POTENTIAL MECHANISMS UNDERLYING THE INTERACTIONS AMONG OBESITY, BRAIN FUNCTION, AND BEHAVIOR

The mechanisms underlying the association between obesity and impairments in cognitive functioning remain speculative. It has been assumed that the comorbid

disorders which accompany obesity, including type 2 diabetes and cardiovascular disease, contribute to these impairments (Reijmer et al. 2010; Uranga et al. 2010).

However, alterations in brain function and cognitive behavior have been observed in obesity prior to the overt development of these disorders (Valladolid-Acebes et al.

2011). These findings indicate that subtle physiological changes which accompany obesity also may be important for mediating changes in neural activity and behavior.

o^besity, b^rAin s^truCture, ^And f^unCtion

Brain-imaging techniques (e.g., computer tomography [CT], MRI, and fMRI) have provided researchers with the ability to assess structural and functional changes in the brain associated with increased body weight. In an initial study using CT scans, Gustafson and colleagues (2004) reported increased temporal lobe atrophy in women as a function of BMI. More recent studies have confirmed a relationship between increased adiposity and a reduction in brain size in young, middle-aged, and elderly individuals (e.g., Ward et al. 2005; Pannacciulli et al. 2006; Gazdzinski et al. 2008; Taki et al. 2008; Debette et al. 2010; Raji et al. 2010; Walther et al.

2010). Additionally, these studies have identified specific areas of the brain that may be altered in obesity. For example, Pannacciulli et al. (2006) reported that relative to lean individuals, obese individuals display reductions in gray matter density in the frontal lobe and postcentral gyrus, areas of the brain implicated in taste, the regulation of food intake, and reward and cognitive behavior. Moreover, reductions in the volume of the inferior and frontal cortex, the posterior cortex including the parahippocampal gyrus, and the cerebellum have also been observed in obese indi-viduals relative to their lean counterparts (Taki et al. 2008; Walther et al. 2010). In contrast to the observed reductions in gray matter in obesity, larger volumes of both posterior and anterior white matter have been reported in obese individuals (Walther et al. 2010).

Body weight may moderate neuronal activity as well as brain structure (Volkow et al. 2009; Gazdzinski et al. 2010; Gonzales et al. 2010). Volkow and colleagues (2009) observed a negative association between BMI and baseline brain glucose metabolism in the anterior cingulate gyrus and prefrontal region of the brains of healthy middle-aged adults. Additionally, others have found that obesity in middle age is related to decreased brain activation during a cognitive challenge (Gonzales et al. 2010) and that a higher BMI is associated with a reduction in neuronal integrity in the anterior cingulate cortex of healthy elderly individuals (Gazdzinski et al. 2008, 2010). Taken together, the results of the previously described studies seem to indicate that obesity is most often associated with reductions in the size and activity of the frontal lobe and parahippocampal region, areas of the brain that are closely tied to processes related to executive functioning and that are most commonly impaired in age-related dementias.

Hippocampus

The hippocampus is one of the key brain structures involved in cognitive behavior.

It plays an essential role in a host of memory processes, including the consolida-tion of short-term memories into long-term memories, and is particularly important

for spatial memory (Shimamura 2010). Damage to the hippocampus resulting, for example, from trauma, stress, or aging leads to deficits in learning and memory.

Impairments in hippocampal function may also mediate obesity-related deficits in cognitive behavior (Kanoski and Davidson 2011). For example, consumption of energy-dense diets is associated not only with obesity and deficits in spatial memory but also with reductions in dendritic spine density and impairments in synaptic plas-ticity within the hippocampus (Molteni et al. 2002; Stranahan et al. 2008; Hwang et al. 2010). Additionally, intake of energy-dense diets has been associated with reduced hippocampal neurogenesis (Lindqvist et al. 2006; Park et al, 2010).

o^besity, g^luCose r^egulAtion, ^And b^rAin f^unCtioning

Abnormalities in glucose homeostasis, including peripheral hyperglycemia and insulin resistance, are frequently observed concomitants of obesity. As glucose is the primary fuel for the brain, it has been proposed that these abnormalities contribute to obesity-related deficits in cognitive behavior. Consistent with this proposal, among nondiabetic healthy middle-aged and elderly individuals, those with poorer glucose regulation perform more poorly on tasks of memory and executive functioning and have smaller head size-adjusted hippocampal volumes than those with better glucose regulation (Convit et al. 2003; Messier et al. 2010). Moreover, improvement in glu-cose tolerance has been associated with improvements in performance on cognitive tasks (Convit et al. 2003; Convit 2005).

Insulin resistance is one of the most common metabolic problems associated with obesity. Insulin receptors are widely distributed in the central nervous system, particularly in areas involved in cognitive behavior including the hippocampus and cerebral cortex. Given that insulin resistance decreases glucose uptake and cellular functioning, decreased sensitivity to insulin in hippocampal neurons has been pro-posed as one possible mechanism for obesity-related deficits in cognitive behavior.

According to this proposal, in obesity, neurons in the hippocampus become less able to use glucose, resulting in disruptions in neurotransmitter transport and release.

This cellular disturbance is thought to hinder neural transmission leading to impair-ments in learning and memory (Hoyer 2003; Bissells et al. 2004; Convit 2005). In support of this proposal, manipulations which improve insulin utilization, such as central administration of insulin or administration of a drug which increases the effectiveness of insulin, facilitate performance on cognitive tasks in both humans and animals (Park et al. 2000; Ryan et al. 2007; Reagan 2007; Pathan et al. 2008;

McNay et al. 2010). In contrast, blockade of endogenous intrahippocampal signaling can impede memory performance, while chronic intake of a high-fat diet impairs cognitive functioning and attenuates both the cognitive and metabolic responses to hippocampal insulin administration (McNay et al. 2010). Further evidence of a defi-cit in hippocampal functioning in obesity comes from work demonstrating that rats chronically fed energy-dense diets displayed reduced insulin signaling in the hip-pocampus (Meilke et al. 2006).

In addition to moderating glucose metabolism, insulin can affect brain microvas-culature. Insulin resistance is associated with vasoconstriction, which can ultimately reduce blood flow to the brain. This reduction in blood flow could contribute to

obesity-related impairments in cognition. Taken together, the results of these studies are robust indicators that one way in which obesity could alter cognitive behavior is by interfering with insulin actions in the central nervous system.

o^besity, o^xidAtive s^tress, ^And inflAmmAtion

The detrimental effects of energy-dense diets on brain functioning and cognitive behavior may be mediated, at least in part, by oxidative stress (Zhang et al. 2009;

Morrison et al. 2010; Park et al. 2010). Oxidative stress is one of the earliest nega-tive consequences of obesity and may trigger the development of insulin resistance.

Oxidative stress resulting from intake of energy-dense diets could result in damage to nucleic acids, proteins, and lipids important for normal brain functioning (Furukawa et al., 2004; Zhang et al. 2009). In support of this possibility, Morrison and colleagues (2010) reported that in aged mice, consumption of a high-fat diet impaired long-term spatial memory and increased oxidative damage to proteins integral to the hippo-campus. Moreover, they found that both cognitive dysfunction and oxidative stress were highly correlated with body weight gain across the experiment. Other types of oxidative stress could also influence brain functioning. For example, obesity could also stimulate the production of a variety of lipid peroxidation products which could be toxic to the nervous system (Zhang et al. 2009; Park et al. 2010). In support of this possibility, Park and colleagues (2010) reported that mice consuming a high-fat diet gained more weight, had larger fat depots, and had higher hippocampal levels of malondialdehyde, a measure of lipid peroxidation, than animals given a standard diet.

Increases in oxidative stress can ultimately lead to inflammation. Epidemiological studies have revealed that obesity is often accompanied by chronic, low-level inflam-mation (Schoelson et al. 2007). These inflammatory responses are correlated with the degree of obesity and insulin resistance, and may result from increased levels of serum lipids (Pistell et al. 2010). Based on studies demonstrating that inflammation can disrupt brain pathways involved in cognitive behavior, it has been proposed that the cognitive impairments observed in animals fed high-fat diets are associated with brain inflammation. In support of this proposal, mice fed a diet high in saturated fat displayed impaired cognitive performance on a test of spatial memory and signifi-cant increases in the expression of a number of cytokines (e.g., TNFα, and IL-6), as well as increased reactive astrocytosis and microgliosis.

b^rAin-d^erived neurotrophiC f^ACtor (bdnf)

Brain-derived neurotrophic factor (BDNF) is one of a family of proteins that is important for a host of essential neural processes, such as neural differentiation, pro-liferation, survival, and plasticity. BDNF is synthesized predominantly by neurons in the hippocampus, and is hypothesized to be a key part of the neuronal processes that mediate hippocampal-dependent learning and memory (Kanoski and Davidson 2011). In support of this hypothesis, the expression of BDNF is elevated in the hip-pocampus of animals that have learned a spatial task (Mizuno et al. 2000). In con-trast, impairments in learning and memory have been observed in transgenic mice animals with reduced expression of BDNF (Linnarsson et al. 1997).

Reductions in the expression of BDNF within the hippocampus may contribute to the detrimental effects of diet-induced obesity on learning and memory. Molteni and colleagues (2002) reported that, relative to rats chronically consuming a low-fat/complex-carbohydrate diet, rats consuming a high-fat/high-sugar diet did more poorly on the Morris water maze, a test of spatial learning, and displayed a reduction in hippocampal levels of BDNF. Moreover, the longer that animals were maintained on the high-fat/high-sucrose diet, the poorer their performance on the Morris water maze and the greater the reduction in hippocampal BDNF. Subsequent studies have confirmed that animals with diet-induced obesity display impairments in spatial and nonspatial learning and reductions in hippocampal levels of BDNF (Wu et al. 2003;

Moltini et al. 2004; Kanoski et al. 2007; Stranahan et al. 2008).

l^ipidsAnd C^ognitive f^unCtioning

Obesity-related alterations in serum lipids could also contribute to impairments in cognitive behavior. Chronic intake of an energy-dense diet can lead to elevations in cholesterol and triglyceride levels. In turn, these elevations could result in decreased blood flow to the brain, alterations in the brain’s fatty acid content, and decrements in cognitive functioning. In support of a role of lipids in determining obesity-related cognitive deficits, recent studies have shown that administration of triglycerides into the hippocampus can impair long-term potentiation and acquisi-tion of cognitive tasks. In contrast, administraacquisi-tion of a drug which reduces hypertri-glyceridemia improved cerebral blood flow and cognitive capacity (Farr et al. 2008).

It is unlikely that there is one critical factor mediating the effect of obesity on brain functioning and behavior. Rather, it is more likely that multiple factors contrib-ute to the reported decrements in cognitive capacity observed in obesity.