The present study was performed to examine the central response to food-related visual cues during states of energy balance and short-term positive energy balance in thin individuals screened to be resistant to weight gain and obesity as compared to reduced-obese (RO) individuals, who are prone to weight gain/regain. The results of this study demonstrate that during energy balance, food-related food cues result in activation of brain regions known to be important in energy intake regulation in both study groups. Thin individuals, however, have a more robust response to food-related visual cues than RO individuals. In addition, thin individuals appear to be more sensitive to the positive energy balance associated with overfeeding with significant attenuation of the neuronal responses to visual food cues as compared to RO individuals.
In the overnight fasted state, the neuronal response to food-related visual cues as compared to non-food objects is complex, associated with the activation of a network of brain regions, including the insula, inferior temporal visual cortex, posterior parietal cortex, ventral striatum, posterior cingulate, hippocampus, sensory cortex, and lateral prefrontal cortex. The activation of a number of these regions is consistent with increased attention to food cues and enhanced motivation to eat. Interestingly, thin individuals appear to be more sensitive to food cues than RO individuals as demonstrated by increased activation of the insula and visual cortex. While we are not aware of any other published study that has examined the difference in response to visual food cues between normal weight and reduced-obese or obese individuals, studies examining regional cerebral blood flow (rCBF) as measured by positron emission tomography (PET) also have shown that obese and RO individuals appear to have altered brain responses to fasting 
. While Rosenbaum et al showed that the reduced-obese state was associated with significantly greater activation of the brainstem, parahippocampus, culmen, globus pallidus, middle temporal gyrus, inferior frontal gyrus, middle frontal gyrus and lingual gyrus and significantly reduced activation of the hypothalamus, amygdala, parahippocampus, cingulate, hippocampus, middle frontal gyrus, inferior parietal lobule, fusiform gyrus, supramarginal gyrus and precentral gyrus in response to visual food cues as compared to the obese state they did not compare these states to normal weight individuals 
. We interpret our findings to mean that in the fasted or “hungry” state, obese resistant individuals are more sensitive to food cues, promoting enhanced attention toward food and motivation to eat perhaps in defense of their lower body weight or energy stores.
Two days of positive energy balance as produced by 30% overfeeding has a much more dramatic impact on the neuronal response to visual food cues in thin as compared to RO individuals. Similar to our previous report 
, overfeeding results in diminished activation in cortical regions associated with visual processing and motivation, suggesting that the salience of the food cues is reduced after overfeeding in thin individuals. In addition, reduced hypothalamic activation in response to overfeeding may reflect interactions between visual cues and the energy status of the individual. In a state of positive energy balance the “gain” on the homeostatic regulation of energy balance may be changed, promoting reduced salience to food related cues and a return to energy balance. In contrast, RO individuals have increased activation of cortical regions associated with visual processing and attention as well as in the hypothalamus, suggesting altered ability to sense positive energy balance. This altered response in RO individuals signifies an impaired interaction between visual food cues and brain regions important in the regulation of food intake and may represent a potential mechanism for explaining the difficulty individuals have with maintaining weight loss.
While we are not aware of any other studies that have examined the effects of positive energy balance on the neuronal response to visual food cues, the neuronal responses to food-related stimuli have been shown to be affected by acute satiation, supporting the concept that the metabolic state effects the response and processing of external food-related stimuli 
. In addition, acute satiation has been shown to be associated with increased rCBF in the prefrontal cortex and decreased rCBF in the hypothalamus and insula 
. It may be that the changes in corticolimbic activation with alterations in energy state drive the hypothalamic response, or it may be that the hypothalamus integrates homeostatic and nonhomeostatic signals directly 
. Again, this signaling appears to be altered in RO individuals who are prone to weight gain.
The findings of the present study and of others suggest that the insula plays a central role in the response to food stimuli. Although usually considered the primary taste cortex, the insula has also been shown to be a brain region important in the regulation of feeding behaviors 
and may relate to the memory of the rewarding effects of food 
. The fasted or ‘hungry’ state is consistently associated with not only increased rCBF in the insula 
but also increased activation of the insula in response to visual food-related stimuli 
, and insular activation in response to food cues has also been found to be correlated with the desire to eat 
as well as to hunger and prospective food intake as seen in our current findings. Satiation, on the other hand, is associated with reduced insula rCBF, and overfeeding results in the attenuation of the insula in response to visual (current findings) and olfactory stimuli 
. It, therefore, appears that visual food cues may be associated with activation of the memory of the rewarding effects of food and goal directed behavior potentially preparing the individual for ingestion, and that these signals are ‘normally’ turned off in times of positive energy balance. The insular response to food cues, however, appears to be altered in RO individuals who do not appear to appropriately “turn off” the insula in response to overfeeding.
The insula has also been shown to be important in somatosensory, visceral sensory, and visceral motor functions, such as in response to esophageal stimulation and gastric distension 
. Furthermore, peripheral signals such as leptin and ghrelin have been found to impact the insular response to food stimuli. In leptin-deficient adults, the leptin deficient state is associated with greater activation of the insula in response to visual stimuli of high-calorie foods than during leptin replacement. These authors concluded that “these findings may reflect the role of the insula in representing information about the internal bodily states as conscious emotional feelings, or interoception. Leptin deficiency may enhance insular interoception of cue induced feelings of hunger” 
. Leptin replacement in reduced obese individuals is also associated with reduced insular activation in response to visual food stimuli 
. Malik et al found that ghrelin administration was associated with increased activation of insula in response to visual food stimuli 
. It is unclear, however, how these peripheral signals mediate activation of the insula. In addition to the hypothalamus, receptors for these hormones have been found in the cerebral cortex, hippocampus, basal ganglia, brainstem, and cerebellum 
, but it is not known whether there are receptors for these hormones in the insula specifically. Although an indirect effect is possible, the hypothalamus is a likely region mediating the response seen in the insula. These findings support that the insula is a brain region that is important in the processing of food-related cues, both internal and external, and appears to be important in processing the motivational value of food and feeding.
In conclusion, the results of this study demonstrate that there are important differences in the responses to visual food-related cues between thin individuals, who have been screened to be resistant to weight gain and obesity, and reduced-obese individuals, individuals who are prone to weight gain/regain. In the baseline fasting state, thin individuals have a much more robust neuronal response to food-related visual cues than reduced-obese individuals. Overfeeding results in significant attenuation of the response to visual foods cues in thin but not reduced-obese individuals. These findings emphasize the important role of external visual cues in the regulation of energy intake and suggest that there are important phenotype differences in the interaction between external visual sensory inputs, energy balance status, and brain regions important in the regulation of energy intake.