Cross-Talk Between Obesity and Central Nervous System: Role in Cognitive Function

Obesity is a health problem in western societies being usually associated with low-grade inflammation [1]. White adipose tissue (WAT) accumulation contribute to an increased risk of obese subjects develop several related diseases, such as type 2 diabetes and neurodegenerative diseases [2-4]. Obesity is associated to mild cognitive impairment, and increased risk of developing dementia and Alzheimer´s disease [5,6]. Obesity-induced neuroinflammation has shown to affect brain areas related to cognitive performance and memory, such as the hippocampus, and cortex [7,8]. The expanded hazard for obese subjects to develop a CNS pathology mirrors the connectivity of WAT to the cerebrum through different pathways to affect the mind work [4-6]. It is now well established that WAT is not just a fat storage organ, as it was considered for many years, but an endocrine organ that secretes different substances called adipokines, which play a role in cognitive function [6,9,10].

Adipokines circulating levels are changed in overweight, and obesity due to the expansion of WAT [6,9]. Low-grade inflammation state is produced by the increased level of several pro-inflammatory adipokines, such as leptin, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6 [11]. The levels of circulating pro-inflammatory mediators can affect the central nervous system (CNS) through lymphatic vessels, coroid-plexus and blood brain barrier (BBB) [1]. The mechanism of affecting CNS occurs due to the development of a peripheral inflammation that leads to the elevation of these pro-inflammatory adipokines, such as TNF-α, leptin and IL-6, which are able to cross the BBB, and might contribute to the development of brain inflammation and insulin resistance [10,12,13]. Intracellular signaling mediated by pro-inflammatory adipokines and insulin resistance are the main mediators of obesity-associated cognitive decline because they will disturb synaptic plasticity, induce oxidative stress and neuroinflammation interfering in the learning processes [7,10,14,15]. On the other hand, anti-inflammatory adipokines are diminished in obese individuals, such as IL-10 and adiponectin [6].

Neurophysiological functions have also been attributed to leptin, another adipokine secreted by WAT that can cross the BBB, which is involved in brain development, neurogenesis, neuronal survival, and behavior [16,17]. In the absence of leptin in early life, even for a short period of time, will favor a poor development of arcuate nucleus neural projection [18]. Leptin also influences reproduction and metabolism acting on the hypothalamus to suppress food intake [16]. Leptin acts as a potential psychological enhancer as it stimulates the cell events involving learning and memory in hippocampi [17]. Leptin responses are diminished in obesity, aging, and neurodegenerative disorders, contributing to insulin resistance and inflammation, and leading to cognitive decline [6]. When leptin is reduced in the organism, we call this physiological change of leptin resistance.

Microglial cells and astrocytes are the main TNF-α producers in human body [19]. Neuroinflammation is strongly mediated by microglial and astrocyte cells activation with consequently secretion of TNF-α [20-22]. Learning and memory failure are associated to inflammation and changes in insulin signaling in the brain [15,23]. Brain regions involved in cognitive decline show exacerbated microglial and astrocyte expression [5,10,24]. Higher expression of TNF-α with activation of stress kinases are the main features for defective neuronal insulin signaling and, consequent, cognitive decline [10,25]. Interestingly, blockade of TNF-α in mouse models leads to an improvement in insulin sensitivity and glucose homeostasis rescuing synaptic plasticity, short and long-term memory [10,26,27].

It has been shown that obesity leads to brain atrophy, reducing volume in a number of brain regions [28,29]. Thus, peripheral inflammation might contribute to cognitive decline and memory loss [5]. A recent meta-analysis showed that increased plasma levels of IL-6 and C-reactive protein are main features of obesity that are associated with an increase in dementia [30]. However, a recent study revealed that IL-6 blockade increased cholesterol levels, and visceral adipose tissue was not reduced even under physical exercise training [31]. Thus, IL-6 is needed for exercise in order to reduce visceral adipose tissue mass and also play an undefined role in cognitive decline [30,31].

Termination of neuroinflammation has the participation of antiinflammatory adipokines, such as IL-10 [32]. It has been shown that the level of IL-10 in different areas of the brain increases in several conditions and diseases, thereby promoting survival of neurons [33-35]. Associations between cognitive decline, memory loss and pro-inflammatory adipokines have been showed and the oppose actions to these mechanisms by IL-10 have also been proved in a recent meta-analysis [35]. It can be suggested that antiinflammatory cytokines, such as IL-10, develop an important role in conditions of memory impairment, since IL-10 is also synthesized in the central nervous system [32-35].

Adiponectin is responsible for the increasing in insulin sensitivity in liver and muscle [36]. Adiponectin develops several anti-inflammatory activities, such as suppression of macrophage activation, in peripheral tissues [37]. It inhibits, in vivo and in vitro, microglia pro-inflammatory profile [38]. Plasma levels of adiponectin are decreased in obesity and contribute to insulin resistance being also linked to cardiovascular diseases [39]. Low levels of adiponectin are also related to cognitive decline, although the specific role in brain functioning related to learning and memory is not completely clarified yet.

Obesity is a world health problem that has been linked to a reduction in cognitive performance. Obese subjects present an increased risk to develop neurodegenerative disorders, such as type 2 diabetes, dementia, and Alzheimer. Excess of white body fat tissue seems to lead to neuroinflammation through activation of different adipokines affecting cognitive performance and memory. The ability of adipokines, pro and anti-inflammatory, to modulate learning and memory emphasizes the special properties of the WAT not only in obesity.

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