['The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown.', 'Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite).', 'In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite.'] Do sex differences in serotonin-hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight?