Structural Brain Changes Associated With Overweight And Obesity Part 1

Obesity is a global health problem with a broad set of comorbidities, such as malnutrition, metabolic syndrome, diabetes, systemic hypertension, heart failure, and kidney failure. /is review describes recent findings of neuroimaging and two studies of cell density regarding the roles of overnutrition-induced hypothalamic inflammation in neurodegeneration. /ese studies provided consistent evidence of smaller cortical thickness or reduction in the gray matter volume in people with overweight and obesity; however, the investigated brain regions varied across the studies.

Systemic hypertension is a common chronic disease characterized by long-term elevation of blood pressure, which brings great harm to human health. Memory is one of the indispensable and important functions in people's daily life. It plays an important role in work, study, life, and other aspects. So, what is the relationship between systemic hypertension and memory?

Research shows that there is indeed a relationship between systemic hypertension and memory. High blood pressure can directly affect people's brain health. Insufficient blood supply to the brain caused by long-term elevated blood pressure will cause direct damage to neurons and vascular cells in the brain. In addition, high blood pressure is often accompanied by multiple comorbidities such as hyperlipidemia, coronary heart disease, stroke, and diabetes. These conditions will also aggravate the impact of high blood pressure on the brain. These factors will directly or indirectly affect people's development and thinking ability, and inhibit the development of memory.

However, don't be too pessimistic. In fact, for most patients with hypertension, as long as they take timely and effective measures, actively treat and scientifically control blood pressure, it is entirely possible to protect brain function. Various lifestyle adjustments, such as a reasonable diet, appropriate exercise, reducing stress, and ensuring adequate sleep, are very effective ways to prevent and treat high blood pressure. In addition, antihypertensive drugs prescribed by a doctor must also be taken according to the doctor's instructions, and the drugs must not be changed or stopped at will.

In short, the relationship between systemic hypertension and memory is indeed related to a certain extent, but it does not mean that hypertension is the culprit of memory decline. As long as we take effective treatment measures and control high blood pressure scientifically and rationally, a healthy brain and sharp memory will become important advantages in our lives and work. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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In general, bilateral frontal and temporal areas, basal nuclei, and cerebellum are more commonly involved. Mechanisms of volume reduction are unknown, and neuroinflammation caused by obesity is likely to induce neuronal loss. 

Adipocytes, macrophages of the adipose tissue, and gut dysbiosis in overweight and obese individuals result in the secretion of the cytokines and chemokines that cross the blood-brain barrier and may stimulate microglia, which in turn also release proinflammatory cytokines. /is leads to chronic low-grade neuroinflammation and may be an important factor for apoptotic signaling and neuronal death. 

Additionally, significant microangiopathy observed in rat models may be another important mechanism of induction of apoptosis. Neuroinflammation in neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) may be similar to that in metabolic diseases induced by malnutrition. 

Poor cognitive performance, mainly in executive functions, in individuals with obesity is also discussed. /is review highlights the neuroinflammatory and neurodegenerative mechanisms linked to obesity and emphasizes the importance of developing effective prevention and treatment intervention strategies for overweight and obese individuals.

1. Introduction

Obesity is a major global problem that intimately involves biological, physiological, behavioral, social, environmental, economic, and political factors [1]. Epidemic proportions of obesity have been reached by the end of the century since obesity has become one of the leading causes of death, a worldwide disability [2], and a significant financial burden [3]. 

In the 1970s, groups of specialists from the United Kingdom and the United States highlighted the need to consider the new phenomenon of obesity as an important disease, which at that time only affected adults, particularly women [4]. Moreover, obesity is exacerbated by the lack of effective treatment options [5]. In 2016, more than 1.9 billion adults aged 18 and older were overweight, of which more than 650 million had obesity. /these numbers correspond to 39% of adults over 18 years of age (39% men and 40% women), who were overweight, and 13% of the global adult population (11% men and 15% women) developed obesity [6]. 

In the last four decades, the prevalence of obesity has nearly tripled worldwide. More than 340 million children and adolescents aged from five to nineteen years were overweight or obese by 2016, and an estimated 38.2 million children under five years of age were overweight or obese in 2019 [6]. If recent trends continue, it is estimated that, by 2030, 60% of the world population (3.3 billion people) will be overweight (2.2 billion) or obese (1.1 billion) [7].

Overweight and obesity are linked to a higher number of deaths worldwide than underweight, with obesity rates surpassing 50% in many countries [8]. Body mass index (BMI) is one of the most widely used measures to identify excessive weight concerning height and age. /e World Health Organization categorizes obesity in terms of BMI: underweight (BMI less than 18.5 kg/m2 ), normal weight (range from 18.5 to 25 kg/m2 ), overweight (range from 26 to 30 kg/m2 ), and obese (greater than 30 kg/ m2 ) [6, 9]. 

However, the use of BMI as an index of overweight or obesity is not reliable for all individuals; BMI has been mainly used in adults, although it is now being used in children and elderly individuals. In the case of children and adolescents, BMI z-scores are used because, in this population, BMI varies with age and sex [10] (BMI z-score is defined as an index of relative weight adjusted for child age and sex about a reference population). /e waist-to-hip ratio (WHR) is another widely used measure that indexes the distribution of the adipose tissue [11]. 

Central body fat is associated with increased deposition of intra-abdominal adipose tissue, although an increase in subcutaneous abdominal adipose tissue is also involved. However, the WHR is not a flawless measure since abdominal circumference alone can provide the same information [11]. Dual-energy X-ray absorptiometry (DXA) is a technique extensively used in the clinic to assess body composition (bone mineral, fat, lean, and soft tissues) using a low-emission X-ray scan. DXA provides information about excess adiposity and quantifies total fat and lean soft tissue [12]. 

Air displacement plethysmography (ADP) is another useful technique to assess the body composition (bone density, lean tissue, and total body fat). ADP estimates the body volume of an individual by calculating the volume of the air in an empty chamber minus the volume of the air with a person seated inside the chamber [13]. 

Skinfolds are a common anthropometric method used to measure subcutaneous fat thickness, although they are not very indicative in some adults with overweight and obese. Moreover, standardized skinfold caliper measures are lacking; hence, there is no consensus regarding the actual distribution of subcutaneous fat measurements in the population [11].

2. Pathogenesis of Obesity

Obesity develops as a consequence of a lack of balance between food intake and energy consumption [14]. Energy expenditure includes the energy required to maintain vital functions (resting metabolic rate), perform physical activity, and provide diet-induced thermogenesis. 

Published studies have not supported the assumption that obesity is caused by disturbances of energy expenditure related to metabolism and/or diet-induced thermogenesis; instead, evidence suggests that diminished physical activity may significantly contribute to body weight gain [15]. /e energy expenditure required to maintain the weight varies widely between individuals, including people with similar constitutions. Differences in metabolic efficiency may explain this variability and play a role in susceptibility to weight gain [15]. 

Transformations of the lipids and carbohydrates into actual task performance require oxidation of the nutrients to yield adenosine triphosphate (ATP), which serves as a metabolic currency [15], and ATP is subsequently utilized to perform actual tasks (e.g., vital body functions and physical activity) [15]. Both of these metabolic processes involve heat production. /us, metabolic efficiency refers to the proportion of ATP vs. the production of heat derived for the performance of a given task [16]. /e ability to dispose of a part of excess energy as heat decreases the ability to store excess energy as fat and thus prevents weight gain [16]. Low metabolic efficiency implies an increase in heat production at the expense of ATP production [16]. 

Enhanced metabolic efficiency has been reported to contribute to obesity [16]. /e sympathetic nervous system (SNS) participates in homeostatic control. Fasting reduces SNS activity while eating, especially carbohydrate overfeeding, increases SNS activity. /e SNS innervates and modulates lipolysis in the adipose tissue [17]. Parasympathetic input may mediate the etiology of obesity by directly influencing the metabolic state of the adipose tissue. 

Neuroimmune interactions between the SNS and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue [18]. /us, SNS-mediated reduction in fat tissue lipolysis contributes to lipid accumulation and, consequently, excess weight [17]. /e brain and gastrointestinal tract are connected via the vagus nerve. Intra-abdominal adipocytes promote glucose and fatty acid intake by stimulating the SNS; these cells express adrenergic receptors that can respond to catecholamines of the sympathetic system. /e cholinergic part of the vagus nerve participates in the regulation of glucose and insulin [17]. 

Acetylcholine acts through the vagus nerve to potentiate the M3 muscarinic receptors of the pancreas to increase insulin secretion, improving the synthesis of cellular lipids and absorption of glucose, which causes storage of the calories and gain of lipids [17]. /The enteric nervous system produces more than 30 neurotransmitters; these hormones and peptides are released into the bloodstream, cross the blood-brain barrier (BBB), and stimulate the central nervous system (CNS). During ingestion, intestinal hormones are released due to the distension of the stomach, such as the peptides cholecystokinin, ghrelin, and leptin, which regulate the sensations of hunger and satiety. Ghrelin stimulates food intake by inhibiting the vagal signals and suppressing the release of insulin [17]. 

Leptin and insulin are involved in these effects on SNS activity. Leptin is an adipocyte-produced hormone that is upregulated in obesity [19]. Leptin signals in the brain largely at the level of the hypothalamus to modulate the activity of specific neuronal subsets (including orexigenic Agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) neurons), reduce appetite, and increase energy expenditure [20].
Leptin functions as a signal to circulate energy reserves by providing feedback inhibition in the hypothalamic orexigenic pathway; thus, obesity is strongly associated with hyperleptinemia [5]. Obesity is characterized by impaired leptin signaling despite elevated leptin levels, that is, leptin resistance, which explains why leptin administration to most people with obesity is not effective [20]. 

Leptin resistance is believed to be a result of inflammation and hypothalamic gliosis [20–22]. Long-term feeding of a high-fat diet to rats increases mediobasal hypothalamic activation of the inflammatory signaling intermediates c-Jun N-terminal kinase (Jnk) and nuclear factorκB (NF-κB), which results in the production of proinflammatory cytokines and impairment in insulin and leptin signaling [22]. 

Additionally, cellular response to a high-fat diet in the hypothalamus involves reactive gliosis [18], which is a CNS-specific process of recruitment, proliferation, and morphological transformation of astrocytes and microglia in response to brain injury. /is cellular response alters neurovascular coupling of POMC neurons due to ensheathment of the synapses to modify neurotransmitter dynamics by altering astrocyte expression of glutamate and glucose transporters to change the firing activity of POMC neurons [22].

Complex systems that regulate eating behavior balance the relationships between intake (diet) and energy expenditure. /ese systems are vulnerable to the disturbances caused by energy imbalance. /e hedonic and homeostatic pathways control the eating behavior. /e hedonic system relies on the striatum and has close connections to the hypothalamus and homeostatic system [23]. 

A reward deficiency is considered to cause an imbalance between homeostatic and hedonic regulation. /is hypothesis suggests that decreased dopaminergic signaling, which typically transmits the rewarding aspects of (food-related) stimuli, promotes overconsumption of tasty foods beyond homeostatic needs to compensate for lower sensitivity to the reward [24]. 

Decreased serotonin signaling in the hypothalamus is assumed to contribute to obesity by affecting negative feedback of energy ingested at food intake, thereby promoting excessive consumption [25]. /e paraventricular nucleus of the hypothalamus produces peptides that decrease with food intake, including thyrotropin-releasing hormone, corticotropin-releasing factor, and oxytocin. Cannabinoids regulate appetite, and inflammatory cytokines are also involved in the regulation of the gastrointestinal nervous system [19]. 

Inflammation in the hypothalamus can produce widely variable effects on behavior. /us, substantial elevations in hypothalamic cytokine levels have been observed in deep-anorexia animal models, both dependently and independently of leptin [5]. Hypothalamic resistance to the effects of leptin on the adipose tissue is essential for obesity. Hypothalamic inflammation is triggered in response to the consumption of large amounts of fat daily and is an important mechanism in the development of leptin resistance [26]. de Araujo et al. [27] considered the important effects of the energy content of food mediated by gut-innervating sensory vagal neurons (the gut-brain axis pathway) that act as a form of an interoceptive reward system, which is independent of palatability. 

Individuals with obesity do not report liking food more than their healthy-weight counterparts. Palatability affects what an individual eats but does not reflect how much this individual eats. /e energy content of food is reinforcing. According to de Araujo et al. [27], subcortical gut-brain pathways sense nutritive properties independently of palatability and activate the brain reward circuits. /e motivational power of energy density appears stronger in people with obesity. 

However, the gut microbiota is thought to play a role in the mechanisms governing the stress response via the hypothalamic pituitary adrenal (HPA) axis, and the deregulation of this axis has also been related to obesity [28]. /e gutbrain axis is a complex system that enables communication between the gut and brain through hormonal, immunological, and neural signals. /e CNS, autonomous nervous system, enteric nervous system, HPA axis, and gut microbiota are components of the gut-brain axis. 

All these components establish bidirectional communications from the CNS to the gut and from the gut to the CNS [29]. 

Gut hormones are released by enteroendocrine cells that trigger signaling in the CNS in response to preabsorptive nutrients and subsequently impact energy homeostasis [29]. As a part of the gut-brain axis, the gut microbiota (microorganisms that live in the human digestive tract) play an important role in adiposity and weight gain via energy harvesting, posterior generation of various metabolites (e.g., short-chain fatty acids), changes in host behavior, and satiety through the gut-brain axis that induces inflammatory responses [29]. 

Obesity, metabolic diseases, some psychiatric disorders, and cognitive impairments can result from dysregulation of this system [28, 29]. /There are positive associations between stress (high levels of glucocorticoids), weight gain, adiposity, BMI [30], basal glucose, basal insulin, and insulin resistance [31]. Associations of stress with metabolic dysfunction are stronger in individuals with higher BMI than in people with lower BMI [32], suggesting that stress increases obesity risk, especially in individuals with higher BMI. 

Chronic high levels of glucocorticoids and insulin boost an increase in palatable food intake and abdominal fat deposition [33]. Stress can trigger metabolic dysfunction and modify eating behavior; moreover, individuals with obesity are more sensitive to stress. /e HPA axis plays an important role in the onset of metabolic alterations and obesity [34].

3. Obesity and Neuroinflammation

Macrophages regulate inflammation according to various activation states depending on their state of differentiation; thus, classically activated macrophages (M1) initiate the process by secreting proinflammatory cytokines and reactive oxygen species (ROS) [35], whereas subsequent phases of the immune response are controlled by "alternatively" activated macrophages (M2) to reduce inflammation and promote tissue remodeling and release of the growth factors [35]. 

In healthy, nonobese humans, macrophages in the adipose tissue function similarly to M2 macrophages; that is, they produce little to no proinflammatory cytokines and express arginase, which inhibits nitric oxide production and leads to polyamine generation [36]. However, adipose tissue-associated macrophages located at the sites of chronic inflammation in obesity can act as the sources of proinflammatory cytokines [37]. 

Both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis [38]. Accumulation of adipose tissue in obesity is the key factor of systemic inflammation. Both hypertrophic adipocytes and immune cells residing in the adipose tissue (mainly lymphocytes and macrophages) contribute to a pro-inflammatory state via an increase in the levels of tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1, C-reactive protein, interleukin-1-beta (IL-1-beta), and interleukin-6 (IL-6) [39, 40]. /e inflammatory response mediated by M1 during obesity may be analogous to the mechanisms of necrotic clearance [41, 42]. 

Macrophages secrete cytokines, especially TNF and IL-6, and chemokines, such as CC-chemokine ligand 2 (CCL2; previously known as monocyte chemotactic protein-1 (MCP1)). TNF and IL-6 can interfere with insulin signaling in adipocytes, leading to type 2 diabetes (T2DM) [43]. Macrophages accumulate in adipose tissue over time, and the cytokines that they produce can lead to insulin resistance and T2DM [36, 37]. 

Overexpression of procoagulant proteins by these inflammatory macrophages can contribute to atherogenic and cardiovascular risks that constitute a part of obesity-associated metabolic syndrome [43]. However, obesity-associated gut microbiota may also contribute to neurochemical and inflammatory alterations [28, 44]. /e gut microbiota is an intermediate factor between environmental pressures (e.g., diet and lifestyle) and host physiology, and its alteration (i.e., dysbiosis) can partly explain obesity [28]. 

Gut dysbiosis (imbalance in gut microbiota composition caused by host genetics, lifestyle, and exposure to microorganisms) [45] may promote diet-induced obesity and metabolic complications via a variety of mechanisms, including immune dysregulation, altered energy regulation, altered gut hormone regulation, and proinflammatory mechanisms (such as lipopolysaccharide endotoxins that cross the gut barrier and enter the portal circulation) [44, 46]. 

Recent studies demonstrated that compositional changes in the gut and inflammation related to a leaky gut (a loss of intestinal barrier integrity reducing its ability to protect the internal environment) may contribute to the pathophysiology of several diseases, such as depression, chronic fatigue syndrome, obesity, or T2DM [47]. Inflammation resulting from obesity can affect brain structures, such as the hippocampus, cerebral cortex, brain stem, and amygdala [48]. 

Low-grade inflammation characteristic of obesity can lead to neuroinflammation via various mechanisms, including the choroid plexuses and disruption of the BBB [49]. Peripheral inflammation observed in obesity leads to insulin resistance [36, 37]. /The brain is a privileged organ for immunity; however, transitions between peripheral and central inflammation have been reported. 

Adipokines are produced by the adipose tissue and can also be expressed in the CNS, where receptors for these factors are present. Adipokines produced in the periphery can cross the BBB or modify its physiology by acting on the cells that form the BBB to affect the CNS. 

Adipokines can regulate neuroinflammation and oxidative stress, which are two important physiological processes involved in neurodegeneration and are associated with many chronic neurodegenerative diseases [50]. Damage to the BBB in aging can also lead to inflammation in the brain. Neuroinflammation may be the most important cause of cognitive dysfunction and can thus lead to a central pathological mechanism associated with aging [51].

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