Obesity-Induced Neuroinflammation: Beyond the Hypothalamus

Recent evidence supports the presence of an obesity-driven neuroinflammation in the amygdala, hippocampus, and cerebellum. Based on the numerous studies on the topic it appears that obesity-induced neuroinflammation is dependent on the type of diet and on the duration of the diet. During diet-induced obesity, neuroinflammation does not develop to the same extent in different brain structures. Obesity induces neuroinflammation and cognitive dysfunction. However, obesity-induced cognitive dysfunction has been also found in the absence of neuroinflammation. In obese patients, anthropometric markers (such as waist circumference) have been associated with profound architectural alterations in white and grey matters, and also with microglial activation. Obesity is now a worldwide health issue. Far from being limited to weight gain, obesity is generally associated with low-grade inflammation and with a cluster of disorders collectively known as the ‘metabolic syndrome’. When considering obesity and the subsequent neuroinflammation, the focus was long set on the hypothalamus. More recently, obesity-derived neuroinflammation has been shown to affect other brain structures such as the hippocampus, cortex, brainstem, or amygdala. Furthermore, obesity has been associated with increased occurrence of central disorders such as depression and impaired cognitive function. We discuss here the effects and mechanisms of obesity-derived neuroinflammation, with a specific emphasis on extra-hypothalamic structures, as well as the repercussions of neuroinflammation for some cerebral functions. Obesity is now a worldwide health issue. Far from being limited to weight gain, obesity is generally associated with low-grade inflammation and with a cluster of disorders collectively known as the ‘metabolic syndrome’. When considering obesity and the subsequent neuroinflammation, the focus was long set on the hypothalamus. More recently, obesity-derived neuroinflammation has been shown to affect other brain structures such as the hippocampus, cortex, brainstem, or amygdala. Furthermore, obesity has been associated with increased occurrence of central disorders such as depression and impaired cognitive function. We discuss here the effects and mechanisms of obesity-derived neuroinflammation, with a specific emphasis on extra-hypothalamic structures, as well as the repercussions of neuroinflammation for some cerebral functions. also known as the Quetelet index. An anthropometric tool used to assess the obesity status of individuals. It is calculated as body mass (kg) divided by the square of body height (m). Normal BMI is in the range 18.5 to 25 kg/m2. Individuals are considered to be overweight above 25 kg/m2, and obese at >30 kg/m2. Even though the BMI is the most widely used anthropometric measurement in the context of obesity, other commonly used measures include waist-to-hip ratio (WHR) and waist circumference (WC). a rodent standard diet is generally composed of (in % kcal) 15% protein, 75% carbohydrate, and 10% fat. A Western diet (WD) of 17% protein, 43% carbohydrate, and 41% fat. A high-fat diet (HFD) of 20% protein, 35–20% carbohydrate, and 45–60% fat. Fatty acid (FA) profiles are: standard chow: 17% saturated FAs (SFAs); 24% monounsaturated FAs (MUFAs); 59% polyunsaturated FAs (PUFAs). Lard-based: 32% SFA; 36% MUFA; 32% PUFA. Cocoa butter-based: 64% SFA; 33% MUFA; 3% PUFA. Coconut oil-based: 93% SFA; 3% MUFA; 4% PUFA. the presence of endotoxins (bacterial membrane molecules capable of eliciting an immune response) in the blood. briefly, macrophages can be characterized according to their activation state into M1 ‘proinflammatory’ (or classically activated) or M2 ‘anti-inflammatory’ (or alternatively activated) macrophage subtypes. However, macrophages can be anywhere on the M1–M2 activation state continuum. according to the National Cholesterol Education Program Adult Treatment Panel III, MetS encompasses different metabolic disorders usually associated with obesity. An individual is diagnosed with MetS if they present at least three of the five following criteria: abdominal obesity measured using waist circumference (≥88 cm for women and ≥102 cm for men), plasma triglycerides above 1.7 mM, high-density lipoprotein (HDL) cholesterol below 1.30 mM for women and below 1.04 mM for men, blood pressure higher than 130/85 mm Hg, and finally fasting glucose greater than 6.1 mM. Moreover, most patients with MetS are at greater risk of developing cardiovascular diseases and type 2 diabetes. a complex protein oligomer involved in inflammatory processes. Its activation depends on a priming event such as the activation of the NF-κB pathway that leads to transcriptional upregulation of inactive forms of NLRP3, pro-IL-1β, or pro-IL-18. Following a second event, NLRP3 forms a complex oligomer with ASC and pro-caspase-1 that activates pro-caspase-1 into its active form, caspase-1. Finally, caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18. depending on the cytokines present in their environment, T cells can acquire different phenotypes that are classified based on the mediators they specifically produce. Th1 cells produce IFN-γ and IL-2, whereas Th2 cells produce IL-4 and IL-13. Treg cells represent another activation state of T cells and are implicated in decreasing the amplitude of immune responses.