Named Series: Diet, Inflammation and the BrainObesity and neuroinflammation: A pathway to cognitive impairment
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.
References (203)
- et al.
Childhood obesity and adult morbidities
Am. J. Clin. Nutr.
(2010) The onset of fever: new insights into its mechanism
Prog. Brain Res.
(2007)- et al.
Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus
Brain Res.
(2009) - et al.
Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing
J. Biol. Chem.
(2013) - et al.
Diet-induced obesity induces endoplasmic reticulum stress and insulin resistance in the amygdala of rats
FEBS Open Bio
(2013) - et al.
Obesity-mediated inflammation may damage the brain circuit that regulates food intake
Brain Res.
(2011) - et al.
Body mass index (BMI) at an early age and the risk of dementia
Arch. Gerontol. Geriatr.
(2010) - et al.
Nuclear factor kappa B activation by NADPH oxidases
Mech. Ageing Dev.
(2004) - et al.
Is there any relationship between obesity and mental flexibility in children?
Appetite
(2007) - et al.
Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway
Int. J. Biochem. Cell Biol.
(2006)
Obesity, diabetes and cognitive deficit: the Framingham Heart Study
Neurobiol. Aging
Activation of the endoplasmic reticulum stress response by the amyloid-beta 1–40 peptide in brain endothelial cells
Biochim. Biophys. Acta
Obesity increases cerebrocortical reactive oxygen species and impairs brain function
Free Radical Biol. Med.
Elevated body mass index is associated with executive dysfunction in otherwise healthy adults
Compr. Psychiatry
Body mass index and neuropsychological function in healthy children and adolescents
Appetite
Adiposity indices and dementia
Lancet Neurol.
Obesity
Lancet
Obesity and the hypothalamic-pituitary-adrenal axis in adolescent girls
Metab., Clin. Exp.
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Cell
Attenuation of leptin and insulin signaling by SOCS proteins
Trends Endocrinol. Metab.
Prior stressor exposure sensitizes LPS-induced cytokine production
Brain Behav. Immun.
High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model
Neurobiol. Aging
Pathogen recognition with Toll-like receptors
Curr. Opin. Immunol.
MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity
Cell Metab.
Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation
J. Neuroinflamm.
Role of microglia in neurotrauma
Neurotherapeutics
CNS penetration of small molecules following local inflammation, widespread systemic inflammation or direct injury to the nervous system
Life Sci.
Ursolic acid improves high fat diet-induced cognitive impairments by blocking endoplasmic reticulum stress and IkappaB kinase beta/nuclear factor-kappaB-mediated inflammatory pathways in mice
Brain Behav. Immun.
Psychological characteristics of morbidly obese candidates for bariatric surgery
Obes. Surg.
Cognitive function after bariatric surgery: evidence for improvement 3 years after surgery
Am. J. Surg.
Improved memory function two years after bariatric surgery
Obesity (Silver Spring, Md)
Executive function and the frontal lobes: a meta-analytic review
Neuropsychol. Rev.
The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study
Brain
Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies
Obes. Rev.
Plasma Abeta42 correlates positively with increased body fat in healthy individuals
J. Alzheimers Dis.
Neurodegenerative diseases and oxidative stress
Nat. Rev. Drug Discovery
Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes
J. Neurosci.
Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis
Obes. Rev.
Enduring consequences of maternal obesity for brain inflammation and behavior of offspring
FASEB J.
Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients
Neurosci. Lett.
Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge
Am. J. Physiol. Endocrinol. Metab.
Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease
J. Neurosci.
Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis
J. Exp. Med.
Late-life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study
Int. J. Obes.
Inflammatory cause of metabolic syndrome via brain stress and NF-kappaB
Aging
Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder
Clin. Interv. Aging
Factors associated with cognitive impairment among older Italian inpatients. Gruppo Italiano di Farmacovigilanza nell’Anziano (G.I.F.A.)
J. Am. Geriatr. Soc.
Relation between body mass index and cognitive function in healthy middle-aged men and women
Neurology
Overweight and obesity in old age are not associated with greater dementia risk
J. Am. Geriatr. Soc.
Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus
Endocrinology
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