ORIGINAL ARTICLE Cortico-limbic responsiveness to high-calorie food images predicts weight status among women WDS Killgore, M Weber, ZJ Schwab, M Kipman, SR DelDonno, CA Webb and SL Rauch OBJECTIVES: Excessive weight gain and obesity are currently among the world’s major threats to health. Women show significantly higher rates of obesity and eating disorders relative to men, but the factors contributing to these gender differences remain uncertain. We examined the correlations between regional brain responses to images of high-calorie versus low-calorie foods and self-reported motivational status, including ratings of general appetite, overeating propensity, state hunger and desire for specific foods. SUBJECTS: Thirty-eight healthy right-handed adults (22 male; 16 female) ages 18–45 participated. There were no differences between males and females with regard to age or body mass index (BMI). RESULTS: Overall, motivational status correlated significantly with activation within the amygdala, insula and orbitofrontal cortex. Regional activation was then used to predict BMI, an indicator of long-term food consumption and energy expenditure. The combined model was significant, accounting for 76% of the variance in BMI for women, whereas the same regions were not predictive of weight status among men. CONCLUSIONS: Findings suggest that long-term weight status is related to visual responsiveness to calorie-dense food imagery among women. International Journal of Obesity (2013) 37, 1435–1442; doi:10.1038/ijo.2013.26; published online 5 March 2013 Keywords: food; appetite; sex differences; fMRI; neuroimaging INTRODUCTION Problems with overweight and obesity are currently among the major public health concerns facing westernized societies. Within the United States, 2 of every 3 adults are classified as overweight, 1 and over 1 in 3 now meet criteria for obesity. 2 Excess weight gain is associated with numerous long-term health problems, including increased risk of type 2 diabetes, hypertension, stroke, cardiovascular disease, and a range of other negative health outcomes. 3 In addition, those meeting criteria for obesity are twice as likely than their normal weight peers to succumb to premature death from a variety of causes. 3 Women, in particular, appear to show the greatest problems with excess weight gain, 2 extreme obesity, 4 and higher rates of eating disorders relative to men. 5–7 Food consumption and weight gain among humans is an extraordinarily complex phenomenon, regulated by genetic, 8 central, 9 and peripheral neurobiological factors, 10 as well as complex social, cognitive and psychological variables. 11–14 Consequently, the basis for these sex differences in weight gain and food consumption remain unclear, but some evidence suggests that there are distinctions between men and women in their behavioral responses to food stimuli, 7 and even in the responsiveness of critical brain regions involved in regulating appetite and food intake. 15,16 Individuals vary in their motivational status and behavioral control when confronted with food stimuli. 17 Incentive to consume food in the immediate environment is dictated by an individual’s current hunger state 18 and general hedonic preference for specific foods. 19,20 While the long-term ability to regulate food consumption and to maintain a stable weight is associated with individual hedonic preferences for food stimuli, it may also be related to a general capacity to inhibit behavior and affective responses. 21 In particular, the ability to modulate behavior in response to tempting food is strongly linked to several aspects of impulse control, such as executive attention, inhibitory control and affect regulation, 22 capacities that are often associated with the behavioral 23 and emotion 24 regulation functions of the prefrontal cortex. The medial orbitofrontal cortex, in particular, appears to be one among several nodes within a complex neurocircuitry involved in responding to food stimuli 25–29 and regulating food intake, 30,31 a system that also likely includes the amygdala and posterior insula, among others. In the present study, we used functional magnetic resonance imaging (fMRI) to examine the responsiveness of this system to visual images of unhealthy high-calorie versus relatively healthy low-calorie foods, and correlated that activation with several self- report variables important to food motivation, including general appetite level (Appetite), the propensity to overeat (Overeating), state hunger (Hunger), and hedonic attraction to the individual foods (Food Desire). Based on prior research described above, we restricted our primary analyses to the amygdala, insula and medial orbitofrontal cortex. Activation within the regions found to be related to each of these food motivational indices was then used to predict body mass index (BMI), a stable measure of long-term food consumption. Based on our prior findings that cerebral responses to images of food stimuli were stronger in women than men, 16 and similar findings reported by others, 15 we hypothesized that such responses would be related to BMI among women, but would be weaker or non-existent among men. Social, Cognitive and Affective Neuroscience Lab, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Correspondence: Dr WDS Killgore, Social, Cognitive, and Affective Neuroscience Lab, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. E-mail: killgore@mclean.harvard.edu Received 19 November 2012; revised 21 January 2013; accepted 28 January 2013; published online 5 March 2013 International Journal of Obesity (2013) 37, 1435–1442 & 2013 Macmillan Publishers Limited All rights reserved 0307-0565/13 www.nature.com/ijo