Obesity is a clinical and metabolic condition characterized by a pathological increase in the percentage of body fat with the potential to cause damage to health, in the last 35 years the number of obese people in the world has doubled. This literature review aims to clarify the mechanisms responsible for the neurological disorders related to excess body fat and to gather up-to-date information on the subject. A narrative review of the literature in Medline databases from 2010 to 2022 was performed on neurological disorders, obesity, overweight, neurology and central obesity. In Medline, 154 articles were found by the Mesh descriptor “(neurological disorder AND obesity AND overweight AND neurology AND central obesity)”, of which 59 were selected after the first set of criteria. Exclusion of titles that did not address the topic “obesity and/or neurological disorders”, articles not included in English and gray literature were excluded. As classically in the physiology of the cardiovascular system, it is now also evident that obesity has negative impacts on the brain. Likewise, it was exposed that the increase in BMI is directly related to the presence of attention deficits, poor executive function, impaired ability to make decisions and decreased verbal learning and memory. In addition, studies show that obesity is strongly associated with neurological dementia disorders such as Alzheimer's disease, which has a doubled risk if developed in these patients. Therefore, although the neurological mechanisms of obesity are not completely elucidated, it is a fact that a high-fat diet and increased BMI have correlations with the release of inflammatory mediators that lead to aggression of the nervous system - central and peripheral - through numerous mechanisms.

Keywords: inflammation, alzheimer, disturbances, cheers

Obesity is a clinical and metabolic condition characterized by the pathological increase in the body fat percentage with potential of causing damages to health.^1–3 In fact, the adult individual that has obesity should be stratified in the BMI scale, which represents a triage scale from the individual´s mass in kilograms divided by its height in meters, comparatively in children, the weight percentile scale is utilized, and the diagnosis is confirmed when the result is above 95%.⁴

In the last 35 years the number of obese people in the world doubled, highlighting that in 2014 the percentage of obese people in the world (above 18 years old) was 11% of men and 15% of women, of which 0,64% and 1,6%, respectively, have morbid obesity (BMI ≥40 kg/m²).⁵ In North America, the most important numbers are from the United States that have approximately 38,3% of the female population and 34,3% of the male population with obesity, highlighting the hispanic ethnicity, which represents the biggest portion of this characterized context, due to variables, such as behavior, risk factors and social determinants, which are target of clinical and social interventions to reduce this expressive number.⁴

Obesity affects almost all of the systems in the human organism, a fact that can be unleashed by various mechanisms.^6,7 In fact, frequent metabolic alterations present in this condition, such as hyperglycemia, chronic inflammation, hyperleptinemia and endothelial dysfunction, favor the oxidative stress process, that is related with the development of numerous pathologic events, for example, diabetes, cardiovascular complications, asthma and infertility, Besides, it is known that obesity generates dysfunction in the metabolism of the adipose tissue, in a way that dysregulates the secretion of adipokines, substances that, between other functions, participate in the metabolism of glucose, in inflammation and in the regulation of the blood pressure, which has been associated with the pathogenesis of multiple diseases related with obesity.^8–11 Furthermore, the mechanical effects of the increase in body mass also contribute to the development of comorbidities.^6,12

About the central nervous system, it is viewed that obesity and a diet rich in fats have negative roles,¹³ leading to systemic inflammation, mediated by cytokines, and the excess of free fatty acids circulating, which reaches the brain at a hypothalamic level.¹⁴ The local inflammation causes neurodegeneration of the hypothalamus and synaptic remodeling, which provokes alterations of internal circuits and of other cerebral regions. Therefore, there is, in regions of the hippocampus, amygdala and reward processing centers, an interruption of cognition, of the satiety signals and of the perception of excesses. Some studies in humans suggest that obesity can accelerate the degenerative processes of the cerebral function related to age.¹³

Obesity is related to neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. This association occurs because the fat excess, due to metabolic alterations, can cause a decrease of the brain´s integrity, which results in changes of the synaptic plasticity and death by cellular necrosis or apoptosis.^15,16 Besides, in an american study, it was evidenced that many obese patients presented a decrease in the volume of the hyppocampus. This structure, which is also attacked in Alzheimer's disease, is essential for learning and for memory.¹⁷ Furthermore, as a consequence of modifications in the metabolism of the adipose tissue present in obesity, the development of pathologies such as migraine and pseudotumor cerebri can also be observed as a result of the weight excess.^6,18–23

According with the informations exposed, this literature review aims to enlighten the mechanisms responsible for the neurologic disturbances related with the excess of body fat and gather updated information about the subject, considering the increase in the prevalence of obese people in the world.⁵

A narrative literature review was conducted in the Medline Databases, from 2010 to 2022, on neurological disorders, obesity, overweight, neurology and central obesity. In the Medline, 154 articles were found by the Mesh descriptor “(neurological disorders AND obesity AND overweight AND neurology AND central obesity)”, of which 59 were selected, after the first set of criteria — exclusion of titles not addressing to the topic “obesity and/or neurological disorders”, articles not included in the search period 2010-2022, as well as non-English articles. The second set of criteria — exclusion of the abstracts not addressed to obesity or neurological disorders and of those in which the neurological disorder was the cause of obesity — was applied, by which 11 articles were excluded. Other articles that did not contemplate these conditions were excluded. To ensure content saturation, the authors checked the included research references and related reviews on topics to identify missing publications. Furthermore, 34 articles from the Medline Database were manually screened and added according to their relevance in the qualitative evidence synthesis. Of the total, 82 original articles remained.

Pathophysiology of obesity

Obesity has an important evolutive component, considering that, in the beginning of evolution, the species suffered a selective pressure to adapt in a hostile environment and with little nutritional resources.⁵ Therefore, humans and their ancestors needed to survive in long periods of malnutrition, a situation that selected the genotype that had the capacity to store more energy in adipose tissue,²⁴ with low energy expenditure and physical inactivity. However, it is known that, nowadays, the supernutrition has become extremely problematic to the species, because, according to WHO,²⁵ the mortality due to excess weight has been becoming greater than death because of low weight. This condition negatively affects the individuals and contributes to the development of numerous enfermities, highlighting the neurological disorders (Figure 1).²⁴

Figure 1 Risk factors for obesity: external and internal.

Furthermore, many researches have been made to understand the gut-brain axis, and how the adipose tissue dysfunctions can lead to intestinal and hepatic hormonal dysregulations, and affect the transmission of information, such as satiety and appetite for the hypothalamus.^5,26 In this context, it is expected that this correlation will be useful in the comprehension of how the brain of obese individuals processes the desire for food, and in the therapeutic interventions for obesity.

About pathogenesis, the pro-inflammatory systemic component of obesity is well established (Figure 2). The diet rich in grease leads to the increase in the profile of pro-inflammatory cytokines (as TNF-alpha), through numerous mechanisms,¹³ from which stand out the stimulation of the free fatty acids and lipopolysaccharides (LPS) receptors and toll like receptor 4 (TLR4), the increased infiltration of macrophages, apoptosis of adipocytes and the reduction of the vascularization of the white adipose tissue,²⁷ contributing to the inflammatory cascade.

Figure 2 Pathophysiology of obesity and neuroinflammation.

These events have hepatic and muscular consequences that can favor the systemic resistance to insulin²⁸. Besides, some hypothalamic pathways can be interrupted by neuroinflammation, such as the leptin pathway, an anorexigen hormone, responsible for satiety, which could complicate the control of obesity and the interruption of a diet rich in fats.^13,27

Obesity effects in the central nervous system

Just as classically in the physiology of the cardiovascular system, now it is also evident that obesity has negative impacts in the brain.^13,29–37 Numerous studies have shown a link between a higher BMI - and other measurements of central obesity, such as waist circumference and waist-hip ratio¹⁴ - with the damage of the cognitive function, independently of its relation with cardiovascular and cerebrovascular diseases.^17,38–42 In the same way, it was exposed that an increased BMI is directly related to the presence of attention deficits, bad executive function, impaired capacity to make decisions, and decrease in verbal learning and in memory.⁴³ Besides, studies show that obesity is strongly associated with dementia neurological disturbances,⁴⁴ such as Alzheimer's disease, which has doubled risk if developed in these patients.^45–51

Along with the effect on cognitive performance, it is also known that obesity influences aspects of the cerebral morphology, leading, more precisely, to a brain atrophy,^52–58 which can be enhanced in males.⁵⁹ Studies have reported that there is a decrease, mainly in the frontal and temporal lobes (including the hippocampus), of the gray matter´s focal volume⁵² and an increase of the orbitofrontal white matter associated with axonal and/or myelinic abnormalities, which can reflect the loss of neurons.^60,61 Thus, once a larger hippocampus is closely linked to good cognitive function,⁶² and that frontal regions of the brain are important for executive functions,¹³ it is conceivable that such brain atrophy can contribute to cognitive damage in obese individuals.^14,15

Therefore, it was demonstrated that a hyperlipidic diet increases the expression of pro-inflammatory cytokines in the hypothalamic region,^17,63,64 and that this inflammation can interrupt the normal signalization related to nutrition, favoring the weight gain and maintaining an increased body weight.¹³ Another subject concerning this inflammatory process is that many studies with animal models have shown that this is an initial step in a vicious cycle of dysfunction of the CNS, in ultimate analysis, to the cognitive decline.⁶⁵

Obesity effects on the peripheral and autonomic nervous system

The peripheral nervous system has two divisions, the autonomic nervous system, which is subdivided in sympathetic and parasympathetic, and the somatic nervous system, which is subdivided in sensitive and motor peripheral nerves. In this division, there are regions that are not protected by the blood-brain barrier, differentiating from the regions of the CNS, for example, the autonomic nervous system and the sensorial ganglia, along with the non myelinated fibers and the terminations of the synapses of the PNS, therefore are vulnerable locations and exposed to the aggressive factors of the inflammatory pathophysiology of the adipose tissue.^17,66–68

Therefore, these locals more sensitive to lipidic inflammation present increase of the sympathetic flow in neuro-adipose junctions, stimulating the lipolysis via β, which results in triglyceride hydrolysis, and consequently in an increase of long chain fatty acids (LCFAs).^69–74 This sympathetic flow, besides the damages to the PNS, also causes chronic stimulation of angiotensinogen in the adipose tissue, besides acting on the musculoskeletal system causing insulin resistance, in the pancreas with insulin release and in the liver with gluconeogenesis and glycogenolysis.^68,75–77

Similarly to the blood-brain barrier, the blood-nerve barrier exists in the PNS, which is formed by microvessels of the endoneurium and perineurium, but, anatomically, the dorsal root, the ganglionar neurons and the peripheral sensory receptors are unprotected.^17,69,78 Therefore, a chronic dysfunction secondary to the inflammation caused by obesity can happen, affecting the nervous structures and its subjacent components, through the increase in inflammatory interleukins, such as TNFα, IL-1β and immune cells, such as macrophages and lymphocytes.^68,70,78,79

Additionally, it is possible to evidence the increase of free fatty acids and LCFAs that alter the operation neurophysiology of the PNS, through dysfunction of the Schwann cells, axonal degeneration and polyneuropathies.^68,78,80,81 This lesion caused by LCFAs occurs because these fatty acids cause the stress of the endoplasmic reticulum, mitochondrial depolarization and generation of reactive oxygen species, interrupting, finally, the ATP production by the mitochondria and damaging the PNS profoundly.^17,68,78

Clinical implications and future perspectives

The increase of the visceral adiposity is a risk factor for the development of numerous neurological conditions, but, currently, an ideal intervention to prevent the cognitive damage is still unknown.^8,17 Until this moment, few controlled prospective studies have evaluated the comparative efficiency of the medical, pharmacological, surgical and lifestyle interventions. Furthermore, just as the comparison of the efficiency of the interventions, it is necessary to evaluate the benefit-cost ratio between them. Future studies are necessary to determine a potential role for the neuroinflammation in the cognitive damage related to obesity.^17,82 Given the available evidences until this moment, doctors should advise obese individuals, especially those that present precocious evidences of lesions in the CNS and PNS.

Therefore, despite the neurologic mechanisms of obesity not being completely elucidated, it is a fact that a hyperlipidic diet and an increased BMI have correlations with the release of inflammatory mediators that lead to the aggression of the nervous system - central and peripheral - through numerous mechanisms. The neuroinflammation stands out, which affects the hypothalamic pathway that controls satiety, the cognitive function since childhood until senescence and the peripheral synapsis, leading to sociofunctional related damages, respectively, with the maintenance of a greasy diet, difficulty in learning and in memory and polyneuropathies. Furthermore, it is also known that obesity leads to morphological and structural alterations of the nervous system and that this can also be associated to the cognitive decline in the obese individuals. Finally, even before the analyzed knowledge, it is necessary that there are scientific deepenings in the investigation of pharmacological, surgical and social lifestyle intervention mechanisms, aiming to better approach the control of the damaging effects of obesity.

Medical School and Nutrition Course University Center Christus, UNICHRISTUS, Fortaleza, CE, Brazil.

The authors declare that they have no conflicts of interest. All authors read and approved the final manuscript.

None.

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