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Beyond The Scale: Understanding The Complexities of Obesity



Assistant Professor - Wrocław University of Environmental and Life Sciences, Wrocław, Poland

"The intricate interplay of genetic predisposition, environmental factors, and epigenetic modifications fuels the global health crisis of obesity."

Ölçeğin Ötesinde: Obezitenin Karmaşıklığını Anlamak

Definition

Obesity and overweight are two lifestyle illnesses characterized by the excessive or abnormal deposition of body fat to a degree that can adversely affect health, as a direct consequence of energy imbalance between calorie intake and expenditure [1]
According to the World Health Organization (WHO), the International Diabetes Federation (IDF), and the American Heart Association (AHA) guidelines, overweight is diagnosed in adults at a Body Mass Index [BMI (kg/m2), ratio between body weight and the height square] comprised between 25.0-29.9, while obesity is defined with a BMI greater than or equal to 30 [2].  Furthermore, obesity is categorized into three levels of severity: Class I (Moderate), characterized by a BMI of 30.0 to 34.9; Class II (Severe), with a BMI ranging from 35.0 to 39.9; and Class III (Very Severe or Morbid), where the BMI is equal to or exceeds 40 [3].
 
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Epidemiology

Obesity has become a global health concern with increasing prevalence (frequency) worldwide and constitutes nowadays a real medical burden. National and international surveys regularly assess the frequency of obesity in different populations and show that the global frequency of obesity has risen significantly over the past few decades. Both developed and developing countries, have encountered a dramatic escalation of obesity rates. This trend is associated with various factors including among others changes in lifestyle, inappropriate dietary regimens, and reduced physical activity [4].
The latest World Obesity Atlas report showcased a world frequency of 38% for either overweight or obese in 2023, with a BMI exceeding 25 kg/m2. Moreover, alarming projections for 2035 anticipate a significant increase in obesity global frequency up to 51%, with the South Pacific Islands at the forefront of the obesity surge. Notably, by 2030, an estimated 78% of adults in the United States are expected to be overweight or obese. American populations have been exposed to an increase in the obesity rate of up to 78% by 2023 [5]. 
In Europe, a critical increase in obesity frequency within the next 10 years is expected, while in 2022, according to WHO, nearly 23% of the adult European population fell in moderate to severe obesity

Physiopathology

Obesity is regarded as a mild or low-grade chronic inflammation of fat tissue, which progressively develops over excessive caloric nutrient intake, leading to hormonal and immune system failures. Thus, the mechanisms by which obesity develops encompass complex interactions between various genetic, environmental, metabolic, behavioral, and hormonal factors as detailed below: 
3.1. Energy imbalance
The principal obesity-initiating factor is related to an energetic imbalance. Excessive calorie intake coupled with a sedentary lifestyle and reduced physical activity that limits energy expenditure, promotes the accumulation of fats and an abnormal expansion of subcutaneous and visceral adipose tissue [7].
3.2. Genetic factors
Genetic predisposition plays a pivotal role in the susceptibility to obesity, however, does not solely contribute to the disease onset and progression but is generally a co-factor associated with other risk factors. Certain genetic variations and epigenetic alterations can modify the function of normal metabolic machinery, lipids (fats) turnover and storage rates, and dysregulate the appetite-satiety rhythm [2].
3.3. Environmental factors
The global modernization and improvement of the socioeconomic condition in most developed and developing countries have substantially contributed to the sustained rise in obesity frequency over the past few years. The easy access to high-calorie processed foods, sedentary lifestyles, and reduced physical activity are at the core of the obesogenic (causing obesity) environment that favours the switch to larger body size within affected populations [8].
3.4. Hormonal regulation
Hormones play an important and entire role in the regulation of appetite, metabolism, and fat storage. Several key hormones such as leptin, ghrelin, resistin, visfatin, and adiponectin are released by the adipose tissue and exert a tight control on energy balance via various mechanisms. Numerous researches have thus demonstrated that hormonal imbalances strongly contribute to excessive weight gain and the progression towards an obese phenotype. Resistin is for example an insulin-antagonizing hormone, which triggers tissues desensitization to insulin and excessive fat storage when secreted in large amounts. Changes in the leptin/adiponectin ratio have similarly been correlated with adipose tissue malfunction and the development of its characteristic chronic inflammatory state [9].   
3.5. Fat inflammation
Adipose tissue is no longer regarded as a storage depot for excess energy but is considered as an active endocrine organ that regulates many metabolic processes. Under immoderate nutrition and energy overload, adipose tissue undergoes critical molecular changes and switches to a pro-inflammatory phenotype. Enlarged and compromised adipocytes release a plethora of pro-inflammatory cytokines, which promote insulin resistance and metabolic homeostasis disruption [10].
3.6. Insulin resistance
Obesity is often associated with insulin resistance, where cells become less responsive to the effects of insulin. Despite fluctuations in blood glucose levels governing insulin secretion rates, circulating free fatty acids have similarly been demonstrated to elicit insulin discharge from pancreatic β-cell. Anomalous lipolysis within adipose tissue induces sustained dyslipidaemia (abnormal lipid (fat) levels in the blood) that promotes the excessive release of insulin into the bloodstream. Prolonged hyperinsulinemia further initiates negative feedback that renders target tissues less responsive to insulin signaling. Consequently, elevated insulin levels in insulin-resistant individuals can lead to increased fat storage, contributing to weight gain and obesity [11].
3.7. Nervous system
The central nervous system (CNS), particularly the hypothalamus, plays a key role in regulating appetite and energy disposal. Dysfunction in the brain circuits controlling energy homeostasis (regulation) strongly participates in adiposity extension and body weight gain. Particularly, alterations in the expression and/or activity of several neurotransmitters and neuropeptides including the neuropeptide Y (NPY), dopamine, and serotonin strongly impacts and modifies the nutritional behaviour and energy expenditure rates of overweight or obese individuals [12].  
3.8. Gut microbiota
The gut microbiota, which refers to a population of diverse microorganisms residing in the digestive tract, has been recently associated with obesity and demonstrated to be strain-specific. Physiologically, the digestive microbiome life cycle relies on the utilization of food metabolites and residues that escape human digestion. Unrestrained food consumption triggers a dysbiosis (disruption of intestinal flora) reflecting an imbalance in the types and quantity of enteric microorganisms, leading to an abnormal increase in central appetite and calorie disposal, aberrant fat storage, and persistent systemic inflammation [13]. 
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Obesity comorbidities

Obesity is associated with a range of comorbidities, meaning it often coexists with other health conditions. Many of the obesity-related alterations such as adipose tissue inflammation, lipid metabolism failure, and increased blood glucose and fatty acids levels strongly contribute to the pathogenesis (the source of the disease and the changes that occur in the body during its development) of other metabolic conditions. Some notable comorbidities of obesity include:
4.1. Type 2 diabetes
Obesity is a significant risk factor for the development of type 2 diabetes mellitus (T2DM), and the globally increasing obesity frequency is inevitably correlated with the steadily growing T2DM incidence. T2DM refers to sustained hyperglycaemia (increased blood glucose levels) deriving from an inefficient insulin action and/or production resulting from the peripheral tissues overload with toxic lipids, adipose tissue low-grade inflammation, and dysregulated microbiome-gut-brain axis. Obesity represents thus a great contributor to T2DM, under which impaired insulin signaling, declined β-cell mass, and function as well as lipotoxicity initiate T2DM onset [14]. 
4.2. Cardiovascular diseases
Obesity increases the risk of heart disease and stroke due to factors like adiposity, high blood pressure, atherosclerosis, high cholesterol levels, and inflammation. The characteristic accumulation of fat tissue and lipids depots can contribute to coronary calcification, endothelial dysfunction, altered vascular constriction, and increased deep vein thrombosis and pulmonary embolism, which are all critical heart and circulatory disorders hallmarks [15].
4.3. Dyslipidemia (Abnormal lipid (fat) levels in the blood)
Obesity and associated adipose tissue hypertrophy and adipocyte enlargement are directly involved in the fluctuations of fat levels circulating in the bloodstream. Both insulin resistance and chronic inflammation enhance adipose tissue lipolysis and excessive release of free fatty acids that contribute to the dysregulation of lipoprotein metabolism, which manifests as hypertriglyceridemia (increase in blood triglyceride levels), elevated small dense low-density lipoprotein (LDL) and lowered high-density lipoprotein (HDL) cholesterol level [16].
4.4. Liver diseases
As a central organ responsible for regulating metabolism and body detoxification, the liver is particularly subjected to overweight and/or obesity-induced alterations. In the course of excessive nutrition and calorie overload, a critical hepatic fatty acid metabolism dysregulation occurs, resulting in the abnormal accumulation of reactive lipids including triglycerides within the hepatic tissue, thus contributing to the development of associated pathologies such as non-alcoholic fatty liver disease (NAFLD) and fibrosis. Another liver lipotoxicity (toxicity due to lipids (fats)) hallmark relates to a progressive loss in liver insulin sensitivity, leading to imbalanced glucose homeostasis (regulation) and enhanced hepatic de novo fatty acid synthesis during which excess carbohydrates are converted to lipids (sugars conversion to fats) [17].
4.5. Respiratory issues
Obesity negatively impacts the physiology of the lungs and chest wall, leading to serious pulmonary compromise. The stockpiling of fat tissue in the abdominal area alters both static and dynamic pulmonary volumes due to a pathologic displacement of the diaphragm, limiting ventilatory capacity and the subsequent development of associated constraints such as obstructive sleep apnoea, asthma, and hypoventilation (very shallow or slow breathing) syndrome [18].
4.6. Joint problems
Excess body weight puts additional stress on weight-bearing joints, contributing to conditions like osteoarthritis. Moreover, the typical low-grade chronic inflammatory state of obese individuals perpetuates a constant pro-inflammatory milieu within the joints, leading to progressive cartilage degeneration and bone erosion [19]. 
4.7. Certain cancers
Obesity is considered as a direct risk factor for several common cancers including breast, colon, digestive, and endometrial cancers. The overall obesity-related metabolic instability characterized by altered lipid metabolism and turnover, chronic metaflammation, aberrant tissue matrix remodeling, hormonal imbalance, prolonged hyperlipemia, and dysbiosis (disruption of intestinal flora) participate in the initiation and progression of various carcinogenic and metastatic (spread of cancer) pathways [20].   
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Molecular background

Overweight and obesity primarily manifest as an excessive deposition of fats in form of subcutaneous and visceral adipose tissue. However, the condition initiation and progression are rooted in a number of molecular events dysregulating the metabolism.
5.1. Lipotoxicity
The amassment of fats in non-adipogenic cells including hepatocytes, myocytes, and pancreatic β-cells is responsible for serious cellular malfunctions and death through lipoapoptosis (lipid (fat) related programmed cell death). The continuous generation of reactive lipid intermediates like diacylglycerol and ceramides interrupt essential pathways governing metabolism homeostasis. Free fatty acids and their metabolites can hinder insulin signaling in the liver and muscles, suppress glucose-stimulated insulin secretion by pancreatic β-cells, induce cell cycle arrest, and initiate the pro-apoptotic pathways, leading to a general tissular failure [21]. 
5.2. Oxidative stress
Chronic consumption of a high-fat diet potentiates fatty acid oxidation and lipid peroxidation, resulting in a significant elevation in reactive oxygen species (ROS) generation that worsens the already existing metaflammation. As a consequence, endogenous antioxidant defenses comprising superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) are being depleted and suppressed, leading to oxidative stress. High unscavenged ROS levels further oxidize cellular macromolecules like lipids, proteins, and DNA damaging cells and tissues [22].
5.3. Mitochondrial dysfunction
Mitochondria are the powerhouses of cells responsible for energy conversion and supply through respiration and oxidative phosphorylation. Mitochondria overload during high-calorie intake stimulates the overproduction of superoxide anions through restricted proton gradient dissipation and adenine nucleotide deprivation, creating a deleterious pro-oxidant milieu [23]. Fattened cells generally tend to exhibit a reduced number of mitochondria with compromised biogenesis, damaged DNA, insufficient electron transport chain, depressed membrane potential, and overall depleted oxidative phosphorylation (OXPHOS) causing pathological changes in the glucose and lipid metabolism and energy availability [24]. 
5.4. ER stress
The endoplasmic reticulum (ER) is a multifunctional cellular organelle responsible for lipid metabolism, protein maturation and folding, and calcium bioavailability. In the course of fat overload and associated inflammatory insults, an unfolded protein response (UPR) occurs, which is a direct consequence of improper protein folding within the ER giving rise to truncated and unfunctional proteins. This maladaptive UPR subsequently triggers a cascade of signal transduction for the activation of ER stress arms that perpetuate chronic inflammatory responses and potentiates obesity in both adipose and non-adipogenic tissues, culminating with the elicitation of autophagic cell death [25].

Summary

● Obesity and overweight are two prevalent metabolic conditions characterized by excessive body fat hypertrophy, which adversely impacts the health and life of affected individuals. Overweight is defined with a BMI between 25.0-29.9, while obesity is associated with a BMI equal to or higher than 30.
● The physiopathology of obesity involves a complex interplay between genetic, environmental, metabolic, hormonal, and behavioural factors. Mechanisms including energy imbalance, hormonal dysregulation, uncontrolled adipose tissue expansion, insulin resistance, nervous system dysfunction, and gut dysbiosis (disruption of intestinal flora) strongly contribute to obesity development and progression. 
● Obesity often underlines the existence of associated comorbidities that mainly include type 2 diabetes, cardiovascular and pulmonary diseases, dyslipidemia (abnormal lipid (fat) levels in the blood), liver failure, musculoskeletal degeneration, and some malignancies.
● At the molecular level, obesity involves lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, which are a consequence of excessive calorie intake and aberrant lipid accumulation in adipocytes and non-adipogenic cells, contributing to cellular malfunction and ultimately death.

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