[53]

Table. Classification of Overweight and Obesity Based on Body Mass Index

Truncal obesity contributes to insulin resistance, the primary pathophysiological mechanism for developing type 2 diabetes. Over a century of research led to the discovery of a cluster of clinical features, coined in 1988 as metabolic syndrome, or dysmetabolic syndrome X, by Dr Gerald Reaven. These features included elevated blood pressure, blood sugar, serum triglycerides, and low-density lipoprotein.[54] 

Although being obese is not necessarily a direct causative factor for developing metabolic syndrome, weight loss can be the most beneficial lifestyle modification a person can make to reduce the risk of complications from metabolic syndrome.[55] The clinical classification of metabolic syndrome is debated, and 5 known professional organizations have published several evidence-based criteria to aid clinicians in arriving at this diagnosis. However, all 5 organizations have included truncal obesity as a potential risk factor.[56][57] Patients with obesity have elevated cytokines, including tumor necrosis factor-α and interleukin 1-β, contributing to metabolic syndrome.[7][58] Chronic obesity is also a risk factor for the development of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease or NAFLD), leading to an increased risk of all-cause mortality.[56][59] 

Understanding the multifactorial implications of obesity is paramount to accurately diagnosing and treating the condition. In evaluating a patient who demonstrates features of obesity, the first step is to determine whether the cause is predominately lifestyle factors or the result of a secondary etiology, such as medication use. Clinicians should determine if the patient is taking a medication known to cause obesity. Certain atypical antipsychotics like olanzapine, quetiapine, and risperidone have been shown to cause a net weight gain, with the most substantial weight gain observed with olanzapine.[60] The anticonvulsant and mood stabilizer gabapentin is associated with a 2.2 kg (approximately 5 lb) weight gain within 2 months. Additionally, clinicians should exercise caution with hypoglycemic agents, particularly in the sulfonylurea class, due to known weight gain associated with tolbutamide (2.8 kg/6 lbs) and glimepiride (2.1 kg/5 lbs). Thiazolidinedione-type hypoglycemic agents have also shown a statistically significant weight gain, particularly pioglitazone (2.6 kg/5.5 lbs).[61] 

According to data from the United States Centers for Disease Control and Prevention, from 2015 to 2018, approximately 13.2% of adults were on some form of antidepressant medication, with women predominately receiving prescriptions within this class (17.7%).[62] However, prescribers should be aware of the antidepressants amitryptiline and mirtazapine, which are associated with a 1.8 kg (4 lbs) and 1.5 kg (3.5 lbs) weight gain, respectively. Furthermore, glucocorticoids are commonly prescribed in clinical practice for their potent anti-inflammatory effects, which can be useful for treating a broad range of acute and chronic conditions. Unfortunately, glucocorticoids' mechanism of action typically leads to an approximate 4% to 8% rise in weight gain.[61][63]

Other Issues

Routine clinic visits often fail to address patients' concerns about weight, diet, and physical activity, which might alter the patient's perspective about these conditions. A brief 3-minute lifestyle interview may offer clinicians an understanding of patients' eating habits, weight-loss motivation, and mental and physical difficulties.[64] By stressing diet and obesity-related lifestyle variables, the clinician may urge patients to follow medical advice and consider obesity a serious but manageable health condition.

Larger food portions are the main contributor to increased energy intake and obesity; thus, nutritionists may educate patients on the proper portion size, information about the calories and glycemic index in different food items, the unique calorie needs per physical effort, and misconceptions surrounding various fad diets through easy strategies and also to prevent feeling hungry, which may lead to binge eating. Comprehensive weight reduction counseling must also include methods for both eating less and eating healthier. Patients who consume more low-fat, whole foods, including fruits, vegetables, legumes, and whole grains, are more likely to consume more nutrients overall. The water content of fresh vegetables is very high, increasing weight and volume to maximize fullness without adding calories. 

Diet and exercise together are the most effective obesity treatments. Physical therapists may urge patients to include nonexercise activity thermogenesis, including standing while using the phone and using stairs instead of elevators, as these activities can account for a 2000 kcal difference per day in active vs inactive adults.[65] Walking can be a simple exercise, and physical therapists can lead patients toward incremental, manageable objectives, such as adding 1 minute to a 10-minute walk, ascending 1 more flight of stairs, or adding 100 steps at a time to a day's total. The physical therapist's role is even more critical for patients with musculoskeletal disorders; the therapist may instruct them in exercises that do not need great physical effort and can be as simple as rolling their legs while seated. Knee issues are most prevalent in obese individuals; hence, therapists are of the utmost significance in increasing physical activity among this patient group.

Numerous mental illnesses may cause weight gain and obesity because eating may be a coping mechanism for depression, despair, stress, and anxiety. Study results have shown that depression, in particular, can lead to unhealthy weight gain due to poor dietary and lifestyle choices, eg, choosing to stay inactive out of a lack of motivation or consuming sweet or salty foods. Psychiatric disorders and obesity may form a vicious cycle, with depression and anxiety leading to weight gain and vice versa.

Enhancing Healthcare Team Outcomes

Effectively managing obesity requires an interprofessional, patient-centered approach that fosters collaboration among advanced clinicians, nurses, pharmacists, dietitians, physical therapists, social workers, and psychologists. Advanced clinicians provide clinical expertise and motivation, while dietitians design nutritional plans and physical therapists guide patients in safe physical activity.

Psychologists address underlying mental health issues, supporting emotional well-being, while social workers help patients access essential resources, such as supplying walkers and wheelchairs, medication assistance, or gym memberships. Nurses maintain regular patient contact through education and follow-ups, ensuring adherence to treatment plans. This team approach improves patient outcomes, safety, and long-term weight management strategies through coordinated care and clear communication.

Nursing, Allied Health, and Interprofessional Team Interventions

The roles of nursing, allied health, and interprofessional healthcare teams are vital to patient-centered care. As highlighted above, the strategies for reversing obesity in patients require routine follow-up and consistent evaluation by healthcare professionals. Once the plan is implemented and approved by the patient's clinician, support staff can perform routine follow-ups, monitor hemoglobin A1c every 3 months, lipid panel every 6 months, and assess patients' barriers to weight loss. Support staff can communicate the results to the patient's clinician to modify the plan and ensure the patient remains on track. 

Patients with chronic obesity can often have an unhealthy relationship with food. Cognitive-behavioral therapy can be a valuable tool for helping patients reconcile feelings that may lead to overeating. Various technological applications exist to assist patients with direct access to a therapist.

Applications that measure daily body weight and count calories are primarily effective because they draw users' attention to lifestyle-related details that influence weight gain and loss. For most, cataloging daily caloric intake can be burdensome and arduous, so it is crucial to consistently follow up with patients during their weight-loss journey. Follow-up is the quintessential element of ensuring adherence to a weight-loss plan. Therefore, it is crucial to set expectations that this will require consistent virtual or in-person meetings to ensure continued compliance when beginning the weight-loss journey. If the patient is unwilling to agree to follow-up, the patient will likely fail and revert to previous poor lifestyle choices.

Nursing, Allied Health, and Interprofessional Team Monitoring

Telehealth can be a valuable strategy for managing new patients to a lifestyle modification regimen. Quick face-to-face meetings with weight reporting can be a helpful tool for patients to benchmark their progress and find new motivation.