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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
For decades, scientific efforts have been made to understand obesity and related diseases such as type 2 diabetes and neurodegeneration, and their link with meta-inflammation. Adipose tissue is, at present, viewed as an endocrine organ with important biological effects on metabolism and inflammation, with a possible role in the pathogenesis of obesity-associated metabolic and inflammatory diseases. Chronic systemic low-grade inflammation has gained significant attention as the key player in the pathophysiology of obesity- and aging associated diseases. Keeping view of this trend, Meta-Inflammation and Obesity offers readers state-of-the-art knowledge on this subject. Chapters cover special topics such as gender differences in obesity-related type 2 diabetes as the consequence of inflammatory response, insights into metabolic changes caused by excessive adipose tissue (which lead to abnormal brain metabolism, neuroinflammation, cognitive decline, development of type 3 diabetes), and the importance of inflammaging in the aging process. Graduate, postgraduate and Ph. D. candidates in medicine, pharmacy, and students of applied medicine, health care professionals as well as scientists involved in adipose tissue research, meta-inflammation analysis, obesity-related medical specialties will find this book a useful reference on the link between inflammation and obesity.
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Seitenzahl: 399
Veröffentlichungsjahr: 2020
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PREFACE
With great pleasure, we present you the publication entitled “Meta-inflammation and Obesity”. The book is the result of a joint effort and represents a state-of-the-art compilation and overview of current scientific evidence on the role of meta-inflammation in obesity and obesity-related disorders. Obesity embodies a global epidemic with severe and overwhelming health and economic repercussions. The multifaceted physiological mechanisms control the equilibrium of energy intake and expenditure in the body. These complex mechanisms incorporate neuronal activity within structures of the central nervous system with signals coming from the adipose tissue and endocrine glands as well as from the autonomic nervous and gastrointestinal system. A pivotal role in obesity is played by adipokines, which are cytokines produced and secreted from white adipose tissue. Adipokines use autocrine, paracrine, and endocrine mechanisms in the regulation of copious physiological processes. Studies have shown that adipokines are significant players in the regulation of glucose metabolism and tolerance, insulin resistance, inflammation, and oxidative stress, as well as in angiogenesis and atherosclerosis. Moreover, adipokines have a major role in the equilibrium between satiety and appetite as well as in the maintaining energy expenditure and body fat stores. In obesity, visceral adipose tissue is accumulated and undergoes significant morphofunctional changes with numerous pathophysiological consequences. Visceral obesity is characterized by adipocyte dysfunction, which is followed by a disrupted adipokine discharge pattern and the inception of meta-inflammation. The term "meta-inflammation" denotes chronic metabolic and systemic low-grade inflammation that has an important role in the pathogenesis of various metabolic diseases. The majority of authors thus far agree that meta-inflammation could be the linkage between obesity and obesity-related diseases. Bearing in mind that meta-inflammation is a relatively novel concept, it is still widely investigated. The distribution of visceral adipose tissue exhibits a different gender pattern. Physiological and psychosocial alterations between women and men have an impact on the pathophysiology of numerous disorders, and type 2 diabetes mellitus (T2DM) is one of the examples. Obesity represents a major risk factor for T2DM. One of the possible explanations for gender differences in obesity-related T2DM may be meta-inflammation as well as the actions of sex hormones (estrogens and androgens), that have been shown to affect adipose tissue function and metabolism alongside with biological characteristics. Novel evidence points to the significant role of obesity not only in the development of metabolic and cardiovascular diseases but in the pathophysiology of Alzheimer's disease (AD) as well. Studies have shown that meta-inflammation affects brain function together with disturbed insulin signaling and insulin resistance. Based on this notion, certain authors refer to this condition as brain diabetes or diabetes type 3 to denote cognitive decline in AD patients that develops as the consequence of inflammatory and metabolic trajectories. Obesity is followed by changes in the redox state with consequent oxidative stress. Obese patients have been shown to have decreased antioxidant defense and increased levels of reactive oxygen or nitrogen products. Further on, obesity is accompanied by altered brain metabolism. The neuron's synaptic plasticity may be affected by oxidative stress and meta-inflammation, and these processes often result in apoptosis or cell necrosis within the central nervous system with consequent neurodegenerative disorders characterized by brain atrophy, cognitive impairment, and neuroinflammation. Bearing in mind that the aging population worldwide is on the rise, significant scientific efforts are directed towards the unraveling of the basis for human aging. In recent years the term inflammaging has been introduced to indicate the possible role of chronic systemic low-grade inflammation as the cornerstone for human aging. Although the prominence of inflammaging in the aging process is now proven by the evidence from literature, its etiology is not yet fully elucidated. Moreover, future studies should answer the question whether chronic systemic low-grade inflammation is the cause or the consequence of obesity and obesity- and aging-related diseases.
The preface aims to give an insight into the content of our book, and we as the authors sincerely hope that our readers and colleagues will find it interesting and useful in the acquisition of cutting-edge research novelties on the interplay between meta-inflammation and obesity, that carries significant clinical consequences.
List of Contributors
Etiology of Obesity
Selma Spahić*Abstract
Numerous models have been proposed that try to explain the complex etiology of obesity. Etiology maps have been created to interconnect the various endogenous and exogenous variables that contribute to the pathophysiological pathways that lead to overweight and obesity. No country in the world has solved the problem of overweight and obesity, and the health and economic consequences that are suffered around the world are on the rise since the world population is getting more obese by the day. We aim to reflect on those variables that we see as potential target points for weight loss and to present the best available current data on the overweight and obesity epidemic. The goal of this review chapter is to emphasize the importance of different obesity determinants: host factors, social environment, built environment and behavioral determinants. Obesity is a risk factor for metabolic syndrome, hormonal dysfunction and depression, it lowers lifetime expectancy and reduces the overall health-related quality of life. Searching for a one-size-fits-all solution has been shown ineffective in preventing the escalating obesity rates. Efforts should be directed towards defining targeted, individualized strategies, while creating a network of support that includes healthcare professionals, family members and national regulations. A multi modal interdisciplinary approach and patient-centered care is mandatory to stop the global obesity epidemic.
INTRODUCTION
Obesity is a chronic, non-communicable, adiposity-based, relapsing disease [1]. From data collected around the world during the last century, it is evident that obesity is on the rise. Currently, over 650 million adults (18 years and older) and 340 million children and adolescents are obese. Since 1975, the number of obese people has nearly tripled.
In 2016, more than 1.9 billion adults were overweight, which suggests that, following the current trend, obesity prevalence can easily further multiply [2]. Estimates are that by 2030, every fifth citizen of the world will be obese [3]. The world prevalence of overweight and obesity in children under the age of 5 has expanded from approximately 5% in 2000 to 6% in 2010; and 6.3% in 2013. The most prominent rise occurred in Asia and Africa where an increase from 11 to 19% in certain countries in southern Africa, and from 3 to 7% in South-East Asia was observed. Estimates predict that overweight in children under the age of 5 is going to rise to 11% globally by 2025 if current patterns proceed [4]. Obesity is present in both genders and in all age groups regardless of ethnicity, region or socioeconomic status; however, the prevalence is generally greater in the elderly and women [5]. For decades, obesity was considered a behavioral problem, and we are just starting to uncover all the hidden factors that contribute to the complex pathophysiology of weight gain. Looking at current evidence and reviewing the timeline of obesity research, it seems that tackling the obesity epidemic will be a long and demanding task. No country to date managed to reverse its obesity epidemic [6]. A lack of success is understandable considering that appropriate management of obesity demands addressing not only behavior, but multiple dysfunctions (host, environmental and societal). Although they all play a definite role in disease development, it is safe to say that none of them satisfactorily, to a full extent, explains the obesity epidemic [7]. Defining the mechanisms involved in obesity must engage disciplines that analyze the genetic and epigenetic framework, as well as the development stages in host biology that impact disease pathogenesis; the neurological and psychological background of feeding behaviors; metabolic changes due to specific nutrient intake; the effect of physical activity and body composition; environmental availability of healthy foods and the impact of presentation to ecological factors extending from endocrine-disturbing synthetic substances (EDCs) to the social and cultural machinery that drives public opinions and produces regulations and policies [8]. A simplified overview of these determinants and their interplay is proposed in Fig. (1), and further explained in the text. Recently, to bring together most of the relevant variables that lead to overweight and obesity and to show their interdependencies, Systems Science [9] was used and etiology maps were generated. Those have been very helpful, although not fully comprehensive, as they present an apprehensible overview of the complexity of obesity and highlight multiple levels where the variables interconnect. The maps are in accordance with the obesity paradigm shift, from obesity being perceived as a problem arousing from a lack of willpower with an easy one-size-fits-all solution that comes down to “eat less, move more”; to one of the biggest health hazards of the 21st century [10, 11].
Fig. (1)) Obesity determinants.Body Weight Classification in Adults
The most commonly used measure of obesity is the Body Mass Index (BMI). Based on the BMI, a healthy weight range for height is easily determined by dividing weight in kilograms with height in meters squared. The BMI is widely accepted as a general marker for obesity, and although the index is not representing a genuine proportion of adiposity, it is easy to use in health screenings and epidemiological reviews. The index is considered a reliable measure in estimating worldwide obesity prevalence. However, due to its limitations, it is not recommended to use only the BMI for individual assessment and nationwide studies, especially for children, elderly and the Asian population [12]. A combination of the BMI with other anthropometric measures such as waist circumference, waist-to-hip ratio and other adiposity estimation methods is advocated. A BMI measure above 25 kg/m2 classifies for overweight, and a BMI greater or equal to 30 kg/m2 qualifies as obesity. The BMI is, by itself, a strong predictor of overall mortality both above and below the apparent optimum of about 22.5–25 kg/m2 [13], even though a BMI from 18.5 to 25 kg/m2 is considered normal. The degree of obesity is expressed through further categorization of obesity into subclasses for BMI values above 30 kg/m2. Three subcategories of obesity are defined: class 1 (BMI of 30 to <35 kg/m2), class 2 (BMI of 35 to <40 kg/m2), and class 3 (BMI of >40 kg/m2) [14].
Body Weight Classification in Children
Assessing BMI in children requires adjusting for both biological sex and age with corresponding growth charts; since children are still growing, the children’s body composition changes as they age and it varies between girls and boys. The World Health Organization, the Centers for Disease Control and Prevention (CDC) and the International Obesity Task Force (IOTF) proposed their BMI classification systems adopted for the use in children. A comparison of these tools with respect to prevalence approximation tied with demographic factors yielded different estimates and showed inconsistencies [15]. The CDC and IOTF classification systems are a widely used diagnostic tool for overweight and obesity among children and adolescents aged 2-18 years. Percentile classification charts tailored for age and gender form data referenced in national studies from the UK, Hong Kong, the Netherlands, Brazil, Singapore, and the USA are used when conducting epidemiological studies [16]. The ≥85th BMI centile and the ≥95th BMI centile render age- and gender-specific BMI cut-offs that match the cut-offs for adults' overweight and obesity, respectively. These cut-offs are referred to as the International Obesity Task Force (IOTF) body mass index cut-offs. They allow for international associations of obesity prevalence in children, but their use is not recommended for a clinical setting [17].
Weight Gain as a Consequence of Energy Surplus
An increased energy intake, a decreased energy expenditure or a combination of both processes, result in an energy surplus that ultimately leads to the formation of energy reserves in adipocytes. All proposed obesity determinants affect energy intake, energy expenditure or energy storage, thereby affecting energy balance. Two proposed underlying processes related to obesity pathogenesis are prolonged positive energy balance and an increased value of the body weight “set point” [8]. Researches that support the “thrifty gene hypothesis” claim that a positive energy balance was of an evolutionary advantage [18], because food resources were scarce and the body prepared itself for periods of famine and fasting. However, in an obesogenic environment where calorie-dense, processed food is readily available, with a decrease in time spent in physical activities, energy excess occurs easily and is not counterbalanced. Maladaptive eating behaviors, and subsequently weight gain develop seemingly unnoticed. A slight but consistent energy surplus, of merely 100 kcal more per day, results in a gradual yearly weight gain [19]. On the other hand, the body weight “set point” hypothesis, if true would elucidate why weight loss is hard to maintain and why lost weight will probably be regained over time, which represents an important obstacle for successful and sustained obesity management. Accordingly, new treatment approaches attempt to address the processes that reset the guarded body weight level back to a lower, closer to normal value. At which point, the gained weight becomes refractory to change and biologically defended is still not fully understood [8]. Debate still exists, essentially questioning if outside determinants cause biological control malfunction, and if the internal body’s ‘set point’ feedback system is substituted by several ‘settling points’ that are impacted by energy and nutrient intake which cause new zero-energy balance points. Both proposed models are hypotheses, and fail to fully explain the data from human observational studies, and alternative models based on gene-by-environment interplay are needed to attain a complete understanding of body weight control [20-22].
Obesity is now recognized as an adiposity-based chronic disease, and weight gain is only one component of obesity. Many authors agree that most health repercussions of obesity occur because of an induced low-grade systematic inflammation. Once entered the vicious circle of hormonal and metabolic changes complementary to excess adiposity, weight loss becomes very hard to achieve.
Determinants of Obesity
The questions that still remain unanswered are why do some individuals gain weight easier than others, and why do some individuals remain lean in an obesogenic environment? Host risk factors (Fig. 2) include biological determinants (genetic, epigenetic, perinatal), determinants obtained through long term lifestyle that are not easily modifiable (brain-gut axis, gut microbiome, and viruses) and secondary causes of obesity (neuroendocrine conditions, physical and intellectual disability, medications). Behavior is the key regulating and modifiable factor in obesity prevention and treatment. In order to modulate behavior, a broad understanding of its determinants is needed. A biological foundation that gets expressed in a distinct built and social environment ascertains behavior. Behavioral factors that promote obesity include excessive calorie intake, unhealthy eating patterns, dominantly sedentary lifestyles, insufficient sleep, and inefficient stress management. The biological determinants that underpin the development of obesity include genetic, epigenetic and prenatal factors. Determinants of the built environment or “human-made” determinants include urban planning, the food industry and food availability, utilization of endocrine disruptor chemicals, etc. Social determinants embed the effects of socio-economic and political influences, i.e., traditions and customs, opinions towards food and physical activity, ethnicity, presence of supportive policies, culture, inequalities and stigmatization into the obesity etiology framework [23]. Altogether, the energy balance of the body is regulated within the brain that serves as an integration center for inputs from peripheral receptors, hormones, mediators and neurotransmitters as signals for hunger and satiation. The coordination of the signals received is planned to involve a minimum of 2 parallel systems: the metabolic homeostatic system and the brain reward system [24]. Therefore, is important to note that eating patterns are also changed in response to psychological stress and various external cues [25]. The metabolic homeostasis is primarily controlled by hypothalamic and brainstem neuronal circuits. The hedonic pathway of the consumed food involves the mesolimbic brain area and the cortex. Combinations of several groups of risk factors contribute to the process of gaining excess weight to developing unhealthy obesity. The process is usually polygenic and long.
Biological Determinants
Results from twins, family and adoption studies led to the recognition of causative gene-phenotype interactions in monogenic forms of obesity. However, hereditary factors cannot be considered the primary origin of the global obesity epidemic since the genome is not inclined to change within a few years. Advances in epigenetic studies extended the contemporary understanding of the pandemic of obesity [26]. Epigenetic alterations—DNA methylation, histone tails, and miRNAs modifications—involved in the evolution of obesity are increasingly apparent. There is evidence that the embryo-fetal and perinatal period play a fundamental role in the development and the programming of proper functioning in all human organs and tissues [27]. Hereditary determinants of obesity broadly can be grouped into monogenic causes, syndromic causes and polygenic causes. Monogenic causes are induced by a single gene mutation, principally found in the leptin-melanocortin pathway.
So far, there are eight well-recognized monogenic obesity genes: leptin (LEP), leptin receptor (LEPR), brain-derived neurotrophic factor (BDNF), neurotrophic tyrosine kinase receptor type 2 (NTRK2), prohormone convertase 1 (PCSK1), melanocortin 4 receptor (MC4R), proopiomelanocortin (POMC) and single-minded homologue 1 (SIM1). Severe early-onset obesity and overeating can be explained with single-gene mutations in these eight genes in up to 10% of severely obese children. Single gene mutations commonly result in leptin and leptin receptor deficiency, POMC deficiency, Prohormone convertase deficiency, Melanocortin Receptor 4 deficiency, SIM 1 insufficiency, BDNF and TrkB insufficiency. Syndromic obesity is linked with different phenotypes such as neurodevelopmental anomalies, and other organ and/or system malformations. Syndromic obesity is associated with Prader–Willi syndrome, Bardet–Biedl syndromes, Alstrom–Hallgren syndrome, Beckwith–Wiedemann syndrome, Carpenter syndrome and Cohen syndrome [28]. Polygenic obesity is induced by a large number of genes, with a cumulative augmentation, where the effect of gene dysfunction is magnified within an obesogenic environment. Maternal-fetal stress, poor nutrition of the mother and various intoxications during pregnancy can conflict proper programming of cells, tissues, and organs. The roots of obesity may be fastened in utero. Intrauterine conditioning of the fetus and the plasticity during gestational growth is critical for adapting the fetus to its foreseen environment. Multiple animal and human studies have shown that obesity in pregnancy affects control of appetite and metabolism, immunity, growth, insulin signaling and inflammation [29]. An increased susceptibility to obesity may be predefined in patients born via Caesarean section and in patients whose mothers used antibiotics during pregnancy, because of an alteration in the natural maternal-offspring microbiota transfer. This contributes to anomalous microbial colonization of the infant's gut [30].
The Brain-Gut Axis
The Brain-gut axis is comprised of neuronal pathways in the central nervous system (CNS), enteric nervous system (ENS) and the autonomic nervous system (ANS) and neuroendocrine and immunological systems, including also the gut microbiome, which will be discussed below [31]. These axis components allow the brain and the gut to correspond with each other. Neurohumoral communication within the axis is established via local, paracrine and/or endocrine secretion. It is formed through sensory information being translated into neural, hormonal and immunological signals, which are relayed bidirectional from the CNS to the gut. The axis modulates appetite, energy balance and food consumption, which are centrally regulated in response to homeostatic and non-homoeostatic inputs. The arcuate nucleus of the hypothalamus integrates signals in the homeostatic system and regulates satiety and hunger via relaying inputs to higher cortical centers that stimulate the ANS, gastric function, and hormone secretion accordingly [32]. After a meal, due to the presence of nutrients in the gut, a variety of gut-derived peptides are produced from enteroendocrine cells including glucagon-like peptide 1 (GLP1), cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY3−36 (PYY), and oxyntomodulin, thereby signaling changes in the nutritional status to inform the brain. Gut to brain signaling occurs via afferent nerves, and direct secretion into the blood. Microbiota-derived metabolites, for example, short-chain fatty acids can modify gut hormone secretion, due to binding to receptors on enteroendocrine cells, and thus affect appetite and satiety. Obese patients have decreased satiation, higher fasting gastric volume, quickened gastric emptying, lower levels of CCK and GLP-1, higher levels of acyl-ghrelin, and increased levels of adipocyte secreted leptin, commonly accompanied with leptin resistance. A proposed subclassification of obesity in relation to the main abnormality in the brain-gut axis is based on a principal component analysis of characteristics from obesity patients. Based on the findings, the suggested traits that can differentiate between obesity sub-phenotypes are: abnormal satiety, abnormal gastric motor function and motility, and affect [33]. Whether brain-gut axis alterations that are coupled with excessive food consumption are a cause or an effect of obesity is still uncertain [34].
The Microbiome
The gut microbiota is comprised of 10-100 trillion microorganisms that produce bioactive metabolites in a diet-dependent manner, including short-chain fatty acids and conjugated fatty acids impacting body weight through its effects on energy metabolism and systemic inflammation. Obesity-associated microbiota alter host energy harvesting, insulin resistance, inflammation, and fat deposition. Increased plasma levels of lipopolysaccharide, an endotoxin in the cell wall of Gram-negative bacteria, cause metabolic endotoxaemia, inducing a strong immune system response and contributing to the obesity-related low-grade inflammation. Dietary fat is crucial in this process because it increases intestinal lipopolysaccharide absorption through incorporation into chylomicrons. Moreover, impaired intestinal barrier integrity might also contribute to this metabolic endotoxaemia. The industrialized microbiota has an increased capacity to degrade the intestinal mucus layer [35]. Gut bacteria are therefore becoming increasingly recognized as the key regulators of host physiology and pathophysiology. Microbiota-derived metabolites have peripheral effects and also regulate metabolism, adiposity, homoeostasis, and energy balance as well as central appetite and food reward signaling. Alterations in the composition of the human gut microbiota especially early in life, are linked with metabolic disorders such as obesity, diabetes, and eating disorders, as well as stress-related neuropsychiatric disorders, including depression and anxiety, which are also characterized by changes in eating behavior. Growing evidence suggests that the success of bariatric surgery is due to its effects on the microbiota [36]. Gut bacteria can directly affect the CNS via modulation of endocrine signaling pathways of the microbiota–gut–brain axis such as GLP-1 and peptide YY signaling, or activation of reward pathways that together have crucial roles in obesity. Alterations in diet can profoundly affect the composition of gut bacteria at multiple levels of the gastrointestinal tract, and obesity itself may affect the composition of gut bacteria. Although the gut microbiota is a contributing and potential causal factor for obesity and metabolic syndrome, the exact mechanisms underlying this relationship are unclear. Further investigations are needed to elucidate the intricate gut-microbiota–host relationship and the potential of gut-microbiota-targeted strategies, such as dietary interventions including prebiotics, probiotics and fecal microbiota transplantation, as promising metabolic therapies that can help patients to maintain a healthy weight throughout life.
Viruses
Research into the origins of the obesity pandemic has encouraged the theory that distinct infectious agents might play a causal role in etiology of obesity, but this hypothesis is frequently omitted. Animal models infected with certain viral strains can develop obesity. Primarily adenoviruses Ad36 and Ad37 emerged as pathogens associated with adipogenesis. An Ad36 infection is linked to adipocyte proliferation and a body weight increase as reported in various preclinical models [37]. Obese individuals have significantly higher antibody titers to Ad36 than lean individuals. In a study of 502 US participants, where individuals have been screened for Ad36 prevalence, the virus was significantly more prevalent in the obese than in the lean (30% vs. 11%) [38]. These findings raise the question of whether susceptibility to infections contributes to the development of obesity. Extensive research and more human studies are required to explore this hypothesis and confirm a definitive causation. If enough strong evidence emerges, proving this causation, current approaches to obesity treatment and prevention would be profoundly impacted.
Neuroendocrine Conditions Causing Secondary Obesity
Secondary obesity is caused by several neuroendocrine diseases. Patients need to be evaluated for potential hormone balance dysfunctions. Common disorders like hypothyroidism and polycystic ovarian syndrome, and other rather rare disorders like Cushing's syndrome, central hypothyroidism, hypothalamic disorders, and combined hormone deficiencies lead to obesity via various processes that align with the mechanisms of the primary endocrine condition [39].
Physical and Intellectual Disability
People with physical and intellectual disabilities comprise a vulnerable group since evidence shows that they are more prone to developing obesity than the general population. They may experience difficulties in weight control because creating and sustaining a healthy lifestyle is laborious. The possible obstacles that people with disabilities may face are numerous [40]. Difficulties with chewing or swallowing food, or experiencing food taste or texture, with a concomitant lack of healthy food decisions impact energy intake and digestion. Their prescribed medications may impact energy balance and have weight-related side effects. Physical restrictions due to disability reduce a person’s ability to exercise additionally to physical activity barriers experienced by the general population like motivation and time. There are fewer possibilities for sports participation and/or they are inaccessible. Pain and a general energy deficiency further limit their participation in physical activity. The management of obesity occurring within this vulnerable group is specifically troublesome considering that they are at risk for the same weight-related complications and comorbidities as the general population, while additionally being at increased risk for chronic conditions linked with their disability. The co-occurrence of disability and weight gain forms vicious cycles and poses added health burdens, restricting patient functionality and independence, and reducing health-related quality of life [41]. More health-promotion programs targeting appropriate exercise regimes for people with disabilities are needed.
Prescription Drugs
It seems that the increased utilization of prescription drugs that lead to weight gain as a side-effect, at least partially contributes to the overweight and obesity pandemic. Classes of pharmaceuticals including antihyperglycemics, antidepressants, antipsychotics [42], corticosteroids, and antihypertensives contain medications that were associated with significant weight gain.
Fig. (2)) Host risk factors. Furthermore, diabetes, hypertension, and depression are well-known complications of obesity, and prescribing certain medications to treat these comorbidities worsens obesity, hence, a vicious circle is formed. Medication-induced gain of weight is often agonizing for the patient as well as for health care providers [43]. Reviewing prescribed medications is imperative in the evaluation of the obese patient because it can reveal the cause of the patients' weight being refractory to weight loss, or the cause of inability to achieve weight loss maintenance [44]. When possible changing medication with a weight-neutral or even weight-reducing alternative is preferable in overweight or obese patients. When alternative pharmaceuticals are not available, or therapy change is impossible, adjunctive treatment, changes in dosing, changes in medication delivery or lifestyle modifications should be discussed with the patient.Built Environment Risk Factors
Built environment factors favoring obesity development include the abundance and commercialization of processed calorie-dense food, the utilization of endocrine disruptor chemicals (EDCs), the increasingly sedentary employment settings with a concomitant decrease of occupational physical activity, the absence of bicycle lanes, scarcity of pedestrian zones for walking, etc [45]. Various components of the built environment have been asserted as independent predictors of obesity. Neighborhoods either have or do not have parks and recreational spaces. The stores, supermarkets, theatres, restaurants, and workplaces can be located outside walking distances, inquiring more frequent use of motorized transportation (car, train, bus, taxi) [46]. The United States department of agriculture has mapped out so-called “food deserts” defined as a low-income area with limited access to healthy and nutritious food [47].
Current perspectives imply that BMI tends to lower values in regions where the intake of fruits and vegetables is higher. When investigating obesity risk, a reliable correlation between distances from home to healthy food sources is not easily made. It seems that access to healthier foods is rather associated with economics than with distance from home. Neighborhood characteristics analysis has the potential to contribute to customized obesity prevention programs. Connections between neighborhood-built environment characteristics and obesity have been extensively reported. Healthy People 2020 includes goals for supporting physical activity through neighborhood-built environment inter-ventions [48].
Readily available ultra-processed food often has decreased micronutrient content, little fiber and is stripped of most microorganisms, becoming nearly sterile [49]. Low-cost foods are generally, high in salt content and supplemented with sugars and fats. These inexpensive foods also have a high reward value and are promptly available. It has been hinted that the intake of such foods relieves the stress of daily life in some individuals. Numerous studies link exposure to EDCs to a variety of outcomes of potential relevance to obesity, including stimulation of adipogenesis and changes of insulin secretion, insulin sensitivity, and liver metabolism. Low-level exposure to EDCs is common and widespread in communities. Especially dangerous is maternal exposure to ECDs that can be transmitted to the fetus, where even if present in low levels, a higher susceptibility to obesity is imposed when compared to adult exposure. The Endocrine Society Scientific Statement recently provided a comprehensive review of this topic [50].
Socio-Cultural Environment Risk Factors
The neighborhood social environment is less profoundly studied. The social context, including sociodemographic composition and residential social processes, is potent in shaping obesity risk [51]. The relationships between individuals reflect on social cohesion and collective efficacy. Social norms, social capital, neighborhood safety, and segregation need to be assessed when investigating the social environment and its impacts on individual and public health. Socio-economic status (SES)-encouraged dietary changes and their contribution to obesity prevalence rise have been studied extensively. However, because of confounding variables the real influence of SES on obesity prevalence needs to be further investigated with different approaches like geolocalization and mapping approaches that can track the social, racial, and residential segregation patterns in neighborhoods. Overall, most observations link an increase in obesity risk among lower-income groups to insufficient healthy food budgets [52]. In future linking SES to obesity risk must include the examination of the effect on the energy homeostasis system, and not solely diet, physical activity, and behavior. Obesity among both adults and children has been linked to a lack of neighborhood safety [53]. The social environment is significant for habit formation. The results of a recent study, where a natural experiment was performed to examine whether obesity is more likely to be acquired when individuals are exposed to communities with high obesity rates, indicate that obesity has features of a social contagion [54]. Expressing opinions via online interactions has created a new body of evidence for psychological and sociological research. The stored databases are the hallmark for resourcing public opinions and beliefs nowadays [55]. Weight-related stigmatization within the personal environment on a global scale threatens the mental health of obese patients. Because of idealized body images, body dissatisfaction is common, as well as are eating disorders and a negligence of regular physical activities. The mental health of the youth need special public health programs to shift the perceived body image away from its appearance and towards its functionality. UK Youth Parliament's ‘Make Your Mark’ ballot showed that one million young adults pointed out body image as a one of the primary causes of their life problems [56]. The general public and health professionals stigmatize those who suffer from obesity, and this needs to be urgently addressed [43]. Nutrition is not sufficiently thought in schools, and universities. There is a lack of knowledge about the means of prevention, the burden of the disease and treatment. It seems that in order to build empathy, reduce prejudice, attain and establish social justice, simply spreading information will be insufficient [57]. A conceptual model of the above mentioned is proposed in Fig.(3).
Fig. (3)) Obesity model.Behavioral Risk Factors
Despite being influenced by environmental factors individual decisions are precipitating the obesity disease development. An unhealthy diet, reduced physical activity, insufficient sleep [58], inadequate stress management and smoking cessation are self-inflicted and therefore modifiable risk factors for obesity and cardio-metabolic dysfunctions. The general population does not have a sustained, healthy dietary pattern. Essential nutrients and wholefoods including fruit and vegetables are consumed less when compared to unhealthy and processed foods, and sugar- sweetened beverages (SSBs) [59]. Evidence consolidated a positive association of SSBs consumption with obesity indices in adults and children; therefore a reduction of SSBs consumption through public health policies is advisable [60]. Engagement in physical activity is the most variable element of daily energy expenditure. Estimates are that in the past 50 years occupational physical activity reductions resulted in a decrease in total daily energy expenditure by 100 cal/day [8]. Scientific evidence points out that sleep disruption and circadian misalignment contribute to metabolic physiology dysregulations. Sufficient sleep is of key importance for a healthy metabolic function. However, many people do not sustain a habit of getting enough sleep, by cutting sleeping hours in order to participate in shift work, social activities, or other activities. These behaviors create a predisposition for poor metabolic health, by favoring excess caloric consumption in response to reduced sleep, food intake at times when the internal metabolic physiology systems are not prepared, reduced energy expenditure and disordered glucose metabolism [61]. Physiological stress, if not handled correctly, through efficient stress management methods, has the potential to drive maladaptive eating behaviors and mental health problems. 38 Stress induces cortisol secretion, together with other stress-induced physiological responses, both food intake and energy expenditure are modified, thereby making weight control more difficult to achieve [62].
Luckily, a substantial reduction in cigarette smoking rates was observed in the past decades [63]. Numerous health benefits accompany smoking cessation. Nevertheless, at least partially due to nicotine withdrawal and loss of the pharmacological effect of nicotine to suppress food consumption, smoking cessation is linked to a 3–5 kg average weight gain. The possible mechanisms of weight gain include a positive energy balance due to increased energy intake, reduced energy expenditure and resting metabolic rate, and an increase in lipoprotein lipase activity. Therefore, body weight monitoring and promotion of lifestyle changes need to be part of smoking cessation plans. Nicotine replacement and bupropion may help prevent weight gain in this vulnerable group. However, obesity remains a problem among both current smokers and people who never smoked [64].
Complications and Comorbidities of Overweight and Obesity
In the general population, obesity relates to more deaths than underweight [2]. The risk of death rises by 20%-40% in overweight people and is two-to-three times higher in obese people when compared to normal-weight individuals, as shown in a prospective cohort study of 527,265 U.S. citizens age 50 to 71 years, where the BMI was correlated to all-cause risk of death [65]. The Lancet published a report by the Prospective Studies Collaboration (PSC) that included 57 prospective studies with approximately 900 000 subjects, whose findings were analyzed to evaluate the correlation linking total and disease-specific mortality with the BMI values. The study proved that total mortality associated with a BMI value above 30 kg/m2 is increased in both women and men in all age groups from 35 to 89 years. Increased mortality in subjects with a high BMI was principally caused by ischemic heart disease, diabetes, stroke, and liver disease [13].
The crosstalk between the multiple cell types that compose adipose tissue and the investigation into their function, led to the understanding that adipose tissue does not only serve as a storage organ, but rather has a dynamic metabolic and homeostatic, endocrine response in the regulatory pathways of body composition, hunger and satiety, and inflammatory modulation. Adipocytes and their precursors, immune cells, vascular cells, and neuronal cells constitute adipose tissue [66]. Some obese individuals are prone to developing comorbidities while others express metabolic health despite abundant weight. This observation resulted in two distinct phenotype formulations, metabolically healthy obesity and metabolically unhealthy obesity, based on the presence of complications in patients with an increased BMI. The separation of these two profiles seems justified when calculating the risk for disease progression and deciding on treatment modalities. Impairments in adipocyte amount, distribution and function are the drives of obesity-related health risks. Obesity complications occur mainly due to two processes. Firstly, the amount of stored fat inflicts mechanical complications coming from physical forces exerted on the patient (fat mass disease) [1]. The most commonly described complications resulting from this process are osteoarthritis, gastroesophageal reflux disease, and obstructive sleep apnea [67]. Secondarily, the processes of adiposopathy (sick fat disease) inflict immunological and metabolic/endocrine consequences on the patient through meta-inflammation [1].
The adipocytes adapt to excess energy through hypertrophy and hyperplasia i.e. adipogenesis where new adipocytes are formed from progenitor and stem cells [68]. Excess energy is stored as glycogen or through the metabolic formation of fat. The increase in fat tissue consequently requires a bigger blood pool, therefore the formation of new blood vessels via angiogenesis is also crucial. In physiological circumstances, adipokines signal the regulatory mechanisms involved in these processes, and a molecular exchange with other organ systems is established, protecting the organism from a lipid overflow. Adipose tissue has a limited storage capacity, and cannot expand indefinitely through tissue remodeling. Excess energy is stored partially in subcutaneous adipose tissue, and partially in visceral adipose tissue. In terms of metabolic health, visceral adiposity imposes a bigger threat than subcutaneous adipose tissue. When a capacity maximum is reached, the process of adipocyte apoptosis becomes a key regulator of macrophage activation. Involved are two major classes of macrophages, the classically activated pro-inflammatory M1 class, and the anti-inflammatory M2 class [69]. Activation of pro-inflammatory macrophages is linked with insulin resistance and meta-inflammation. Metabolic obesity-related diseases originate from impairments in fatty acid storage and release as well as under- and overproduction of adipokines. A fatty acids “leak” causes ectopic fat deposition, and a lipid overflow. In obesity, fat is stored in the liver, the pancreas, inside of muscle cells, around the heart and kidney and there is a general body fat distribution dysfunction. These ectopic fat depots disturb the physiological functions of the affected organs.
Individuals who recruit new subcutaneous adipocytes to store excess energy instead of accumulating ectopic fat manage to preserve a relatively healthy metabolic status [14]. The above-mentioned processes imply that more fat does not necessarily mean more metabolic disease. Current guidelines that distinguish between metabolically healthy and metabolically unhealthy obesity [70] yield inconsistencies in management approach [71]. This is partially due to the on-going debate that metabolically healthy obesity only serves as a prologue to metabolically unhealthy obesity, and must not be considered as a stable disease phenotype [72]. More research into adipose tissue inflammation and metabolic inflexibility will provide a better understanding of current dilemmas.
Nevertheless, multiple hormonal signals interpreted by the central nervous system influence appetite, and asking a patient to resist increased appetite through willpower and discipline seems inadequate from this standing point. Certain behaviors are modifiable, whereas others are not [73]. There is evidence that metabolic signaling, glucotoxicity, lipotoxicity, leptin and insulin resistance accompanied by oxidative stress lead to neuroinflammation and cognitive impairment [74]. Another set of complications arose from the socio-environmental frame of obesity. Namely, additional to already faulty homeostatic regulation and impaired hypothalamic signaling, stigmatization and peer-pressures lead to various psychiatric diseases such as depression, anxiety, eating disorders and a higher risk of self-harm and suicide [75].
Cancer incidence is also higher in obese patients. There is an increased risk of predominantly colon, rectum and prostate cancer in men, and breast, endometrium and gallbladder cancer in women [14].
Due to the role of adipose tissue in the hormonal conversion of steroid hormones, adiposity dysfunction is linked with Polycystic Ovarian Syndrome and infertility [76]. Pregnant obese women have an increased risk of gestational diabetes and hypertensive disorders like preeclampsia. Instrumentally assisted births and cesarean sections are conducted more often. There is an increased risk of preterm birth, macrosomia, congenital abnormalities, fetal defects, and perinatal mortality. Compared with healthy weight women, infections of subsequent surgical wounds are more likely to befall obese women. Obese mothers have lower breastfeeding initiation rates, and breastfeeding is ceased earlier when matched with healthy-weight mothers [14].
