Elsevier

Brain, Behavior, and Immunity

Volume 42, November 2014, Pages 10-21
Brain, Behavior, and Immunity

Named Series: Diet, Inflammation and the Brain
Obesity and neuroinflammation: A pathway to cognitive impairment

https://doi.org/10.1016/j.bbi.2014.04.001Get rights and content

Abstract

Obesity is a growing problem worldwide and is associated with a range of comorbidities, including cognitive dysfunction. In this review we will address the evidence that obesity and high fat feeding can lead to cognitive dysfunction. We will also examine the idea that obesity-associated systemic inflammation leads to inflammation within the brain, particularly the hypothalamus, and that this is partially responsible for these negative cognitive outcomes. Thus, obesity, and high fat feeding, lead to systemic inflammation and excess circulating free fatty acids. Circulating cytokines, free fatty acids and immune cells reach the brain at the level of the hypothalamus and initiate local inflammation, including microglial proliferation. This local inflammation likely causes synaptic remodeling and neurodegeneration within the hypothalamus, altering internal hypothalamic circuitry and hypothalamic outputs to other brain regions. The result is disruption to cognitive function mediated by regions such as hippocampus, amygdala, and reward-processing centers. Central inflammation is also likely to affect these regions directly. Thus, central inflammation in obesity leads not just to disruption of hypothalamic satiety signals and perpetuation of overeating, but also to negative outcomes on cognition.

Introduction

The number of obese (body mass index, BMI >30) and overweight (BMI >25) people is reaching epidemic proportions worldwide. The World Health Organization reports that in 2008, more than 1.4 billion adults were overweight and over 200 million men and nearly 300 million women were obese (WHO, 2013). The prevalence of overweight and obese children and adolescents is also high. For example, during 2009–2010 the prevalence of childhood obesity was 16.9% in the United States of America (Ogden et al., 2012). Alarmingly, evidence shows that children who are overweight are more likely to remain so in adulthood (Biro and Wien, 2010).

It is well known that obesity increases the risk for a wide spectrum of conditions including type 2 diabetes, hypertension, heart disease, stroke, musculoskeletal disorders, gastrointestinal and respiratory problems, and many types of cancer (Haslam and James, 2005). In addition, relationships between obesity and cognitive function, as well as risk of dementias such as Alzheimer’s disease (AD), have more recently come to attention. For example, clinical and experimental evidence indicates that obesity and/or high fat feeding are associated with deficits in learning, memory, and executive functioning (Elias et al., 2003, Elias et al., 2005, Cournot et al., 2006, Sabia et al., 2009), and potentially brain atrophy (Enzinger et al., 2005, Ward et al., 2005). Moreover, accumulating evidence indicates obesity during mid-life increases the risk of dementias such as AD later in life (Gorospe and Dave, 2007, Beydoun et al., 2008, Anstey et al., 2011).

In light of the high numbers of overweight and obese individuals, there is a clear need to better understand the pathophysiological mechanisms underpinning obesity and its impact on cognitive function. Inflammation, the body’s defense response to harmful stimuli, is proposed to be an important pathophysiological mechanism underlying cognitive impairment and dementia, and has been implicated in the neuropathological hallmarks of AD (i.e. amyloid plaques and neurofibrillary tangles) (Gorelick, 2010). On the other hand, it is well accepted that obesity is associated with low-grade inflammation in peripheral tissues and the circulation (Gregor and Hotamisligil, 2011, Spencer, 2013). Moreover, accumulating evidence suggests that obesity also results in inflammation in the brain and particularly in the hypothalamus. Thus, whilst several mechanisms are likely to link obesity and cognitive impairment, it might be hypothesized that systemic and central inflammation may converge into a final common pathway leading not only to impairment of hypothalamic regulatory pathways of feeding but also cognitive dysfunction.

In this review we will firstly focus on clinical and experimental evidence that obesity and/or high fat diet feeding, the latter used to induce obesity in animal models, are associated with cognitive dysfunction and also an increased risk of dementias such as AD. Secondly, we will discuss evidence that central inflammation may be an important link between obesity and cognitive dysfunction, with a particular focus on inflammation within the hypothalamus.

Section snippets

Clinical studies of adults

The negative effects of obesity on cardiovascular and metabolic physiology are well known, and it is now apparent that the brain is also negatively affected by obesity. Several studies have reported a link between obesity and risk of dementias including vascular cognitive impairment and AD (see Section 3). Moreover, evidence indicates that obesity is linked with cognitive dysfunction long before the onset of these conditions. Studies have shown higher BMI is associated with deficits in

Association of obesity with risk of dementias

As populations age, cognitive disorders including dementias become more common. AD is the most common form of dementia, accounting for between 50% and 70% of all dementias. Vascular cognitive impairment is a spectrum of cognitive impairments caused by various types of cerebrovascular disease (e.g. stroke), and includes vascular dementia (VaD), which is the second most common form of dementia. Recent systematic reviews and meta-analyses reveal a complex relationship between obesity and risk of

Obesity and cognitive function: cause or consequence?

While there is ample evidence that a relationship exists between obesity and brain health (function and structure), it is important to acknowledge that there still remains a question of causality. Indeed, the relationship between obesity and brain health may not be unidirectional. Obesity is associated with many pathophysiological changes that have the potential to negatively impact the brain, including inflammation, which in turn may be a cause and a consequence of obesity. It is also possible

Systemic inflammation

It is now well accepted that obesity is associated with chronic low-grade systemic inflammation (Gregor and Hotamisligil, 2011, Spencer, 2013). This pro-inflammatory profile appears to be both a cause and a consequence of obesity. Dietary factors such as fatty acids lead to stimulation of the free fatty acid and lipopolysaccharide (LPS) receptor, toll like receptor 4 (TLR4), on immune cells, and initiation of an inflammatory cascade (Shu et al., 2012). High fat feeding is also associated with

Systemic inflammation and cognitive dysfunction

Systemic inflammation, independently of and associated with obesity, has been linked to faster cognitive decline in the elderly (Marioni et al., 2010, Trollor et al., 2012) and with dementias including AD (Hall et al., 2013). Thus, metabolic syndrome (including inflammation and obesity) and systemic inflammation have both been identified as independent risk factors for depressive symptoms, cerebral white matter lesions and cognitive dysfunction in older people (van Dijk et al., 2005,

Potential mechanisms of neuronal dysfunction leading to cognitive impairment

Microglia and astrocytes are the brain’s resident immune cells and can be directly activated by inflammatory mediators including pro-inflammatory cytokines, prostaglandins, and nitric oxide (Loane and Byrnes, 2010). They are also the major brain cell population to express TLR4 (Lehnardt et al., 2003). Upon activation, microglia undergo significant morphological changes. After as little as one week on a high fat diet, microglia demonstrate a reactive gliosis with significant proliferation and an

Summary and conclusion

Obesity and/or a high fat diet appear to have a significant role to play in cognitive dysfunction and ageing-associated cognitive disorders like dementia. Systemic inflammation has long been regarded as a contributing factor to these outcomes. However, there is now accumulating evidence that this peripheral inflammation precipitates local inflammation within the hypothalamus that alters synaptic plasticity, contributes to neurodegeneration, and even initiates brain atrophy. These events will

Acknowledgments

This work was supported by a Discovery Project Grant from the Australian Research Council (ARC) to SJS (DP130100508), and a Project Grant from the National Health and Medical Research Council (NHMRC) to AAM and SJS (APP1068442). SJS is an ARC Future Fellow (FT110100084) and an RMIT University VC Senior Research Fellow. AAM is an RMIT University VC Senior Research Fellow.

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