Meta-Inflammation and Obesity

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.

White adipose tissue secretes adipokines that regulate numerous biological processes by autocrine, paracrine, and endocrine mechanisms. Adipokines are essential in the balance between appetite and satiety, regulation of body fat stores and energy expenditure, glucose tolerance, insulin release and sensitivity, cell growth, inflammation, oxidative stress, angiogenesis, and atherosclerosis. Cytokines are secreted directly from adipocytes, but also from other stromal cells in the adipose depot and primarily play a role in immune regulation. Among adipokines, leptin, resistin, and visfatin were described as markers that are positively related to body weight, fat mass, insulin resistance, and exhibit pro-inflammatory properties. Opposite to the proinflammatory cytokines, adipose tissue can secrete a series of anti-inflammatory adipokines, including adiponectin, apelin, vaspin, and omentin, which play crucial protective roles in inflammation states, insulin resistance, and atherosclerosis. In obese person dysregulation of adipokines secretion, in addition to upregulated inflammatory response, contributes to obesity-induced insulin resistance and systemic low-grade inflammation. Brown adipose tissue (BAT) might also have a secretory role, secreting “brownkines” that act in a paracrine or autocrine manner. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced.

The balance of energy intake and expenditure in the body is maintained by the complex physiological mechanisms that integrate neuronal activity in various central nervous system structures with signals coming from the gastrointestinal system, adipose tissue, endocrine glands, and the autonomic nervous system. The arcuate nucleus (ARC) in the ventral hypothalamus is considered to be the most important integrational centre in the hypothalamus. Very porous hematoencephalic barrier around arcuate nuclei allows numerous hormones, nutrients and cytokines from the periphery to reach the nuclei and inform ARC of the amount of food consumed and energy stored during the preceding hours, weeks, months and years. Information about short-term fluctuations in the amount of food consumed is carried by hormones released from the gastrointestinal tract (ghrelin, cholecystokinin, peptide YY, glucagon-like peptide) and pancreas (insulin, amylin, pancreatic polypeptide), while information about the amount of food consumed and energy stored during the preceding weeks or months is carried by hormones released from adipose tissue (leptin and adiponectin). ARC, when informed, secrete anorexigenic (alpha-melanocyte stimulating hormone) or orexigenic neurotransmitters (neuropeptide Y, agouti-related protein, melanin-concentrating hormone), which modulate the activity of second order hypothalamic nuclei such as the paraventricular, ventromedial and dorsomedial nuclei, as well as the lateral hypothalamus and thereby control eating behaviour and energy expenditure. In this chapter, the interaction of peripheral hormones with anorexigenic/orexigenic neurons and its effects on food intake are discussed.

The term “meta-inflammation” refers to chronic metabolic inflammation, which is thought to have an important role in the pathogenesis of numerous metabolic diseases. Majority of authors agree that inflammation, as a component of immune system, may serve as a link between obesity and numerous diseases. Hence, the role of meta-inflammation in the pathogenesis of obesity-related diseases is extensively investigated. Mitochondrial dysfunction in adipocytes is lately regarded as a primary cause of adipose tissue inflammation. This newly proposed hypothesis contradicts currently prevailing concept that “adipose tissue hypoxia” underlies adipose tissue dysfunction in obesity. Infiltration of adipose tissue by immune cells is one of the hallmarks of adipose tissue dysfunction. Based on the current knowledge, adipose tissue (AT) macrophages are considered to have a pivotal role in the development of adipose tissue inflammation and dysfunction. Macrophages that infiltrate the adipose tissue are divided into: pro-inflammatory (M1) and anti-inflammatory (M2) AT macrophages. Studies have shown that M1 AT macrophages contribute to insulin resistance by producing pro-inflammatory cytokines. Conversely, M2 AT macrophages are involved in the repair or remodeling of tissues. In obesity, adipose tissue becomes inflamed and goes through cellular remodeling. Adipocytes increase in number (hyperplasia) and size (hypertrophy), become infiltrated by macrophages and undergo fibrosis. Hypertrophic adipocytes secrete more pro-inflammatory molecules that lead to a shift of M2 to M1 AT macrophages. Adipose tissue dysfunction in obesity is characterized by changes on cellular and molecular level, which include immune cells such as T cells, B cells and dendritic cells. However, their role in meta-inflammation and adipose tissue dysfunction remains to be fully elucidated. Novel findings suggest that dysregulation of autophagy in adipose tissue has an important role in metainflammation. Studies have shown that there is a strong relationship between the prenatal and perinatal environment and obesity-related diseases. Childhood obesity is associated with meta-inflammation that affects not only adipose tissue but other organs as well. Since adipose tissue dysfunction in obesity plays a pivotal role in disturbing homeostatic processes in the human body, it is of essential importance that health care systems at the global level work on implementation of precautionary strategies in order to prevent the development and progression of meta-inflammation and obesity-related metabolic complications starting at early stages of life.

The pathophysiological consequences of obesity are largely based on morphofunctional changes in visceral adipose tissue. By disrupting all phases of adipogenesis, visceral obesity causes adipocyte dysfunction with changes in the adipokine secretion pattern and the onset of local low-grade chronic inflammation or meta-inflammation. Anatomical position of visceral adipose tissue allows direct drainage of proinflammatory and prothrombotic adipocytokines into the portal bloodstream and liver, which play a key role in the pathogenesis of insulin resistance, metabolic and cardiovascular disorders, forming a complex cardiometabolic syndrome. The emergence of insulin resistance followed by atherogenic dyslipidemia results in an increase in extracellular concentrations of free fatty acids and the expansion of ectopic fat depots primarily in the liver, pancreas, heart, kidneys, skeletal muscles and bones. Large insulin-resistant fat cells of ectopic fat depots contribute to the development of insulin resistance and low-grade systemic inflammation by endocrine, paracrine, and autocrine secretion of proinflammatory molecules such as: interleukin- (IL) - 6, tumor necrosis factor-alpha (TNF-α), IL-8, IL-1, and others, causing a complex clinical disorder which yields a number of interrelated risk factors and long-term cardiometabolic disease risk increase.

Biological and psychosocial differences between men and women affect the epidemiology and pathophysiology of many diseases, including type 2 diabetes mellitus (T2DM). Obesity is a major risk factor for T2DM. Sex hormones, estrogens, and androgens contribute to gender differences in obesity-related T2DM since they regulate not only biological characteristics but also adipose tissue function and metabolism. Obesity, in particular visceral obesity, is characterized by systemic lowgrade inflammation or meta-inflammation. Meta-inflammation that occurs locally in adipose tissue becomes systemic via the release of various active inflammatory cytokines and acute-phase proteins, including TNF- α, interleukins 1β, 6, 17, and Creactive protein (CRP) into the bloodstream and consequently leads to insulin resistance. Understanding the differences between sex and gender is equally important in the prevention of obesity-related T2DM, its diagnosis and therapy. The initial stages of meta-inflammation involve adipocyte hypertrophy, hypoxia and cellular stress. Studies on the role of gender differences in obesity-induced inflammatory response have shown that males have a greater inflammatory response in adipose tissue, increased adipocyte apoptosis and macrophage infiltration, greater accumulation of pro-inflammatory adipose tissue macrophages and increased expression of inflammatory cytokines. These data suggest that adipose tissue in males is more susceptible to inflammation when compared to females and that this might lead to a higher incidence of insulin resistance. It is still debated whether oxidative stress is more pronounced in women than in men with T2DM. However, in female patients with T2DM, serum levels of IL-6, TNF-α and CRP were significantly higher compared to males with T2DM. Gender differences have a major impact on the development and the progression of obesity-related T2DM and its complications. Future studies should contribute to a better understanding of gender differences in obesity-related T2DM and differences in the inflammatory response between men and women to establish prevention and treatment of diabetes by gender-related guidelines.

Current evidence suggests that obesity, in addition to being a contributing factor for cardiovascular and metabolic disorders, also increases the risk of Alzheimer's disease (AD). It is well-documented fact that the brain is significantly affected by the inflammatory condition of obesity i.e. meta-inflammation via several pathways. Some systemic inflammatory and metabolic mediators produced by adipose tissue cross the blood-brain barrier in certain conditions. The most essential outcome is the activation of the brain-resident microglia and astrocytes contributing to CNS inflammation. Multiple studies have shown the existence of inflammatory markers in the brain and serum of post-mortem AD. In addition to the role of meta-inflammation, recent research has shown that insulin resistance and impaired insulin signaling can contribute to the development of AD as well as other neurological disorders. With this in mind, a group of scientists has proposed the term brain diabetes, or diabetes type 3, for cognitive impairment in AD patients, to unify the metabolic inflammatory pathways of the development of the disorder. The purpose of this is to show that AD is more than just an aggregation of oligomeric and fibrillar Ab deposits in the brain tissue. The disorder is represented by many pathological alterations, such as a lower degree of metabolism, blood-brain-barrier disturbance, and glial activation. Although not all signaling pathways involved in these processes are known yet, this new name could open a new field in the treatment of neurodegenerative impairments, to either prevent or slow down their development.

Neurodegeneration refers to the gradual deterioration of neuron structure and function and can lead to debilitating neurological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Common pathogenic mechanisms on which many neurodegenerative disorders (NDDs) are based include abnormal protein dynamics of malfolding, degradation, proteasomal instability, and aggregation; often with molecular chaperone actions and mutations; free radical/reactive oxygen species (ROS) formation and OxS; bioenergetic weakness, mitochondrial dysfunction and damage to DNA, neuronal Golgi system fragmentation, disruption of the movement of cellular/axonal, neurotrophin (NTF) dysfunction and neuroinflammatory/neuroimmune processes. Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of ROS/reactive nitrogen species (RNS) and/or a deficiency of enzymatic and nonenzymatic antioxidants. Oxidative stress can be a result, but also an obesity trigger. It has shown that obesity is coupled with an altered redox state and increased metabolic risk. Antioxidant defenses in obese patients are decreased compared to the control group, and their concentrations correlate inversely with core adiposity. Moreover, obesity is also defined by increased concentrations of reactive oxygen or nitrogen species. Metabolic changes caused by weight are associated with damage to the central nervous system (CNS), which can result in neuronal death, either through apoptosis or cell necrosis, or by modifying the neuron's synaptic plasticity. Adipose tissue dysfunction associated with obesity has been correlated with abnormal brain metabolism, neuroinflammation, brain atrophy, neural impairment, diminished mood, and cognitive decline. Due to their high metabolic rate, visceral fat tissues function as endocrine organs, which secrete adipokines (leptin, adiponectin, visfatin, resistin, apelin, and plasminogen activator inhibitor type 1) and cytokines (TNF-α, IL-6, IL-1β). Inflammatory cytokines bind to their receptors by activating the pathway of the nuclear factor-kappaB, which induces a pro-inflammatory state. Inflammatory pathways and DNA damage may also be triggered by nutritional imbalance, adversely affecting redox control [via glutathione peroxidase (GPx); glutathione (GSH), and oxidized glutathione (GSSG) levels] and thus fostering oxidative stress. Obesity also impacts the glucose and energy metabolism of brain cells, and by secreting pro-inflammatory agents causes neuroinflammation primarily in the brain's hypothalamic area. The general effect is the loss of neuronal activity and its internal molecular machinery, resulting in intracellular or extracellular or both aberrant protein deposition, contributing to neurodegeneration.

The term inflammaging refers to chronic, low-grade systemic inflammation that can be conceptualized as a basis for human aging. Although the importance of inflammaging in the aging process is now well recognized, its etiology remains largely unknown. In this chapter, several possible mechanisms underlying chronic systemic low-grade inflammation are discussed in addition to several pillars of geroscience that attempt to explain the association between aging and age-related diseases. Health preservation strategies that restrict or prevent inflammaging and serve to boost antiinflammaging mechanisms are also discussed. Moreover, this chapter presents an overview of obesity and obesity-related diseases in the elderly. The relationship between inflammaging and obesity in the elderly is explored as well as a potential explanation of the “obesity survival paradox”. The chapter also briefly presents the most common obesity-related complications in older individuals as well as treatment options in aging populations. The final part of the chapter links inflammation with obesity in more detail. The potential of obesity to accelerate the aging process is also discussed, as well as features of dysfunctional, aged adipose tissue. Given that in the last two decades, the role of chronic systemic low-grade inflammation has gained significant attention as the key player in pathophysiology of obesity- and agingassociated diseases, future studies should unravel whether inflammatory processes are the cause or consequence of obesity and aging. Furthermore, although some therapeutic interventions alleviate obesity, it seems that they are not sufficient alone and should be reinforced with the use of medications and other therapeutic modalities proven to decrease inflammatory processes.