Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice

doi:10.1016/j.bbi.2015.07.008

Brain, Behavior, and Immunity

Volume 50, November 2015, Pages 221-231

https://doi.org/10.1016/j.bbi.2015.07.008 Get rights and content

Highlights

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Systemic and brain inflammation was increased in aged mice with visceral adiposity.
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Visceral fat removal decreased systemic and brain inflammation in aged mice.
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Visceral fat removal reduced ischemic brain damage in aged mice.
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Visceral adipose tissue inflammation was enhanced following ischemic stroke.
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Visceral adiposity has a role in the normal and ischemic brains of aged mice.

Abstract

Visceral adipose tissue is accumulated with aging. An increase in visceral fat accompanied by low-grade inflammation is associated with several adult-onset diseases. However, the effects of visceral adipose tissue inflammation on the normal and ischemic brains of aged are not clearly defined. To examine the role of visceral adipose tissue inflammation, we evaluated inflammatory cytokines in the serum, visceral adipose tissue, and brain as well as blood–brain barrier (BBB) permeability in aged male mice (20 months) underwent sham or visceral fat removal surgery compared with the young mice (2.5 months). Additionally, ischemic brain injury was compared in young and aged mice with sham and visceral fat removal surgery. Interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in examined organs were increased in aged mice compared with the young mice, and these levels were reduced in the mice with visceral fat removal. Increased BBB permeability with reduced expression of tight junction proteins in aged sham mice were also decreased in mice with visceral fat removal. After focal ischemic injury, aged mice with visceral fat removal showed a reduction in infarct volumes, BBB permeability, and levels of proinflammatory cytokines in the ischemic brain compared with sham mice, although the neurological outcomes were not significantly improved. In addition, further upregulated visceral adipose tissue inflammation in response to ischemic brain injury was attenuated in mice with visceral fat removal. These results suggest that visceral adipose tissue inflammation is associated with age-related changes in the brain and contributes to the ischemic brain damage in the aged mice. We suggest that visceral adiposity should be considered as a factor affecting brain health and ischemic brain damage in the aged population.

Introduction

Ischemic stroke is an age-related disease because two-thirds of strokes occur in those over the age of 65. Thus, age is a nonmodifiable risk factor for ischemic stroke (Allen and Bayraktutan, 2008). Although ischemic stroke is a leading cause of mortality and morbidity among adults, the only effective treatment is thrombolysis, which has a limited therapeutic window (Asdaghi et al., 2012). Several potential drugs were developed in pre-clinical studies, but none have been clinically proven to be effective for ischemic stroke. One likely reason is related with the use of young healthy rodents in pre-clinical stroke studies, and therefore, the Stroke Therapy Academic Industry Roundtable (STAIR) recommends using aged animals to confirm the therapeutic effects shown in young animals (Fisher et al., 2009). When using aged animals for ischemic stroke studies, age-related physiological changes that may affect ischemic injury should be taken into account.

Normal aging is associated with an increase in inflammatory mediators leading to low-grade systemic inflammation (Salvioli et al., 2006), and systemic inflammation with aging may initiate or aggravate age-related conditions, such as cardiovascular, metabolic, and neurodegenerative diseases (Huffman and Barzilai, 2009). Because several organs and many factors are involved in the proinflammatory status that occurs with aging, the mechanism of age-associated inflammation appears to be complex (Cevenini et al., 2010). Among these organs, visceral adipose tissue, which is an endocrine organ releasing chemokines and cytokines, is likely involved in the establishment of age-related systemic inflammation (Cevenini et al., 2010). Body fat is redistributed during aging from the subcutaneous compartment to the visceral adipose compartment, resulting in visceral adipose tissue accumulation (Beaufrere and Morio, 2000). With increasing adiposity, macrophage infiltration and production of proinflammatory cytokines are increased in adipose tissue. These inflammatory mediators released from visceral adipose tissue are related to low-grade systemic inflammation (Cevenini et al., 2010).

It has been reported that visceral adiposity negatively affects brain health. In human studies examining aged people, visceral fat accumulation measured by waist-to-hip ratio or imaging studies was associated with a reduction in brain volume, cortical thickness, and cognitive performance, such as verbal memory and attention (Debette et al., 2010, Isaac et al., 2011). These studies indicate that visceral adiposity induces structural and functional changes in the brain. Furthermore, brain imaging studies in individuals with or without stroke history suggest that visceral adiposity can be a risk factor for cerebrovascular diseases, because visceral fat accumulation and an increased ratio of visceral adipose tissue to total adipose tissue strongly correlate with white matter lesions and ischemic lesions (Karcher et al., 2013, Nagura et al., 2004, Yamashiro et al., 2014). In addition to being a risk factor, visceral adiposity may have an influence on brain damage following acute ischemic insult, especially in the aged brain. Because of age-related changes in the brain, such as increases in inflammatory mediators and blood–brain barrier (BBB) permeability (Norden and Godbout, 2013, Popescu et al., 2009), elderly people may be more susceptible to inflammatory mediators released from visceral adipose tissue after ischemic stroke. Moreover, one study reported that proinflammatory cytokines in visceral adipose tissue are increased by the activation of the β-adrenergic receptor via the sympathetic nervous system following acute ischemic stroke (Wang et al., 2011); therefore we hypothesize that heighted inflammation in adipose tissue in response to ischemic injury may intensify the inflammatory responses in the ischemic brain of the elderly.

In this study, to define the role of visceral adipose tissue inflammation in age-related changes in the brain and in ischemic brain damage in aged mice, inflammatory markers were examined in the circulation, visceral adipose tissue, and brain. We then compared the levels of these markers between young and aged mice. After the removal of bilateral epididymal adipose tissues, we also compared the inflammatory markers in sham mice before and after the ischemic stroke. To define the effect of ischemic brain damage on visceral adipose tissue inflammation, we examined proinflammatory cytokine production in visceral fat following an ischemic stroke.

Section snippets

Animals

Male C57BL/6 mice (6 weeks old) were purchased from Orient Bio Inc. (Seongnam, Republic of Korea) and were maintained in a specific pathogen-free animal facility at Ewha Womans University School of Medicine on a 12-h light/dark cycle at 22 ± 2 °C. Standard rodent chow and tap water were provided ad libitum, except when overnight fasting was required. Experiments were performed using young adult (2.5 months old) and grossly healthy aged (18 and 20 months old) mice. For the measurement of serum

Systemic inflammation was reduced by visceral fat removal in aged mice

Serum testosterone levels are lower in aged mice than in young mice, and a low total testosterone level in circulation is associated with visceral obesity (Reed et al., 2007, Tchernof and Despres, 2013). In aging studies, rodents in a relatively wide age range (18–24 months) were used. To determine the aging process and to reduce the variation potentially caused by differences in age, serum testosterone levels were measured in 2.5-, 18- and 20-month mice. An age-related decrease in testosterone

Discussion

It has been suggested that that visceral adiposity induces changes in the brain and creates a predisposition for ischemic stroke by increasing the risk factors for vascular diseases, such as atherosclerosis and metabolic dysfunction (Debette et al., 2010, Isaac et al., 2011, Karcher et al., 2013, Nagura et al., 2004, Yamashiro et al., 2014). However, the direct association of visceral adiposity with inflammation in the aged brain and after ischemic brain damage has not been examined. Using

Conflicts of interest

The authors report no conflicts of interest.

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) (2010-0027945, 2010-0011353 and 2014R1A2A1A11051461).

References (55)

W.A. Banks et al.
Regional transport of TNF-alpha across the blood–brain barrier in young ICR and young and aged SAMP8 mice
Neurobiol. Aging
(2001)
S.E. Borst et al.
Association of resistin with visceral fat and muscle insulin resistance
Cytokine
(2005)
L.B. Buckman et al.
Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system
Brain Behav. Immun.
(2014)
A.D. Hart et al.
Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences
Brain Behav. Immun.
(2012)
D.M. Huffman et al.
Role of visceral adipose tissue in aging
Biochim. Biophys. Acta
(2009)
S. Koenig et al.
Leptin is involved in age-dependent changes in response to systemic inflammation in the rat
Brain Behav. Immun.
(2014)
K.J. Livak et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method
Methods
(2001)
B. Manwani et al.
Functional recovery in aging mice after experimental stroke
Brain Behav. Immun.
(2011)
B. Manwani et al.
Differential effects of aging and sex on stroke induced inflammation across the lifespan
Exp. Neurol.
(2013)
A. Michaud et al.
Visceral fat accumulation is an indicator of adipose tissue macrophage infiltration in women
Metabolism
(2012)

I. Murano et al.

Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice

J. Lipid Res.

(2008)

P.J. Pistell et al.

Cognitive impairment following high fat diet consumption is associated with brain inflammation

J. Neuroimmunol.

(2010)

B.O. Popescu et al.

Blood–brain barrier alterations in ageing and dementia

J. Neurol. Sci.

(2009)

J.A. Shin et al.

Activation of estrogen receptor beta reduces blood–brain barrier breakdown following ischemic injury

Neuroscience

(2013)

X. Zhang et al.

High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex

Exp. Neurol.

(2005)

C.L. Allen et al.

Risk factors for ischaemic stroke

Int. J. Stroke

(2008)

N. Asdaghi et al.

Risks and benefits of thrombolysis in the elderly

Int. J. Stroke

(2012)

S. Austad

Recent advances in vertebrate aging research 2009

Aging Cell

(2010)

I. Badan et al.

Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery

J. Cereb. Blood Flow Metab.

(2003)

B. Beaufrere et al.

Fat and protein redistribution with aging: metabolic considerations

Eur. J. Clin. Nutr.

(2000)

E. Cevenini et al.

Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches

Curr. Pharm. Des.

(2010)

C. Coisne et al.

Tight junctions in brain barriers during central nervous system inflammation

Antioxid. Redox Signal.

(2011)

A. Corsonello et al.

Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions

Curr. Med. Chem.

(2010)

S. Debette et al.

Visceral fat is associated with lower brain volume in healthy middle-aged adults

Ann. Neurol.

(2010)

H. Dhungana et al.

Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection

Aging Cell

(2013)

Y.V. Dubrovsky et al.

Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice

Aging (Albany NY)

(2010)

M. Fisher et al.

Update of the stroke therapy academic industry roundtable preclinical recommendations

Stroke

(2009)

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¹: These authors contributed equally to this work.

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Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice

Highlights

Abstract

Introduction

Section snippets

Animals

Systemic inflammation was reduced by visceral fat removal in aged mice

Discussion

Conflicts of interest

Acknowledgments

Neurobiol. Aging

Cytokine

Brain Behav. Immun.

Brain Behav. Immun.

Biochim. Biophys. Acta

Brain Behav. Immun.

Methods

Brain Behav. Immun.

Exp. Neurol.

Metabolism

J. Lipid Res.

J. Neuroimmunol.

J. Neurol. Sci.

Neuroscience

Exp. Neurol.

Risk factors for ischaemic stroke

Int. J. Stroke

Risks and benefits of thrombolysis in the elderly

Int. J. Stroke

Recent advances in vertebrate aging research 2009

Aging Cell

Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery

J. Cereb. Blood Flow Metab.

Fat and protein redistribution with aging: metabolic considerations

Eur. J. Clin. Nutr.

Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches

Curr. Pharm. Des.

Tight junctions in brain barriers during central nervous system inflammation

Antioxid. Redox Signal.

Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions

Curr. Med. Chem.

Visceral fat is associated with lower brain volume in healthy middle-aged adults

Ann. Neurol.

Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection

Aging Cell

Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice

Aging (Albany NY)

Update of the stroke therapy academic industry roundtable preclinical recommendations

Stroke