Abstract
The metabolic dysfunctions induced by high fat diet (HFD) consumption are not limited to organs involved in energy metabolism but cause also a chronic low-grade systemic inflammation that affects the whole body including the central nervous system. The brain has been considered for a long time to be protected from systemic inflammation by the blood–brain barrier, but more recent data indicated an association between obesity and neurodegeneration. Moreover, obesity-related consequences, such as insulin and leptin resistance, mitochondrial dysfunction and reactive oxygen species (ROS) production, may anticipate and accelerate the physiological aging processes characterized by systemic inflammation and higher susceptibility to neurological disorders. Here, we discussed the link between obesity-related metabolic dysfunctions and neuroinflammation, with particular attention to molecules regulating the interplay between energetic impairment and altered synaptic plasticity, for instance AMP-activated protein kinase (AMPK) and Brain-derived neurotrophic factor (BDNF). The effects of HFD-induced neuroinflammation on neuronal plasticity may be mediated by altered brain mitochondrial functions. Since mitochondria play a key role in synaptic areas, providing energy to support synaptic plasticity and controlling ROS production, the negative effects of HFD may be more pronounced in synapses. In conclusion, it will be emphasized how HFD-induced metabolic alterations, systemic inflammation, oxidative stress, neuroinflammation and impaired brain plasticity are tightly interconnected processes, implicated in the pathogenesis of neurological diseases.
Highlights
Genetic predisposition, sedentary lifestyle, eating habits, environmental factors and altered metabolism are the main and convergent contributors in the onset of obesity, a well-known complex and multifactorial pathology that has reached pandemic proportions
Chronic low-grade inflammation induced by obesity reduces AMPK activity in multiple tissues including skeletal muscle [18,19,20], liver [21,22,23] and adipose tissue [23,24], with a mechanism still partly unknown but probably involving altered mitochondrial fatty acid oxidation
Recent data indicate that this systemic inflammation affects the central nervous system (CNS), leading to neurological diseases
Summary
Sedentary lifestyle, eating habits, environmental factors and altered metabolism are the main and convergent contributors in the onset of obesity, a well-known complex and multifactorial pathology that has reached pandemic proportions. Chronic low-grade inflammation induced by obesity reduces AMPK activity in multiple tissues including skeletal muscle [18,19,20], liver [21,22,23] and adipose tissue [23,24], with a mechanism still partly unknown but probably involving altered mitochondrial fatty acid oxidation. Mitochondrial dysfunction in liver and skeletal muscle leads to reduced FAs oxidation, impaired glucose homeostasis, increased ectopic lipid accumulation and decreased insulin sensitivity [15,19] This is a hallmark of IR and type 2 diabetes [27,28,29,30,31]. Several results show that the activation of AMPK, by appropriate diet supplementation, reduces obesity and IR [18,19,41] (Figure 2)
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