SUMMARY Obesity affects 2.8 billion people worldwide and is the second leading cause of premature mortality. Unfortunately, current treatments do not produce lasting weight loss, potentially because of an incomplete understanding of the risk processes that promote obesity. After eating to fullness individuals with obesity versus without obesity show weaker satiation signaling, as indexed by elevated responsivity of reward valuation and gustatory regions in response to food cues and food tastes and stronger connectivity between these brain regions. Behaviorally, obesity is associated with consumption of excess calories ab libitum when sated, along with reduced perceived fullness and less perception of homeostatic signals during satiation. Although research has established that obesity is correlated with weaker satiation signaling, no study has determined whether weaker satiation signaling increases the risk for future overeating and weight gain or is a consequence of overeating. Thus, we propose to conduct a rigorous prospective study designed to determine the direction of influence between these two variables. We will recruit 132 healthy-weight adolescents (aged: 13-16; n=80 at high risk for obesity virtue of maternal obesity) for a multimodal, repeated-measures study using a novel fMRI paradigm designed to capture neurobehavioral changes over the course of eating to satiation. We will also include objective measures of body fat, food intake, gut hormones, and cognitive measures. Aim 1: We will a) test the hypothesis that over the course of eating to satiation healthy-weight adolescents at high-risk versus low-risk for obesity (virtue of maternal obesity) will show persistently elevated brain response to energy-dense food tastes in the striatum, postcentral gyrus, and gustatory cortex. Aim 2: We will a) test the hypothesis that participants who show weaker satiation signaling, as evidenced by persistently elevated responsivity in the striatum, postcentral gyrus, and gustatory regions after eating to fullness will show elevated future body fat gain over a 3-year follow-up, and b) test the ability of individual differences in a satiated brain fingerprint to predict future body fat gain over a 3-year follow-up. Aim 3: Test the hypothesis that the degree of percent body fat gain at 3-year follow-up will be related to a reduction in satiation signaling, as indexed by a) higher responsivity in striatal, postcentral gyrus, and gustatory regions after eating to fullness over the course of satiation, and b) increased engagement of these regions in a brain fingerprint when satiated. If data provide support for Aims 1 and 2, but not Aim 3, results would suggest that weaker satiation signaling increases risk for weight gain. In contrast, if data provide support for Aim 3, but not Aim 1 and 2, results would suggest that weaker satiation signaling is a consequence of overeating. Finally, if data provide support for all 3 Aims, results would suggest that weaker...