OR35-06 Four-week intranasal oxytocin treatment modulates functional brain activation in reward, homeostatic, and cognitive control regions in adults with obesity

Abstract Disclosure: M. Wronski: None. A. Shreekumar: None. M. Bredella: None. L. Kerem: None. T. Deckersbach: None. K. Holman: None. S.E. Smith: None. E. Asanza: None. F. Plessow: Dr. Plessow is an inventor on US provisional patent application no. 63/467,980 (Oxytocin-based therapeutics to improve cognitive control in individuals with attention deficit hyperactivity disorder). L.M. Holsen: None. E.A. Lawson: Dr. Lawson receives grant support and research study drug from Tonix Pharmaceuticals and receives royalties from UpToDate, Dr. Lawson and/or immediate family member holds stock in Thermo Fisher Scientific, Zoetis, Danaher Corporation, Intuitive Surgical, Merck and West Pharmaceutical Services, Dr. Lawson is an inventor on US provisional patent application no. 63/467,980 (Oxytocin-based therapeutics to improve cognitive control in individuals with attention deficit hyperactivity disorder. Objective: Oxytocin (OXT), a hypothalamic hormone secreted into brain regions regulating eating behavior and metabolism, is under investigation as an anti-obesity therapeutic. In animals and humans, OXT administration reduces caloric intake, and a pilot functional MRI (fMRI) study in 10 men with overweight/obesity showed that single-dose intranasal (IN) OXT reduced food-related activation in reward (ventral tegmental area, VTA; orbitofrontal cortex, OFC; anterior insula, aINS) and homeostatic (hypothalamus) brain regions, while increasing activation in a cognitive control area (dorsal anterior cingulate cortex, dACC). There are no data regarding the mechanisms underlying the anorexigenic effects of chronic OXT administration in humans. In a trial of IN OXT in adults with obesity (NCT03043053), we hypothesized that 4-week IN OXT would similarly reduce brain activation in food reward and homeostatic regions while increasing activation in cognitive control regions. Methods: Sixty-one non-diabetic adults with obesity were randomized 1:1 to 24 IU IN OXT 4x/day or placebo; of these, 58 had usable MRI data. OXT was held on the morning of visits. In a 3T Skyra scanner, participants completed a visual food cue paradigm and a stop signal task (SST), assessing neural response to food stimuli and inhibitory control, respectively, at baseline and week 4 visits. We used Statistical Parametric Mapping for quality control and first-level modeling of fMRI data, MarsBaR for β extraction, and R for second-level models. Linear mixed-effects models, incorporating a treatment-by-visit interaction term, were applied to examine OXT vs placebo effects on fMRI activation for predefined contrasts and regions of interest (food cue: VTA, OFC, aINS, hypothalamus; SST: dorsolateral prefrontal cortex [dlPFC], dACC, anterior supplementary motor cortex [preSMA]). Results: Treatment groups (OXT n=30, placebo 28) did not differ in sex (OXT 17 [56.7%], placebo 15 [53.6%] female), age (OXT mean±se=33.7±1.1, placebo 32.8±1.2 years), and BMI (OXT 36.6±0.7, placebo 36.2±0.8 kg/m2). Four-week IN OXT vs placebo reduced fMRI activation in aINS (F=3.69, p=0.028, d=0.28) in response to high-calorie food cues vs objects; and in OFC (F=4.71, p=0.016, d=0.36), aINS (F=3.07, p=0.041, d=0.26), and hypothalamus (F=9.85, p=0.001, d=0.51) in response to low-calorie foods vs objects. Four-week IN OXT vs placebo increased activation in dACC (F=3.16, p=0.040, d=0.37) and preSMA (F=2.81, p=0.049, d=0.35) during successful vs failed SST response inhibition. Conclusion: We found that prolonged IN OXT administration (in the absence of acute OXT effects as drug was not given on morning of visits) attenuated fMRI activation of reward and homeostatic brain areas while enhancing activation of cognitive control-related regions, providing potential neural mechanisms for anorexigenic effects of exogenous OXT in obesity. Presentation: Monday, July 14, 2025