Obesity and Impulsivity Examining the role of diet-induced obesity on dopamine transporter function, and effects in adolescents

What is obesity? Abnormal or excessive fat accumulation that can impair health – World Health Organization Determined with Body Mass Index (BMI) >25 = overweight >30 = obese Causes: Imbalance between calories expended/consumed Excessive consumption of energy dense foods Sedentary lifestyle Genetics(?) Consequences: Risk factor for: cardiovascular disease, diabetes, cancer, death

Worldwide Obesity

Worldwide Obesity 1.4 billion overweight people worldwide (2008) 500 million of those are obese (2008) Today, roughly 10% of worlds population Now major problem in developing countries Increased access to processed, high calorie foods Changes in lifestyle and lack of access to medical services

Obesity in America 35.7% of American adults are obese Doubled since 1980 17 % of American adolescents are obese Tripled since 1980 Radical differences in prevalence by race, socioeconomic status

Obesity in Adolescents Youth obesity in America recently saw a slight decline Childhood obesity associated with premature death, disability Linked to enhanced reward sensitivity and reduced impulse control during food processing

Obesity and Impulsivity What is the relationship? Both are kind of murky concepts Obesity: A disease which is tangentially related to genetic predisposition, cultural and socioeconomic factors Fundamentally: Caused by eating too much Is that impulsive? From Cliff’s Presentation, Phenotypic Impulsivity is: Negative consequences Risky Behavior Repetitive* Not able to discern want from need Underdeveloped PFC less feedback from PFC to limbic impatience make choices even recognizing the negative consequences for that choice

Obesity and Impulsivity Assuming over-eating is impulsive behavior… Previous studies suggest that over-eating may be a result of reduced sensitivity to food reward in the dorsal striatum Reduced sensitivity = compensatory eating Links obesity to other impulsive behaviors - drug use However, in obese people, over-eating itself leads to down-regulation of D2 receptors Leading to reduced sensitivity to food reward Leading to more over-eating So does impulsivity predict obesity, or is it an outcome of it?

Obesity and Reward Response Stice et al. Rats: Overweight = ↓ basal DA, ↓ D2 receptor availability, ↓ induced DA release in dorsal striatum, NAc, mPFC Humans: Obese = ↓ D2 receptor availability in striatum, ↓ striatal response to food intake But ↑ response to food cues (anticipation)

Obesity and Reward Response Stice et al. Proposes three theories to explain conflicting findings Individuals at risk experience ↓ reward from eating, leading to compensatory over-eating and hyper-responsivity of reward circuitry via conditioning – Reward Deficit Theory Individuals at risk initially show ↑ responsivity to reward value of food cues, leading to over-eating and a reduction in DA signaling in response to food intake – Reward Surfeit Theory Individuals at risk initially experience ↑ reward from eating, leading to overeating that reduces DA signaling in response to food intake and hyper-responsivity of reward circuitry to food cues, both of which may drive further overeating - Synthesis

Obesity and Reward Response Stice et al. experimental design 60 lean human youths 35 at high risk for obesity (both parent’s BMI > 30) 25 at low risk for obesity (both parent’s BMI < 25) fMRI Anticipation/Receipt of Food Reward – Tasteless Solution Receipt of Food Reward – Tasteless Solution First academic paper to contain milkshake recipe Anticipation/Receipt of Monetary Reward Winning Money/ Possibly Winning Money/Neutral Response

Stice et al. Experiment

Stice et al. Results High Risk/Low Risk found the milkshake equally pleasant High Risk group showed greater activation in right caudate/right frontal operculum For both milkshake receipt/tasteless solution receipt No difference in unpaired cue test for food reward High Risk group showed greater activation in putamen in response to winning money/reward neutral display No difference in anticipatory response for winning money/reward neutral display

Figure 2. A–D, Greater activation in the right caudate (A: 6, 9, 24; Z3.14; p0.04, FDR; k3; B: 6, 9, 30; Z3.23, p0.04, FDR; k3), right frontal operculum (C: 39, 21, 21; Z3.44, p0.02, FDR; k5), and left parietal operculum (D:54, 15, 21; Z3.36; p0.02, FDR; k2) in the high-risk versus low-risk group during milkshake receipt–tasteless receipt, with the bar graphs of parameter estimates from those peak voxels.

Figure 3. A–D, Greater activation in high-risk versus low-risk group in response to the win–neutral display in the right putamen (A, square: 18, 0, 9; Z3.44; p0.018, FDR; k3), left putamen (circle:18, 0, 12; Z3.74, p0.007, FDR, whole brain; k5) with bar graphs of the parameter estimates from those regions (B, right putamen; C, left putamen) and in the right orbitofrontal cortex (D: 45, 33,6; Z5.61, p0.001, FDR; k16) with bar graphs of the parameter estimates from that voxel.

Obesity and Reward Response Normal weight, high risk adolescents showed greater response in dorsal striatum to food receipt Elevated sensitivity to food reward may be a cause of obesity ↓ striatal response, ↓ D2 receptor availability in obese people is then a consequence, not a cause of over-eating High risk adolescents also showed greater striatal response to monetary reward Suggests initial hyper-responsivity to various reward types in people at risk for obesity … impulsivity?

Obesity and Impulsivity Moreno-Lopez et al. Why are some people susceptible to obesity, and others not? Demonstrated by high-risk, low-risk groups in previous paper Does the structure of the brain correlate with impulsive behavior? Obesity? Both? Previous evidence: Reduced GM in orbital frontal cortex in obese vs. lean adoloscents Volumetric changes to GM in striatum Obese adolescents show greater trait disinhibition, poorer cognitive control

Obesity and Impulsivity Moreno-Lopez et al. experimental design 52 adolescent humans 16 normal weight 16 overweight 20 obese Tests SPSRQ – 48 item questionnaire to assess reward/punishment sensitivity UPPSP – 59 item inventory to assess facets of impulsive behavior Sensation seeking, lack of perseverance, lack of premeditation, negative urgency, positive urgency Stroop Test – Measures inhibitory control MRI to show structural correlates

Moreno-Lopez et al. Results No significant differences between groups for any of the measurements assessed Regional differences in GM between normal weight, overweight groups ↑ volume of right hippocampus in excess weight individuals Structural correlates between ROI and behavioral test scores showed differences only in normal weight individuals Reward sensitivity, positive urgency negatively associated with GM volume in left somatosensory cortex

Figure 1. Clusters of significant gray matter volume increase in excess weight compared with normal weight subjects. Peak coordinates were located in the right hippocampus (x, y, z_ 38, 213, 218; t = 4.21; pFWE-SVC,0.05). Results are overlaid on coronal and sagittal sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘x’ coordinates in MNI space. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.50). doi:10.1371/journal.pone.0049185.g001

Figure 2. Between-group interaction between regional gray matter volume and reward sensitivity. A. Voxel-wise correlations between regional gray matter volume and reward sensitivity score specifically observed in normal weight subjects. Peak coordinate was located in the left secondary somatosensory cortex (SII, Brodmann area 43) (x, y, z =260, 27, 11; t = 4.51; pFWE-SVC,0.05). Results are overlaid on coronal (left) and axial (right) sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘z’ coordinates in MNI space, respectively. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.100). B. Plot of the correlation between gray matter volume at the peak coordinate and the reward sensitivity score. Normal weight group (filled circles, solid line) showed a significant correlation between these two measures (r =20.750; p,0.005), while in the excess weight group the correlation was not significant (r = 0.284; p.0.05).

Figure 3. Between-group interaction between regional gray matter volume and positive urgency. A. Voxel-wise correlations between regional gray matter volume and positive urgency (UPPS-P) score specifically observed in normal weight subjects. Peak coordinate was located in the left secondary somatosensory cortex (SII, Brodmann area 43) (x, y, z =263, 27, 15; t = 4.89; pFWE-SVC,0.05). Results are overlaid on coronal (left) and axial (right) sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘z’ coordinates in MNI space, respectively. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.100). B. Plot of the correlation between gray matter volume at the peak coordinate and the positive urgency score. Normal weight group (filled circles, solid line) showed a significant correlation between these two measures (r =20.856; p,0.0005), while in the excess weight group the correlation was not significant (r = 0.058; p.0.05).

Figure 4. Between-group interaction between regional gray matter volume and response inhibition. A. Voxel-wise correlations between regional gray matter volume and the Stroop response inhibition score specifically observed in normal weight subjects. Peak coordinate was located in the left dorsolateral prefrontal cortex (Brodmann area 9) (x, y, z =261, 6, 24; t = 5.01; pFWE-SVC,0.05). Results are overlaid on coronal (left) and axial (right) sections of a normalized brain, and the numbers correspond to the ‘y’ and ‘z’ coordinates in MNI space, respectively. Color bar represents t value. For demonstration purposes the images are displayed at p,0.001 (uncorrected, k.100). B. Plot of the correlation between gray matter volume at the peak coordinate and the Stroop response inhibition score. Normal weight group (filled circles, solid line) showed a significant correlation between these two measures (r = 0.769; p,0.005), while in the excess weight group the correlation was not significant (r =20.327; p.0.05).

Moreno-Lopez et al. Results ↑ volume of right hippocampus in excess weight individuals Region associated with motivational signals for appetite So there are structural differences in obese/normal weight brains Structural correlates between ROI and behavioral test scores showed differences only in normal weight individuals Excess weight individuals didn’t show significant correlations, and scored no differently than normal weight on the tests So there are structural correlations with impulsivity, but these are not linked to obesity (at least not according to this test)

Obesity and Impulsivity Obesity and impulsivity linked by brain function, not structure Adolescents who are at risk of obesity are more sensitive to reward But adolescents who are actually obese are not more impulsive So what’s the connection? Stice et al: Individuals at risk initially show ↑ responsivity to reward value of food cues, leading to over-eating and a reduction in DA signaling in response to food intake – Reward Surfeit Theory

Obesity, Impulsivity, & Dopamine Is the reward surfeit theory viable? ↑ reward sensation (impulsivity) →overeating →Diet induced obesity (DIO) ↓ DA function ↓ impulsivity Seems illogical on the surface Let’s get some hard evidence for this stuff I’m talkin’ Animal Models! Oh Yeah!!! (His brain was dissected and analyzed)

Obesity, Impulsivity, & Dopamine Narayanaswami et al. Used rat model to study DAT function, impulsivity and motivation as outcomes/predictors of obesity Narayanaswami’s definition of impulsivity: “…a multifaceted behavioral construct involving urgent actions, lack of premeditation and perseverance, and increased sensation-seeking behaviors” Asserts that cognitive and motivational factors of impulsivity are linked to obesity via inability to resist excessive eating Thanks, Captain Picard

Narayanaswami et al. Experiment Experiment One – Outcomes of obesity 32 rats used to generate DIO model 24 on High Fat Diet (HF) for 8 weeks Split into Obesity Prone and Obesity Resistant based on weight gain 8 on Low Fat Diet (LF) for 8 weeks Impulsivity evaluated with Delayed Discounting task Sucrose pellets Food motivation evaluated with reinforcers (HF and LF pellets) First using Fixed Ratio (FR) schedule Then a Progressive Ratio (PR) schedule with the alternate reinforcer

Narayanaswami et al. Experiment Experiment Two – Predictors of Obesity 22 rats used to test for predictors All fed standard chow Impulsivity evaluated with Delayed Discounting task Sucrose pellets Food motivation evaluated with reinforcers (HF and LF pellets) First using Fixed Ratio (FR) schedule Then a Progressive Ratio (PR) schedule with the alternate reinforcer After testing, HF diet introduced for 8 weeks Split into OP and OR (n=6) Correlations between neurobehavioral measures and weight

Fig 1

Narayanaswami et al. Experiment Striatal D2-receptor density/affinity Shift in control from NAc to striatal DA pathways →habitual behaviors Striatal involvement in food motivation ∆Fos B overexpressed in rats with high PR breakpoint D2 receptor density decreased in obese individuals Maximal velocity/affinity of VMAT2 With DAT, regulates extracellular dopamine DAT-deficient mice have ↑ extracellular DA, ↑ food consumption Likely plays a role in regulating binge eating

Fig 2

Obesity, Impulsivity, & Dopamine Effects of DIO OP rats exhibited: ↓striatal D2 receptor density compared with OR ↓ maximal velocity of uptake at DAT compared with OR ↑ extracellular dopamine in striatum compared to OR Predictors of DIO No correlation between delay for reinforcer and weight gain Positive correlation between PR breakpoint for HF reinforcers in OP compared to OR BUT there were no differences in dopamine concentration

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Narayanaswami Results Motivation to obtain HF foods predicts obesity Not impulsivity (according to this test) ↓ in striatal DAT function is an outcome of DIO Upon development of DIO: Motivation to obtain HF foods was maintained in OP Impulsivity decreased in OP after DIO (compared to OR)

The Big Picture Where do we stand on obesity and impulsivity? They’re linked, but we’re not sure how Do the models used accurately illustrate impulsivity? Probably not How do we explain conflicting results? With great effort, although… Reward Surfeit theory does a good job (IMO): Individuals at risk of obesity are more sensitive to reward (and maybe more impulsive) Eventual onset of obesity leads to reduced DAT/D2 function This leads to maintenance of over-eating (impulsive?) but a decrease in other forms of measured impulsivity