Obesity and Comorbid Conditions

Function

The central control of hunger and hormonal regulation is critical in maintaining energy balance and regulating food intake. Various regions in the brain mediate hunger and satiety signals, responding to hormonal cues and nutrient availability. Hormones are key factors in this intricate system, signaling hunger or fullness and modulating metabolic processes to maintain equilibrium.

Central Control of Hunger

The primary center for hunger control is located within the hypothalamus, specifically in the arcuate nucleus, also known as the infundibular nucleus. The arcuate nucleus communicates with the brainstem and paraventricular nuclei, which relay pathways to the brainstem and limbic system. Together, they regulate metabolism and the emotional and behavioral changes associated with hunger and satiety.

Hormonal Control

Hormonal control plays a significant role in obesity. Hormones such as leptin, ghrelin, and insulin influence appetite regulation and metabolism. Imbalances in these hormones can lead to increased food intake and reduced energy expenditure, contributing to obesity.

Insulin: This is the primary hormone responsible for maintaining blood sugar homeostasis and regulating obesity.

• Insulin is secreted by the β-cells of the Islets of Langerhans in the pancreas in response to elevated blood sugar levels and other nutrients.

• In addition to its role in blood sugar regulation, insulin directly induces satiety. A study conducted in 1983 demonstrated that injecting insulin into the cerebral ventricles led to satiety. Further research revealed that insulin signaling receptors in the hypothalamus induce satiety and suppress hunger.[3][4][5]

Leptin: Leptin is produced by adipose tissue, and it primarily acts in the hypothalamus to decrease neuropeptide Y and downregulate hunger.

• Increased lipid levels in the blood stimulate the secretion of leptin. However, leptin levels are directly proportional to body adipose tissue.

• While meals trigger leptin secretion, the degree of stimulation is relative to total body adipose tissue. Hence, the suppression of hunger drive is present in individuals with normal or low body weight. However, this effect is less pronounced in individuals who are overweight or experience obesity due to chronically elevated leptin levels and hypothalamic desensitization. This is supported by studies where subjects with normal weight exposed to exogenous leptin experience weight loss—a response not typically observed in patients with obesity.[6][7][8][9]

Ghrelin: This peptide hormone is predominantly produced in the stomach and duodenum. 

• Ghrelin exhibits higher levels in the fasting state and spikes shortly before food ingestion, known as the cephalic response.

• Ghrelin acts within the hypothalamus by stimulating neuropeptide Y, which induces hunger and increases calorie intake. 

• Food ingestion downregulates ghrelin levels, with a more pronounced effect observed when consuming carbohydrates compared to protein and fat.[10]

Glucagon-Like Peptide-1

• Glucagon-like peptide-1 (GLP-1) is a hormone produced by L cells in the small intestine.

• GLP-1 is secreted in response to detecting nutrients in the intestinal lumen and released into the bloodstream.

• Within the hypothalamus, GLP-1 binds to the GLP-1 receptors, downregulating neuropeptide Y and hunger.[11]

Other polypeptides secreted in the gut, such as cholecystokinin (CCK), pancreatic polypeptide, and polypeptide YY, are known to increase satiety, although the mechanisms are not fully understood.

Issues of Concern

Obesity is a systemic issue that, as a result, affects multiple organ systems.

Cardiovascular System

Hypertension: Hypertension in patients with obesity involves complex mechanisms, including a combination of increased sympathetic activity and reduced parasympathetic activity. 

• Activation of the renin-angiotensin-aldosterone system (RAAS) changes the kidney. Certain ethnic groups have relatively low rates of hypertension, which is attributed to relatively decreased sympathetic activity. Furthermore, sympathetic blockade tends to lower blood pressure more effectively in patients with obesity.

• The sympathetic nervous system activates the RAAS system, leading to increased fluid and salt retention, and catecholamines can further enhance sympathetic activity. However, interestingly, adipocytes produce angiotensinogen and angiotensin 2 independently. Animal studies suggest that knockout genes for adipocyte angiotensinogen do not induce hypertension when animals consume obesogenic diets.

• Increased perinephric fat around the kidney can compress it, causing chronic inflammation, reduced blood flow, and enhanced sodium reabsorption in the medulla, thereby increasing salt retention. This sets off a self-perpetuating feedback loop through increased sodium levels, leading to further RAAS activation.[12][13][14][15][16]

Coronary artery disease: The development of coronary artery disease (CAD) is typically associated with diabetes, hypertension, dyslipidemia, and obstructive sleep apnea (OSA), which are known and frequent comorbidities of obesity. Whether obesity directly contributes to CAD is unclear and challenging to study in isolation due to the high prevalence of metabolic and respiratory conditions in patients with obesity. However, for each 5-unit increment of BMI, the risk of CAD increases by 30%.[17][18][19]

Heart failure: Obesity has been directly correlated with congestive heart failure with preserved ejection fraction (HFpEF). Although risk factors for congestive heart failure are prevalent in patients with obesity, the incidence rates are notably higher when risk-stratified for obesity alone.

The development of HFpEF is theorized to result from a combination of mechanisms. These include left ventricular hypertrophy due to increased cardiac output, which reduces myocardial function through lipotoxicity, systemic inflammation, and impaired protein function caused by increased glycosylation and collagen cross-links, ultimately leading to diastolic dysfunction. Additionally, increased epicardial fat and inflammation may further compound these effects.[20][21]

Atrial fibrillation: Atrial fibrillation is the most common cardiac arrhythmia associated with the development of heart failure and thromboembolism, potentially leading to strokes and life-threatening infarctions elsewhere in the body. Atrial fibrillation is prevalent in patients with obesity, as evidenced by the Framingham Heart Study, which identified a 5% increase in the risk of developing atrial fibrillation for each unit increase in BMI, particularly more than 30 kg/m².

The association between atrial fibrillation and obesity is hypothesized to result from the increase in cardiac output, leading to elevated pressures on the left side of the heart, particularly affecting the left atrium. This effect may be further exacerbated by diastolic dysfunction.[22][23][24]

Stroke: An increased risk of stroke exists with increasing BMI, including early-onset ischemic stroke. This correlation is further supported by a national survey study that identified patients with metabolically healthy obesity, who also face an increased risk, although less than those with metabolically unhealthy obesity and healthy individuals. The survey suggests that obesity independently serves as a risk factor for stroke development.[25][26]

Venous thromboembolism: Patients with obesity have reduced mobility, which increases the risk of venous thromboembolism (VTE). Increased abdominal pressure in obesity results in additional pressure on the iliac veins, leading to compression, reduced flow, and predisposition to chronic venous insufficiency. Obesity also contributes to a hypercoagulable state mediated by adipokines, which causes chronic inflammation and impaired fibrinolysis, leading to endothelial dysfunction and platelet activation. The risk of VTE in patients with obesity is up to 6 times higher than in those with normal BMI, with elevated rates of both deep vein thrombosis and pulmonary embolism.[27][28][29][30]

Respiratory System

Obstructive sleep apnea: OSA involves complete airway obstruction during sleep despite normal breathing efforts. This has widespread effects on the body, particularly negative cardiovascular and metabolic effects, likely mediated by systemic inflammation. These effects contribute to insulin resistance, dyslipidemia, hypertension, and CAD, with OSA independently increasing the risk for CAD.

As a recurring theme in obesity-related conditions, the cardiometabolic effects compound and significantly increase the risk of further negative consequences.[31]

Obesity hypoventilation syndrome: This condition is alternatively referred to as Pickwickian syndrome and is defined by 3 criteria in the absence of other causes—obesity, daytime hypercapnia, and sleep-disordered breathing.

• The development of obesity hypoventilation syndrome is complex but can be attributed to sleep-disordered breathing, which is often a manifestation of OSA, along with altered lung function and ventilatory control.

• During apneic periods, carbon dioxide accumulates, triggering an increased ventilatory response to clear the excess carbon dioxide. However, this regulatory mechanism is not observed in patients with obesity hypoventilation syndrome. The gradual buildup of carbon dioxide and adaptation by the body, such as increased bicarbonate retention by the kidneys and reduced central sensitivity to carbon dioxide for increasing ventilatory drive, leads to retention and results in daytime hypercapnia.

• Coupled with reduced respiratory muscle strength, increased abdominal splinting, and less effective breathing patterns in obesity, a significant ventilation/perfusion (V/Q) mismatch occurs.[32][33]

Endocrine System

Type 2 diabetes: Type 2 diabetes is a well-established association and complication of obesity, with around 80% of patients with type 2 diabetes being obese.

• The primary mechanism leading to the development of type 2 diabetes in patients with obesity is insulin resistance. Adipose tissue releases non-esterified fatty acids (NEFAs), which result in endothelial dysfunction, obesity-induced inflammation, and β-cell dysfunction.

• Insulin resistance has been strongly associated with elevated NEFAs. NEFAs are increased more in truncal obesity than in peripheral adipose tissue, suggesting increased lipolytic properties of abdominal-visceral fat.

• To further support the link between obesity and insulin resistance, losing just 5% of body weight during weight loss improves β-cell function and insulin sensitivity, with a steady correlation of improvement with increased weight loss.[34][35][36][37][38]

Dyslipidemia: Up to 70% of patients with obesity have comorbid dyslipidemia, seen clinically as elevated low-density lipoproteins (LDL) and reduced levels of high-density lipoproteins (HDL).

The pathophysiology is multifactorial and involves increased consumption and production of lipids and a reduced ability to break down and metabolize triglycerides.[39]

Metabolic syndrome: This constellation of clinical features includes truncal obesity, dyslipidemia, hypertension, and impaired fasting glucose. Up to 30% of patients with obesity are referred to as "metabolically healthy," as they lack these metabolic derangements. However, metabolic syndrome remains a significant risk factor for cardiovascular complications, particularly stroke.[40]

Vitamin D deficiency: Lower concentrations of vitamin D are well-documented in patients with obesity. This is thought to be secondary to vitamin D being fat-soluble and sequestered in the abundant adipose tissue of patients with obesity. However, lower levels of vitamin D have not demonstrated adverse effects on bone health, and vitamin D supplementation has not been shown to improve the metabolic state of obesity. Hence, the role of vitamin D in obesity remains inconclusive despite the well-documented association of low levels in patients with obesity.[41]

Nervous System 

Idiopathic intracranial hypertension: This condition is also referred to as benign intracranial hypertension or pseudotumor cerebri; the mechanism behind its development is unclear.

• As the name suggests, the condition causes symptoms of raised intracranial pressure, typically manifesting as severe headaches, which can be acute, chronic, or acute-on-chronic. Other symptoms include nausea, vomiting, and visual changes such as blurring or double vision.

• Elevated intracranial pressure results in pressure on the optic nerve, which may be seen as papilledema during fundoscopic examination. If the elevated intraocular pressure is sustained, this may result in vision loss. 

• This condition is not solely linked to obesity, as most individuals with obesity are unaffected and may have other risk factors such as the combined contraceptive pill or thyroid disease. However, idiopathic intracranial hypertension disproportionately affects patients with obesity, with 90% of cases occurring in those who are overweight or obese.

• The link is further supported by an increasing correlation with higher BMI, higher rates of induced vision loss, and disease remission in individuals who successfully lost between 6% and 10% of their weight.[42]

Musculoskeletal System

Osteoarthritis: The increased weight on the joints results in greater compressive forces and altered biomechanics.

• The knee is the most commonly affected joint, although the hand is at a higher risk despite not being a weight-bearing joint. This suggests a role for systemic inflammation in disease development. 

• Osteoarthritis can promote a vicious cycle, leading to a sedentary lifestyle that further contributes to weight gain.

• Surgical management is associated with an increased risk for complications, including prolonged hospital stays, infection, and the necessity for further surgery.

• Obesity-associated osteoarthritis has a significant economic burden, costing an estimated 89 billion USD per year. Moreover, significant indirect costs accrue from lost workdays and reduced productivity, which some have estimated to be roughly 4000 USD lost per person per year.[43][44]

Patients with obesity are more prone to experiencing falls and fractures in both children and adults. Additionally, conditions such as slipped upper femoral epiphyses and genu varus and valgus are more common among children with obesity.[45][46][47]

Gastrointestinal Tract

Nonalcoholic fatty liver disease: Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in both the United States and the United Kingdom, affecting approximately 30% of the population.

NAFLD is estimated to be the leading cause of liver transplantation by 2030 in the United States. The mechanisms underlying its development remain poorly understood but are closely linked to metabolic features associated with obesity. Please see StatPearls' companion resource, "Nonalcoholic Fatty Liver," for more information.

Gallstones: The positive correlation between increasing BMI and the development of gallstones is well-recognized. The risk increases even within the healthy weight range, indicating a strong link between weight gain and gallstones.

Gastroesophageal reflux disease: GERD is attributed to patients with obesity with nonspecific motility disorders within the esophagus, reduced lower esophageal tone, increased prevalence of hiatal hernias, and increased intra-abdominal pressures. As a result of acid reflux, patients with obesity are more likely to experience erosions, strictures, and pre-cancerous transformations, such as Barrett esophagus, as well as esophageal adenocarcinoma. Please see StatPearls' companion resource, "Gastroesophageal Reflux Disease (GERD)," for more information.[48][49]

Urinary Tract

The development of chronic kidney disease (CKD) is observed in patients with obesity, although the mechanism and risk factors are contentious. Prior studies have found conflicting evidence regarding the causal association between obesity and CKD. Systemic inflammation, increased oxidation, insulin resistance, and activation of the RAAS are proposed as potential mechanisms for developing CKD in obesity.[50][51]

Reproductive System

Due to peripheral aromatization of estrogens, increased androgens by insulin resistance, and decreased levels of sex-binding globulins, obesity leads to alterations in the hypothalamus-pituitary-ovarian axis. This results in potential disruptions to the female reproductive system, manifesting clinically as:

• Irregular menstrual cycles
• Ovulatory dysfunction and infertility
• Increased risk of miscarriage
• Endometrial hyperplasia and malignancy [52] 

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, irregular periods, and polycystic ovaries. PCOS can present many of the aforementioned reproductive physiological changes. The condition shares many features with obesity, affecting up to 88% of PCOS patients. The genetic predisposition for PCOS, through insulin resistance and increased steroid production, contributes to weight gain, with obesity as an independent risk factor. Urinary incontinence, especially stress incontinence, correlates strongly with increasing BMI, and weight loss proves effective as a treatment option.[53][54]

Obesity is also associated with sexual dysfunction in both women and men. Women with obesity often experience higher sexual dysfunction scores, which can significantly improve with weight loss interventions such as bariatric surgery. In men, obesity is an independent risk factor for developing erectile dysfunction, with 80% of those experiencing erectile issues having a BMI of 25 or greater.[55][56]

Psychiatric Disorders

The incidence of depression is higher in patients with obesity, especially among young women. Additionally, an association between obesity and dementia has been observed; however, the mechanism remains poorly understood, and whether obesity constitutes an independent risk factor for dementia is uncertain.[57][58][59][60]

Integumentary System

Obesity affects the skin in several ways by reducing skin hydration, decreasing collagen deposition relative to skin surface area, increasing sebum and sweat production, and altering circulation and lymphatics. Moreover, obesity increases the risk of infections, delays wound healing, and promotes the development of pressure sores. Additionally, elevated androgens and insulin resistance contribute to conditions such as hirsutism and acanthosis nigricans.[61]

Infections

Obesity is associated with higher rates of bacterial infections, post-surgical infections, and increased mortality from flu and COVID-19. Patients with obesity often require higher than typical doses of medications, which can lead to adverse outcomes. Notably, COVID-19 shows delayed viral shedding in individuals with obesity, although the rationale for extending the self-isolation period for these patients remains unclear.[62][63][64]

Neoplasm

The positive association between cancer and obesity is well-recognized. Proposed mechanisms include:

• Elevated growth factors and sex hormones.
• Adipocytokines such as leptin, adiponectin, and visfatin promote positive growth function and downregulate immunity and tumor regulation.
• Systemic inflammation.
• Altered gut microbiome.[65]

The risk of cancer is higher among women with obesity compared to men, and obesity increases the likelihood of cancer-related mortality. In the United States, obesity is attributed to 14% to 20% of cancer-related deaths in men and women, respectively.

Several well-associated cancers include:

• Esophageal adenocarcinoma
• Gastric cancer, particularly of the cardia
• Colorectal cancer
• Hepatocellular carcinoma
• Cholangiocarcinoma
• Pancreatic cancer
• Endometrial carcinoma
• Ovarian cancer
• Breast cancer
• Renal cell carcinoma
• Multiple myeloma [66][67][68][69][70]

Clinical Significance

Obesity is a prevalent comorbidity in medicine, posing a significant risk during hospital admissions, particularly for VTE. Therefore, an assessment is necessary, which typically involves administering anticoagulation injections and using anti-thromboembolic stockings. Another frequent issue is post-surgical wound infections, for which negative pressure wound dressings and stringent infection control during surgery are recommended.[71]

Other Issues

The probable association between obesity and depression has been extensively studied in scientific literature. Both conditions exhibit high prevalence rates and an increased risk of cardiovascular disease. While numerous cross-sectional studies have documented this relationship, its exact significance remains unclear.[72] Prospective studies have revealed inconsistent findings regarding the sequence in the onset of depression and obesity.[73] This discrepancy could be due to the methodological differences among studies, including variations in sample selection, follow-up duration, and/or the evaluation and diagnosis of depression and obesity.

The association between obesity and depression has also been examined in childhood and adolescence. A prospective study found that adolescent girls with obesity were up to 4 times more likely to develop major depression.[74] However, this risk was not significant for men. A meta-analysis of 8 longitudinal studies concluded that there is a bidirectional relationship between depression and obesity.[75] Thus, people with obesity had a 55% increased risk of developing depression over time, and individuals with depression had a 58% increased risk of obesity. Moreover, the relationship between obesity and depression showed a dose-response gradient, indicating a stronger association with higher levels of obesity.

Enhancing Healthcare Team Outcomes

Given the significant comorbidities associated with obesity, an emphasis on prevention is necessary to decrease the associated risks. While diet modification is straightforward, promoting weight loss through a comprehensive approach, including low-calorie diet plans, exercise regimens, and cognitive-behavioral therapy in psychotherapy, proves significantly more effective. An interprofessional healthcare team is optimal for supporting patients through pharmacological, surgical, dietary, and psychological interventions. Each specialty contributes evidence-based practices to develop personalized and effective weight loss programs. 

The ideal members of the interprofessional healthcare team include: 

• Primary care physician with expertise in obesity management
• Bariatric surgeon
• Specialist nurse
• Dietician
• Behavioral health professional
• Exercise physiologist [76][77]

Nursing, Allied Health, and Interprofessional Team Interventions

Obesity and its associated comorbidities present a significant health challenge. Nursing, allied health professionals, and interprofessional healthcare teams are crucial in addressing these issues. Below are key interventions they might undertake.

• Patient education and counseling: Nurses and allied health professionals can educate patients about the risks of obesity and associated comorbidities. This includes providing information on healthy eating, physical activity, and lifestyle modifications. Counseling helps patients set realistic goals and develop strategies for behavior change.

• Nutritional counseling: Registered dietitians and nutritionists collaborate with patients to create personalized meal plans to promote weight loss and manage comorbid conditions such as diabetes, hypertension, and hyperlipidemia. They provide guidance on portion control, reading food labels, and making healthy food choices.

• Exercise prescription and physical therapy: Allied health professionals, such as physiotherapists and exercise physiologists, specialize in designing exercise programs customized to the specific needs and abilities of patients with obesity and comorbidities. These programs typically incorporate aerobic exercises, strength training, and flexibility exercises to enhance overall fitness levels.

• Behavioral therapy: Psychologists and behavioral therapists play a crucial role in helping patients address psychological and emotional factors contributing to obesity, such as stress eating, emotional eating, and poor body image. They use cognitive behavioral therapy techniques to modify unhealthy thought patterns and behaviors related to food and exercise.

• Medication management: Nurses and advanced practice clinicians can assist in medication management for patients with obesity and the associated comorbidities. This may involve prescribing or adjusting medications for conditions such as diabetes, hypertension, dyslipidemia, and obesity (eg, weight loss medications).

• Interdisciplinary team collaboration: Interprofessional teams comprising physicians, nurses, dietitians, physical therapists, psychologists, and other allied health professionals collaborate to develop comprehensive care plans for patients with obesity and comorbidities. Frequent team meetings facilitate continuous assessment, care coordination, and the development of effective treatment strategies.

• Monitoring and follow-up: Healthcare professionals are crucial in monitoring patients' progress, including weight loss, improvements in comorbid conditions, and adherence to treatment plans. Follow-up appointments are essential for gathering patient feedback and evaluating clinical outcomes.

By implementing these interventions, nursing, allied health professionals, and interprofessional teams can effectively treat patients with obesity and associated comorbidities, thereby enhancing patients' health outcomes and quality of life.

Nursing, Allied Health, and Interprofessional Team Monitoring

Naturopathy in Obesity Management

Naturopathy, a form of complementary and alternative medicine, provides holistic approaches to managing obesity, often incorporating dietary supplements. Notably, it is crucial to approach all treatments, including naturopathic interventions, with caution and consideration.

Herbal supplements: Herbal supplements offer a natural approach to weight management, utilizing various plant-derived compounds with purported benefits, as mentioned below.

• Green tea extract: Green tea extract is derived from green tea leaves that are rich in catechins. Catechins are compounds known for their antioxidant properties, which may aid in weight management by boosting metabolism and promoting fat oxidation.

• Garcinia cambogia: Garcinia cambogia is extracted from a tropical fruit, which is reputed to suppress appetite and potentially inhibit fat production, although research findings are inconclusive.

• Forskolin: Forskolin is an herb from the mint family and is believed to increase the production of cyclic adenosine monophosphate, which may aid in fat breakdown and promote weight loss.

Fiber supplements: Fiber supplements that help in weight management are listed below. 

• Psyllium husk: Psyllium is a soluble fiber that can promote feelings of fullness, regulate bowel movements, and support healthy digestion, which may aid in weight management.

• Glucomannan: Glucomannan is a soluble fiber derived from the konjac root. This absorbs water in the digestive tract, creating a feeling of fullness and reducing calorie intake.

Probiotics: Probiotics are increasingly studied for their potential role in weight management.

• Certain strains of probiotics may help regulate gut microbiota composition, which could influence metabolic processes and inflammation related to obesity.

• Lactobacillus gasseri and L rhamnosus are among the strains studied for their potential benefits in weight management.

Mineral and vitamin supplements: Certain supplements, such as vitamin D and magnesium, aid in weight loss.

• Vitamin D: Low vitamin D levels have been associated with obesity, and supplementation may help improve insulin sensitivity and support weight loss.

• Magnesium: Magnesium deficiency has been linked to metabolic dysfunction, and supplementation may help improve insulin sensitivity and support weight management.

Omega-3 fatty acids: Fish oil supplements, rich in omega-3 fatty acids, may have anti-inflammatory effects, aid in weight loss, and reduce obesity-related complications.