Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits.

The hypothalamus regulates metabolic homeostasis by influencing behavior and endocrine systems. Given its role governing key traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function could yield insights into disease pathogenesis. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generate a high-resolution chromatin architecture atlas of an established embryonic stem cell derived hypothalamic-like neuron model across three stages of in vitro differentiation. We profile accessible chromatin and identify physical contacts between gene promoters and putative cis-regulatory elements to characterize global regulatory landscape changes during hypothalamic differentiation. Next, we integrate these data with GWAS loci for various complex traits, identifying multiple candidate effector genes. Our results reveal common target genes for these traits, potentially affecting core developmental pathways. Our atlas will enable future efforts to determine hypothalamic mechanisms influencing disease susceptibility.

Mindful Eating, General Mindful Awareness, and Acceptance as Predictors of Weight Loss.

OBJECTIVES: The goal of the present study was to determine whether baseline mindful eating, general mindful awareness, or acceptance was most strongly associated with short- and long-term weight loss in a lifestyle modification program. METHODS: Data were from 178 participants (baseline BMI=40.9±5.9 kg/m2, age=44.2±11.2 years; 87.6% female; 71.3% black) who enrolled in a two-phase trial. All participants attended an initial 14-week lifestyle modification program that included a meal replacement diet. Participants who had lost ≥5% of initial weight (N=137) were then randomized to 52 weeks of lifestyle modification with lorcaserin or placebo. Linear mixed models examined whether mindful eating (Mindful Eating Questionnaire) and general mindful awareness and acceptance (Philadelphia Mindfulness Scale) predicted short-term weight loss at week 14 in the full sample and long-term weight loss at the end of the trial in the subsample of randomized participants. RESULTS: In the full sample, higher baseline acceptance predicted greater short-term weight losses (p=.004). At week 14, individuals low in acceptance (-1SD) lost an average of 8.7 kg (SE=0.6) compared to 11.2 kg (SE=0.6) among those high in acceptance (+1SD). In the subsample of participants who successfully lost weight in phase 1, the independent effect of acceptance on total losses at the end of the trial did not reach statistical significance (p=.058). Neither mindful eating nor general mindful awareness independently predicted weight loss at either time point. CONCLUSIONS: Acceptance was a stronger predictor than either general or eating-specific awareness of weight loss with lifestyle modification.