The Effects of Obesity on Brain Structure and Size
An examination of both the pathophysiology of the link between obesity and brain injury, and available strategies that may reverse it.
Obesity is defined as having a body mass index (BMI) of 30 or higher. In the United States the prevalence of obesity among adults is 35.7 percent and 17 percent among adolescents ages 2-19.1 The rate of obesity is also on the rise worldwide with over 400 million adults who are considered obese. The number of obese adults is expected to nearly double by 2015.2 These findings are disturbing in that they indicate the rise of an epidemic, in which the global population is becoming obese at an exceedingly rapid rate.3 Traditionally, obesity has been linked to numerous health conditions including cardiovascular disease, type II diabetes, and hypertension. In recent years, however, obesity has been attributed to significant brain atrophy and cognitive impairment. In this review, we examine both the pathophysiology of the link between obesity and brain injury, and available strategies that may be able to reverse it.
Obesity can cause a clear and distinct reduction in brain size without additional contributing factors. A 2.4 percent decrease in brain parenchymal volume is observed for obese individuals compared to those with a normal BMI (p=.010).4 Brain areas particularly vulnerable to obesity-related atrophy include the hippocampus, cingulate gyrus, and frontal lobes.4-8 As would be expected, a BMI of 30 or higher has been linked with a decline in executive function over a ten-year period (p=0.035).5
Moreover, an elevated BMI is significantly correlated (p < 0.01) with a reduction in neuronal fiber bundle length (FBL), which is believed to contribute to brain atrophy. The reduction of FBL throughout the brain was correlated with increasing age and BMI. However, in the temporal lobe, shorter FBL was independent of age and uniquely associated with a high BMI.9
Several studies of cognitive testing demonstrate that extensive cerebral atrophy noted in overweight and obese individuals impairs the cognition of individuals with a higher BMI.6 Additional evidence suggests the effects of obesity on cognitive function increase with age.10
A subset of obesity, central obesity, has a distinct association with vascular and metabolic disease. Also known as abdominal obesity, central obesity is determined by a waist-hip ratio (WHR). A high risk waist circumference is classified as >40 inches in men and >34 inches in women.11 Increasing evidence shows a significant positive correlation between WHR and brain atrophy.12, 13 Greater WHR (p = 0.02) is associated with a smaller hippocampal volume. WHR accounts for 4 percent variability in hippocampal volume. The distribution and amount of body fat per individual is also related to the amount of white matter hyper-intensities (WMHs). While a 1- SD increase in WHR is associated with 0.2-SD decrease in hippocampal volume, it is associated with a 27 percent increase in WMHs compared to individual baseline measurements obtained previously.13
Central obesity is related to an increased risk of memory loss and dementia 30 years later. In a longitudinal study, participants were divided into normal, overweight, and obese categories, as determined by their BMI, and were evaluated for three decades to determine whether abdominal obesity was independent of total obesity in influencing the risk of developing dementia. Those in the highest quintile of abdominal diameter had a 2.72-fold increased risk of developing dementia compared to those in the lowest quintile. Those who were overweight or obese, and had central obesity had a 2.34-fold and 3.60-fold increase in dementia risk, respectively. Even those in the normal BMI category were at a higher risk (89 percent more likely) of developing dementia if they had a large abdominal area, than their normal BMI counterparts without abdominal obesity.12
Additionally, abdominal obesity is associated with lowered immediate memory. In individuals with abdominal obesity and associated metabolic syndrome, there is a 15 percent reduction in mean gray matter cerebral blood flow when compared to controls. This reduction is believed to impair immediate memory function.14
The exact mechanisms through which obesity leads to brain atrophy and cognitive decline are complex and may involve a number of factors such as associated diabetes, genetic vulnerability, brain metabolites, and cytokines. Although, extensive research has revealed the degree to which these factors are linked with obesity, further analysis is required to understand the way these elements interact with each other.
Type II Diabetes Mellitus
Obesity and type II diabetes mellitus (T2DM) are two interlinked conditions that have been attributed to brain atrophy. Recent studies indicate that T2DM significantly reduces the volume of the hippocampus and other brain structures.
Brain MRIs of individuals with T2DM and a high BMI show significant atrophy (p<0.001) in the frontal lobes (r = -0.24), prefrontal cortex, the genu and splenium of the corpus callosum (r = -0.17 and r = -0.21, respectively), middle cingulate gyrus, superior parietal lobe, the occipital lobe, and the cerebellum. The study also showed a reduction in the white matter volumes (WMVs) of the frontal lobes.6
An increase in the size of the temporal horn of the brain ventricles can be used as an indirect measure of atrophy in the hippocampus. Midlife diabetes is associated with a significant increase in temporal horn volume, suggesting a reduction in hippocampal volume (p=0.017) less than 10 years after initial measurements. As would be expected, this reduction is associated with a decline in memory with aging.5 Those with T2DM have more temporal lobe atrophy (p=0.004) than those not afflicted by the disease.16
The brain atrophy found in patients with diabetes could be due to stroke. T2DM individuals are 1.7 times more likely to have brain infarcts.16 In one study, the brains of those in the obese group appeared 16 years older, while the brains of the overweight subjects appeared 8 years older in comparison to the normal BMI control group. The obese group had 8 percent lower brain volume than the normal BMI group, while the overweight group had 4 percent lower brain volume.6, 17
Obesity and diabetes have severe consequences for adolescents too. In the past three decades, obesity rates have nearly tripled in children and adolescents, and with this increase, the prevalence of T2DM among adolescents has increased dramatically.18 According to a recent study, obese adolescents with T2DM have atrophy in the hippocampus and frontal lobe in parallel with their poor glycemic control, a trait generally seen in adults with T2DM. In the study, obese adolescents with T2DM underwent brain imaging to compare the sizes of various brain structures with those in adolescents without T2DM. T2DM adolescents had prefrontal lobe and global cerebral atrophy associated with increasing HbA1c (p=0.007 and p=0.027, respectively). 19 It is important to note that a control group of adolescents with type I diabetes mellitus did not display similar atrophy.18
HbA1c has been implicated as a direct factor responsible for brain atrophy. Significant brain atrophy is correlated with a higher HbA1c. One study found that other than age, the most significant indicator of brain atrophy is HbA1c. Individuals with an HbA1c higher than median level (5.6 percent) experienced rates of atrophy that were twice as high as those in the lowest quartile (Hb1Ac 4.4 to 5.2 percent). Those above the median HbA1c had annual brain volume changes of −0.49 ± 0.25%, while those in the lowest quartile saw a change of -0.24 ± 0.17% (p=0.0001).7
Chronic hyperglycemia exhibits a clear inverse correlation with cognitive function in individuals with T2DM. One study indicated that a 1 percent higher HbA1c level was associated with a 0.20 point lower MMSE score (p < 0.001), and a 0.11 point lower memory score (p=0.0142).20
Hyperinsulinemia has been identified as a major contributor to brain atrophy. Hyperinsulinemia affects the brain through vasoactive effects on cerebral arteries, neurotoxicity because of diminished clearance of amyloid from the brain, and stimulation of the formation of neurofibrillary tangles. High levels of insulin are associated with atrophy in the hippocampus (left: r= -0.31; right: r= -0.33), the splenium of the corpus callosum (r= -0.27), and the orbital frontal cortex (r= -0.33).6
T2DM also causes damage through excessive glycation of key brain structural proteins. The production of advanced glycosylation end products (AGEs) contributes to the development of atherosclerosis in individuals with T2DM due to increased oxidative stress. The interaction of AGEs with their receptors elicits drastic vascular cell changes such as alterations in vascular tone control. The extensive damage caused by these species on the vasculature of patients with diabetes, in turn substantially increases their risk of stroke.21
T2DM’s detrimental effect on hippocampal integrity in adults is evident in cognitive testing. In one study, the mean IQ of a diabetic group (104.2511.88) was significantly lower than the IQ of the control group (114.238.44, p ≤ 0.001). The impairments were generally restricted to verbal declarative memory. Elderly individuals, however, showed additional impairments in multiple cognitive domains. This is attributed to the hippocampus’ high vulnerability to metabolic insults, or hypoxia.22 Additionally, a meta-analysis of the effects of diabetes found a 1.5-fold increased risk of developing mild cognitive impairment in individuals with diabetes.23 The cognitive impairments attributed to T2DM atrophy are evident even in adolescents. A T2DM group demonstrated that cognitive domains in the prefrontal cortex were subject to damage even though the subjects were adolescents and not more mature. Within the group, the obese teens with T2DM performed poorly on tests of verbal memory and processing speed.18, 19
Fat Mass and Obesity-Associated Gene
In recent years, a genetic component of obesity has been identified within variants of the fat mass and obesity-associated (FTO) gene. One allele for the FTO gene that is associated with obesity is a base-pair substitution at single-nucleotide polymorphism (SNP) rs9939609 with an A allele. Each additional copy of the A allele is significantly associated (p= 3 x 10-35) with an increase of ~0.4kg/m2. This accounts for an average 1.2 kg higher weight gain and a 1-cm greater waist circumference.24Similarly, a meta-analysis of 1729 adolescents determined that the G allele for rs9930333 of the FTO-gene was significantly associated with higher total body fat (p=0.002).25
FTO is expressed at the highest level in the cerebral cortex of the human brain. Knowing that FTO is related to variances in BMI, a study was designed to determine if there were structural differences in the brain of individuals who carried the obesity-related risk alleles that were correlated to higher BMI. Two SNPs associated with obesity are a C allele for rs1421085 and a G allele for rs17817449.
There is an association between BMI and carrying at least one copy of the risk allele at a predetermined FTO tagging SNP. Carrying a risk allele is also associated with statistically significant differences in regional brain volumes (p=1.31x10-3). For every1-unit increase in BMI there was an associated 1-1.5 percent average brain tissue reduction in the frontal, parietal, temporal and occipital lobes. There were also signs of atrophy in both the brain stem and cerebellar regions.26
In order to confirm that these changes were not attributed to microvascular damage in white matter, a measure of white matter burden (WMB) was regressed against brain structure. WMB did not explain the brain atrophy related to FTO because WMB affected different brain regions than the FTO risk allele. With a unit increase in WMB, there was approximately a 10 percent reduction in the frontal lobe and precuneus brain region (p=0.0016). Also, an observed 15-20 percent increase in ventricular volume was attributed to WMB.
On average, carriers of the obesity-related risk allele had an 8 percent reduction in brain tissue in the bilateral frontal lobe, and a 12 percent reduction in the bilateral occipital lobe compared to non-carriers. These results suggest that BMI does affect brain structure and FTO exerts a significant additive effect.26 The meta-analysis of adolescents also determined that carrying an obesity-related risk allele reduced total brain volume (p=0.005).25
Gazdzinski and colleagues further examined the mechanisms by which adiposity alters the brain by examining the concentration of metabolites throughout the brain and their association with atrophy. The study focused on the concentrations of N-acetylaspartate (NAA), choline-containing compounds, creatine-containing metabolites, and myo-inositol (m-Ino). NAA is a marker for neuronal viability. Choline is utilized as an indicator of cell membrane deterioration and synthesis, while m-Ino is used as a marker for glial cells. A higher BMI was significantly correlated with three distinct features: (1) reduced NAA concentration in the frontal (p=.0001), parietal (p=0.006), and temporal (p=0.008) white matter; (2) reduced NAA concentration in frontal GM (p=0.01); and (3) a reduced concentration of choline in the frontal white matter (p=0.05).
The reduced concentrations of NAA and choline suggests axonal and myelin abnormalities throughout the white matter, especially in the frontal lobe. The researchers deduced that because the white matter in the frontal lobe is more susceptible to the effects of aging these results may reflect accelerated aging in overweight and obese individuals. This accelerated aging poses an increased risk for cognitive decline and the development of Alzheimer’s disease.27
Cytokines and Other Peptides
In 2009, Isabella Soreca led a longitudinal study to determine whether a change in BMI during midlife would predict the total volumes of gray and white matter in the brain later in life. In the study, researchers examined whether an increase in BMI for women, during their premenopausal and postmenopausal period, would be associated with gray matter volume (GMV) reduction. They noted an increase in BMI during this transition was uniquely associated with a reduction in GMV. On average, there was a 15 percent reduction in GMV for obese women from pre- to post-menopause.28
The changes observed in the women were determined to be independent of microvascular disease, hypertension and stress, conditions generally associated with brain atrophy. It was suggested that the changes were a result of interactions between neuropeptides because the degree of reduction in GMV has only been associated with the transition from pre- to post-menopause. It is possible that circulating inflammatory cytokines may explain the results of the study.28 Adipocytes produce inflammatory cytokines, like interleukin-6 (IL-6), in which higher levels are associated with being overweight or obese. IL-6 production in adipocytes is stimulated by the pro-inflammatory mediators released in the tissue. It is believed that IL-6 may affect glucose homeostasis and thereby produce similar outcomes to increased cortisol production. Increased levels of IL-6 are also associated with a reduction in hippocampal volume in both women and men.29, 30 There was a significant reverse relationship between IL-6 and GMV in the left hippocampus (p=0.02). It appears that IL-6 explains for about 19 percent of the variance in left hippocampal GMV and approximately 6 percent of the right hippocampal GMV.29
Additionally, neuropeptides such as leptin and insulin, both regulators of eating, may have influenced the results. Leptin, a neuropeptide produced by adipocytes, is positively correlated to weight gain, and thereby may influence brain structures.31 Elevated levels of leptin in obese individuals are believed to be a consequence of reduced sensitivity to endogenous leptin, caused by inefficient leptin receptors in the brain. Although it is unclear how exactly leptin is related to insulin, research has demonstrated that increased levels of insulin elevate the level of leptin.32 Many of the neurochemical systems that regulate eating behavior are implicated in psychiatric disorders as well. Serotonin, dopamine, norepinephrine and other compounds are all involved in receiving information from the hypothalamus as well as regulating mood and behavior. A commonality among these compounds may account for an increase in ventricular volume in both obesity and mood disorders.28, 31 The correlations between obesity and psychiatric disorders described here are imperative in future research to determine whether the changes observed in the brain are related to mood disorders rather than obesity.
Obesity, as well as numerous related factors, is associated with significant atrophy throughout the brain. The reduced brain volumes are associated with impaired performance on cognitive testing. The extensive volume reduction attributed to a high BMI is concerning, but evidence suggests that these effects may be reversible.
For example, exercise and improved cardiovascular fitness may reverse some of the obesity-related brain atrophy. Several studies have shown that better fitness is associated with an increase in brain volume.4, 33-35 This may be secondary to the increased production of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).33 These factors appear to stimulate neurogenesis.34 Moreover, in a placebo-controlled study, individuals who walked 40 minutes three days a week showed an increase in GMV in the prefrontal, parietal, and lateral temporal regions and an increase in WMV in the genu of corpus callosum. Increased cardiovascular fitness improves blood flow to the brain and thus reduces the vascular injury secondary to obesity and related conditions.35 Therefore there is hope that brain volume reduction with obesity, though severe, can be reversed over time with interventions such as exercise. Such interventions may also minimize the risk of late-life dementia secondary to midlife obesity.
Majid Fotuhi, MD, PhD, is the Chairman of the Neurology Institute for Brain Health and Fitness.
Brooke Lubinski is a pre-med student intern at the University of Maryland.
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