Obesity: One word encompassing a multitude of diseases

Highlights:

• Obesity is a multi-faceted condition that affects the entirety of the body
• Obesity exerts its effects through increasing levels of inflammatory mediators, reactive oxygen species, and toxic substances
• The distribution of body fat plays a significant role in disease development

Introduction

The World Health Organization (WHO) defines obesity as “abnormal or excessive fat accumulation that presents a risk to health”. Obesity is mainly measured using the body mass index (BMI). Using BMI measure, obese individuals are defined as those with a BMI of more than or equal to 30 kg/m2. According to the United States Centers for Diseases Control and Prevention (CDC), more than 1 In every five adults suffer from obesity in the country. Obesity increases the risk of fertility loss and illnesses linked to higher death rates like kidney disorders, cardiovascular conditions, metabolic diseases, cancer, etc.

Why and how does obesity develop?

The etiology of obesity is multifactorial and driven by elements like food intake and energy balance, level of physical activity, environmental factors, genetic component, socio-economic status, hormonal imbalance, including reward-system in brain, and others (1). The dietary factor is among the highest contributors to obesity due to the availability of energy-dense food types (1, 2). One example of the energy-dense food type contributing to obesity is fast food (1, 2). A large study carried out on over 4800 teenage participants aged between 13-15 years old in the United Kingdom found that fast food consumption was associated with a 23% increase in obesity (3). One of the issues associated with fast food is the lack of satiety, since it contains highly processed sugars and additives.

Physical activity (PA) has also been implicated in obesity (4). In this context, obese individuals were found to be less physically active. In addition, excess body weight has been shown to have a negative impact on musculoskeletal health (5). To determine the impact of a sedentary lifestyle on body weight, Campbell et al. performed a meta-analysis (6). Results of their study revealed that a daily increase of 1 hour (from baseline of 1 hour/day) in sedentary behavior translated into a 0.02-millimeter increase in waist circumference over a 5-year follow-up period.

The genetic factor is another component that significantly influences obesity (1). According to research, the heritability of obesity is estimated to be 40% to 70% (7). Genes involved in obesity usually contribute to the condition by influencing pathways involved in energy regulation and homeostasis (1). Genes and their products such as peptide YY (PYY) and AgRP (agouti-related peptide) have been found to contribute to excess weight gain through disrupting the regulatory system of weight and appetite (8). These genes have been also found to influence regulatory hormones involved in weight and appetite regulation, such as ghrelin, leptin, and insulin (1, 8). Despite being a dominant factor in obesity, recent research has highlighted that dietary intervention can soften the genetic impact (9). This means that individuals with genetic susceptibility to obesity can still attain control of their weight.    

In addition to the above, the role of factors like the gut microbiome and their contribution to obesity has also been explored (10). Evidence from preclinical studies carried out on mice highlighted that animals without microbiota had a 42% lower mass of total body fat even upon consuming 29% more food a day compared to normal mice (11). The reason for the latter could be attributed to the inefficient metabolism of food products due to the lack of gut microbiota, meaning that larger food portions were required to be consumed to compensate for the inefficiency. When microbiota was introduced into these mice, they gained 57% more body fat coupled with a 27% decrease in food consumption. This highlights that gut microbiota composition and their presence influence weight (1). It is important to note that, under normal conditions, gut microbiota have a substantial role in health, as they are involved in metabolizing lipids and carbohydrates, synthesizing amino acids and vitamins, breakdown of indigestible molecules like milk oligosaccharides, protecting against invasive pathogens, and other critical functions. Diet plays a crucial role in gut microbiome health and diversity, therefore a balanced diet that provides adequate nutrients is important (1). Other factors that could contribute to weight gain include these that arise from disturbance of the circadian rhythm. An example of the actions regulated by the circadian clock is the feeding pattern. It is important to note that the circadian clock is responsible for regulating many bodily actions and their disturbance could potentially lead to obesity (12).   

The impact of obesity on cardiovascular diseases

There is abundant literature connecting obesity with cardiovascular diseases (CVDs) and associated mortality. Evidence from large clinical trials, like the Framingham Cohort Study, suggests that for every two years lived with obesity, the risk of CVD death increases by 7% (13). Additional research highlights that the presence of type 2 diabetes, which is a consequence of obesity, along with other metabolic irregularities can predispose individuals to CVDs (14).

According to research, obesity influences CVDs both directly and indirectly (15). The former is mediated by structural and functional changes in the body, like increased wall thickness of the left ventricle, to accommodate the fat tissue (15, 16). This leads to an internal environment that promotes inflammatory and thrombotic meditators. The indirect effects are mediated by the presence of another CVD risk factor, like glucose intolerance, hypertension, and dyslipidemia (15). Interaction between thrombotic and inflammatory mediators promotes thrombus formation by activating clotting factors through interacting with cytokines like tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-1 (IL-1).

The adipose (fat) tissue produces and regulates endocrine and paracrine hormones that modulate metabolism and inflammation (17). Cytokines produced by the adipose tissue (adipokines) that are upregulated in obesity include TNF-α, plasminogen activator inhibitor-1, IL-6, and others (17). Some adipokines regulate endothelial function (a thin layer of cells lining the blood vessels), therefore contributing to atherosclerosis development and progression, while others cause insulin resistance and dyslipidemia (abnormal fat levels in the blood).

How obesity relates to kidney disorders?

Obesity represents a potent risk factor for developing kidney disorders (18). The risk arises from the presence of metabolic abnormalities and associated diseases like hypertension and obesity. Additionally, obesity causes a rise in renal pressure and induces a compensatory hyperfiltration to meet the increased metabolic demand, exhausting the kidney (18). A meta-analysis by Garofalo et al. found that obesity increases the risk of albuminuria by 51% (19). The latter is a marker of kidney failure and carries negative implications about future renal and cardiac health states (20).

Despite the above, research highlights lifestyle modifications in obese patients with type 2 diabetes could reduce the risk of developing chronic kidney disease by 31%. Additionally, weight loss has been found to decrease renal compensatory hyperfiltration, proteinuria, and blood pressure (21).

Obesity is a risk factor for cancer!

Obesity is an established risk factor for cancer. According to the CDC, obesity is linked to a higher risk of developing 13 different types of cancer, constituting up to 40% of all cancers diagnosed in the United States (22). These cancers include breast, colorectal, ovarian, liver, thyroid, and many other types.

The link between obesity, insulin resistance, and disruptions in the cytokines released from the adipose tissue has been suggested as contributors to the pathogenesis of cancer (23). The said triad leads to a myriad of subclinical low-grade inflammation coupled with an increase in oxidative stress. Additionally, alterations in the gut microbiome count and composition result in the release of carcinogenic by-products (23). Examples of the latter include lipopolysaccharides. Their release, due to bacterial death, leads to increased production of inflammatory mediators such as TNF-α and IL-6 (23). The outcome of these processes is an increased risk of cancer development and propagation due to the accumulation of free radicals, toxic substances, and inflammatory mediators.    

Obesity metabolic syndrome

The metabolic syndrome is a collection of modifiable risk factors for CVDs and type-2 diabetes (24). The main driver for the condition is the intrabdominal fat accumulation and increased waist circumference. The latter plays a major role in developing insulin resistance. According to literature, fat distribution in the body plays a role in diseases associated with obesity, with intrabdominal distribution being associated with significant negative effects on health. This accumulated fat leads to a reduction in the high-density lipoprotein (the good cholesterol),  elevated levels of low-density lipoprotein (the bad cholesterol), triglycerides and plasma glucose, and increased blood pressure (24). The outcome of these processes is inflammation and the development of conditions like hypertension, diabetes, heart failure, kidney disorders, and many more (24). According to literature, metabolic syndrome affects 30% to 40% of people by the time they reach 65 years of age.

It is important to note that high levels of visceral fat are dangerous (25). Implications from the latter mean that people may not appear to be overweight despite being metabolically obese. Metabolic obesity leads to numerous conditions like the ones included in the article and more.

Obesity and neurological disorders

By now, it is evident that obesity negatively affects various body parts and systems, and the central nervous system (CNS) is no different. There is a substantial body of evidence suggesting a link between obesity and neurological disorders (26). This link has been confirmed based in results from 2 meta-analyses that found an association between obesity and Alzheimer’s disease (AD) and dementia (27, 28). One of the studies above highlighted that overweight BMI increases the risk of developing AD by more than 1/3 compared to healthy BMI (28). Additionally, obese individuals appear to have higher levels of depression.

Factors like metabolic dysfunction and inflammation drive the effect of obesity on the CNS. Results from postmortem studies highlighted that compared to those who were not obese, elderly patients with morbid obesity had higher levels of amyloid β and tau, both of which are markers of AD (26). Further evidence highlights that obesity induces structural and functional changes in the hippocampus, leading to cognitive impairment (26). Additionally, Inflammation causes impaired hypothalamic autophagy, leading to loss of control of energy balance and accelerated obesity, which further complicates the case (29). 

The influence of obesity on aging

It has been found that obesity reduces life expectancy by about six years in males and over seven years in females after the age of 40 (30). Additional research has highlighted that obesity could decrease life expectancy by about 14 years in individuals with a BMI of 55–59.9 kg/m2 (31). This effect has been attributed to age-related dysfunction and diseases at earlier stages of life in obese individuals (32).

According to the literature, obesity influences multiple aspects of the aging process. For example, the excessive formation  of reactive oxygen species (ROS) in obese individuals compromises the integrity of cellular and mitochondrial DNA, therefore acting as a driver for the aging process (30). Additionally, research has highlighted that obesity negatively impacts telomere length. Evidence suggests that obesity is associated with the shortening of telomere length by 240 base pairs (30), which contributes to almost nine years of aging. Telomeres are specialized nucleoprotein complexes with a repetitive pattern of “TTAGGG” located at the termini of chromosomes (33). The average length of telomeres has been used as a reliable biomarker to predict the healthspan and longevity in human populations (34).

Additional research has highlighted that the low-grade systemic inflammation caused by obesity resulted in alternations in proliferative and regenerative capacities of stem cells (35). Stem cells and their renewal capacity play an important role in the aging process. Obesity exerts its effect on stem cells by impacting adipose stem cells (ASCs), which are involved in immunomodulatory functions that control inflammatory cytokines like IL-6 and TNF-α (35).   

Tips

• Recommend your clients to avoid unhealthy, energy-dense food types like fast food. Highlight to them that they should make their diet greener.
• Advise your clients to stay active throughout the day and to avoid a sedentary lifestyle.
• To get your clients to do more physical activity, recommend a training partner to make the exercise more enjoyable.
• Inform your overweight clients that obesity is a modifiable risk factor for CVDs, meaning that they can reduce or even eliminate their risk of diseases like hypertension and heart conditions if they decrease their weight by 5–10%.
• Advise your clients to determine the health of their microbiome using suitable tests. Additionally, recommend they undergo genetic testing if necessary to assess their risk of developing obesity.
• Highlight to your clients that while BMI is used for calculating body fats, it has its own weaknesses. For example, it might indicate that a person is overweight, while in fact the majority of it is due to a higher muscle mass.
• Recommend your clients to maintain a balanced diet, as imbalances could lead to conditions such as obesity or anorexia.

Conclusions

Obesity and overweight are major risk factors with negative implications on the body’s overall health. There is a concrete body of evidence that obesity gives rise to multiple conditions that affect various systems of the body. Obesity drives the development of disease conditions through ROS, mitochondrial dysfunction, inflammatory mediators, and other mechanisms. Despite the seriousness of obesity, lifestyle modifications that reduce weight have been found to curb the risk of many diseases that arise due to being overweight.

Disclaimer: This article is an introduction to a series that discusses the link between obesity and a myriad of conditions.

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