Obesity and dementia: Adipokines interact with the brain
Introduction
Each year, obesity or obesity-related conditions lead to the death of 2.8 million adults around the world (WHO, 2012). This epidemic in Western societies, and burgeoning epidemic in non-Western societies, increase the risk for multiple adverse health conditions and contributes to multiple morbidities (Olde Dubbelink et al., 2008). Obesity has an obscure etiology but it is generally ascribed to an imbalance of energy intake versus energy output and a complex interplay between genes and environment (Doherty, 2011), leading to the highest prevalence of overweight and obesity ever observed in the world׳s history (Bray and Popkin, 1998). Adipose tissue, mainly white adipose tissue (WAT), functions as the largest endocrine organ by secreting hundreds of hormones, peptides and cytokines which are collectively referred to as adipokines. These adipokines affect processes in the periphery and the central nervous system (CNS).
Obesity has been associated with alterations in brain structure and function, cognitive deficits and even dementia and Alzheimer׳s disease (AD) (Businaro et al., 2012, Delgado et al., 2011, Gustafson, 2008, Gustafson, 2010, Gustafson et al., 2004, Haltia et al., 2007). In 2003, the first association was reported between AD and being more overweight in women (defined within the overweight category of body mass index (BMI) between 25 and 29.99 kg/m2) (Gustafson et al., 2003). Thus, the year 2013, marks 10 years of published epidemiologic reports relating higher mid-life and late-life BMI to dementia (Fitzpatrick et al., 2009, Gustafson et al., 2009, Gustafson et al., 2003, Hayden et al., 2006, Kivipelto et al., 2005, Whitmer et al., 2007, Whitmer et al., 2008). Levels of mid-life and late-life BMI associated with AD are in overweight and obese ranges based on traditional cutpoints used for cardiovascular disease and overall mortality. While higher levels of adult BMI may increase risk for chronic neurodegenerative diseases of aging, some studies show that the direction of the BMI-AD relationship changes direction, and BMI declines in association with AD, later in life (Besser et al., 2014, Gustafson et al., 2012, Gustafson et al., 2009). Higher BMI in middle adult life could be reflecting higher vascular risk and declining BMI reflecting more neurodegenerative events in latest life. This theory is illustrated by observations of both higher absolute level of baseline BMI and more body weight decline among those with Mild Cognitive Impairment (MCI) being associated with clinical dementia progression (CDR-Sum of Boxes) (Besser et al., 2014).
Accompanying the literature on dementia and AD, are observed alterations in brain structure and function including decreased total and gray matter volumes, increased white matter lesions and reduced white matter integrity (Brooks et al., 2012, Gustafson et al., 2004, Pannacciulli et al., 2006, Raji et al., 2010, Stanek et al., 2011). More specifically, abnormalities in brain regions such as the amygdala, hippocampus and frontal cortex (Cazettes et al., 2011, Widya et al., 2011); decreased cortical thickness (Haltia et al., 2007, Hassenstab et al., 2012); axonal degradation (Mueller et al., 2011); and decreased functional connectivity in the brain (Nummenmaa et al., 2012, Stoeckel et al., 2009) have been observed.
It is known that adipokines, secretory products of adipose tissue such as leptin, interact directly with specific nuclei in certain areas of the brain such as the hippocampus. This results inregulation of not only feeding behavior, but also neurodegeneration, synaptic plasticity, neurogenesis and memory consolidation (Doherty, 2011). Reviewed herein are the adipokines, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), angiotensinogen (AGT), adiponectin and leptin. These adipokines are not exclusively secreted by adipose tissue, nor is adipose tissue the only or primary source of these compounds. However, the adipokines selected for review have been associated with obesity-related morbidities that have also been implicated in dementia and AD, such as chronic low levels of inflammation, hypertension, and direct impaired in regulation of energy metabolism (Gustafson, 2006, Harrison, 2013, Iadecola and Davisson, 2008, Jequier, 2002, Rocha and Folco, 2011, Xu et al., 2011). More specifically, AGT is an important mediator of hypertension; TNF-α, IL-6 and PAI-1 are involved in chronic inflammation and fibrinolysis; and leptin and adiponectin regulate several processes including energy metabolism (Diez and Iglesias, 2003, Gardes et al., 1982, Guerre-Millo, 2004, Jequier, 2002, Ouchi et al., 2003a, Rocha and Folco, 2011, Villarreal-Molina and Antuna-Puente, 2012). Before circulating peripheral adipokines are able to interact with the brain, they must cross the blood brain barrier (BBB) to enter the central nervous system (CNS). This large neurovascular interface controls the transport of a variety of blood-borne factors such as amino acids, peptides, polypeptides and proteins, as well as many other molecules, such as adipokines, into the CNS (Banks, 2006, Kastin et al., 1999a, Pan and Kastin, 2007).
To better understand the epidemiologic associations between obesity and dementia and AD, we focus this review on how adipose tissue may influence the brain via adipokine action, the biology of each adipokine in the periphery, as well as its ability to cross the BBB and influence brain processes. First will be described how adipokine levels are altered in the obese versus non-obese condition. Second will be described possible pathways and processes by which these adipokines might affect the BBB and brain in obesity. Because very little literature is available regarding detailed molecular pathways in humans, these last descriptions are mainly based on findings from in vitro (cell culture) studies and in vivo experiments using animal models.
Section snippets
Leptin
Leptin is a protein hormone that has drawn the most attention in obesity research since its discovery in 1994 (Zhang et al., 1994). Leptin was discovered as a hormone involved in long-term regulation of energy intake and expenditure, body weight, and neuroendocrine functions in mammals (Jequier, 2002). Furthermore, it has significantly broadened our understanding of the mechanisms underlying the development of obesity and its complications. In the non-obese condition, energy intake increases
Adiponectin
Adiponectin is a protein hormone, most well-described for modulating inflammatory responses, energy expenditure (CNS and periphery), food intake (CNS) and a number of metabolic processes, including glucose regulation and fatty acid catabolism in the periphery (see Figure 2) (Diez and Iglesias, 2003, Holland et al., 2013, Ouchi et al., 2003a, Qi et al., 2004, Villarreal-Molina and Antuna-Puente, 2012). In the periphery, adiponectin is released from adipose tissue into the blood circulation as
Angiotensinogen
Almost every tissue in the human body, including adipose tissue and the brain contain a fully functional renin–angiotensin system (RAS) (Grobe et al., 2010, Weiland and Verspohl, 2008, Yvan-Charvet and Quignard-Boulange, 2011). Initially, the role of peripheral RAS in blood pressure regulation was described, but RAS is now recognized to regulate a variety of tissue-specific functions (Crowley and Coffman, 2012, Gonzalez-Villalobos et al., 2013). In the periphery, angiotensinogen (AGT), is the
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin gene family. PAI-1 influences vascular health via inhibition of fibrinolysis, a process that prevents blood clots that clog arteries (Guerre-Millo, 2004). PAI-1 causes inhibition of fibrinolysis via inhibition of tissue type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) (Guerre-Millo, 2004, Loskutoff et al., 1989). However, the biological role of PAI-1 extends beyond the regulation of inflammation and
Interleukin-6
The inflammatory cytokine, IL-6, is produced by adipocytes, macrophages and T-cells, and is involved in the acute phase reaction in inflammation (see Figure 2). In the liver, IL-6 stimulates the production of acute phase proteins such as C-reactive protein and fibrinogen. Obesity is marked by a peripheral chronic low inflammation state partly mediated via production of inflammatory adipokines such as IL-6 and TNF-α (Das, 2001). This chronic low inflammation state is already observed in obese
TNF-α
TNF-α regulates the acute phase reaction of inflammation (see Figure 2), and is therefore an important mediator of the chronic inflammation found in obesity in the periphery and hypothalamus (Das, 2001, Thaler et al., 2012). In obese adults, elevated plasma levels of TNF-α have been observed when compared to normal weight adults (Mousa, 2005). In the periphery, TNF-α is produced by adipocytes and macrophages, and binds to two receptors, TNF-R1 and TNF-R2. TNF-R1 is expressed in most peripheral
Conclusion
After a decade of research on overweight and obesity in AD, a research focus on the endocrine aspects of adipose tissue and the brain has been birthed and escalated. Of the adipokines reviewed herein, it is known that peripheral leptin, TNF-α and IL-6 are able to cross the BBB and affect brain function (see Figure 2/Table 1). However, the other adipokines discussed including adiponectin, AGT and PAI-1, are either not able to cross the BBB, or possible transport mechanisms have not been
Role of the funding source
This study was supported by the EU 7th Framework LipiDiDiet project (FP7/2007-2013) under Grant agreement no. 211696; in part by Grants NIH/NIAID 1R01MH076537, 1R01MH079880, and U01 318345; Swedish Research Council Diarienummer: 523-2005-8460, and the State University of New York Research Foundation.
Contributors
Deborah R. Gustafson was invited to submit this review. Subsequently, all contributors, Ilse A.C. Arnoldussen, Amanda J. Kiliaan, and Deborah R. Gustafson, participated equally in the drafting of this review manuscript.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgments
None.
References (227)
- et al.
Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice
Brain. Res.
(1999) - et al.
Pressor responses of angiotensin II microinjected into the dorsomedial medulla of the dog
Brain Res.
(1987) - et al.
Impaired transport of leptin across the blood–brain barrier in obesity
Peptides
(1999) - et al.
Penetration of interleukin-6 across the murine blood–brain barrier
Neurosci. Lett.
(1994) - et al.
Leptin enters the brain by a saturable system independent of insulin
Peptides
(1996) - et al.
Association between genetic variants of IL-1beta, IL-6 and TNF-alpha cytokines and cognitive performance in the elderly general population of the MEMO-study
Psychoneuroendocrinology
(2008) - et al.
Identification of SOCS-3 as a potential mediator of central leptin resistance
Mol. cell
(1998) - et al.
Divergent signaling capacities of the long and short isoforms of the leptin receptor
J. Biol. Chem.
(1997) Neurodevelopmental actions of leptin
Brain Res.
(2010)- et al.
Dietary fat intake does affect obesity!
Am. J. Clin. Nutr.
(1998)