Meaningful weight reduction in obesity is difficult to achieve and sustain, and available therapies have significant limitations. Oxytocin (OXT), a hypothalamic hormone that regulates food intake and energy metabolism, is an exciting potential novel therapeutic in obesity management. A small study of obese adults demonstrated weight loss of nearly 20 lbs with 8 weeks of intranasal (IN) OXT at the proposed dose. Data in rodent and nonhuman primate models indicate that OXT drives weight loss by (1) increasing energy expenditure, (2) inducing lipolysis, and (3) reducing food consumption. We propose a randomized, placebo- controlled study of sustained IN OXT to determine whether OXT reduces body weight, increases energy expenditure and reduces total, visceral and liver fat in obese humans, as it does in animal models. We will also characterize the effects of sustained OXT on caloric intake and relevant neural pathways using cutting-edge neuroendocrine, neuroimaging, and behavioral measures. In a study of 60 obese men and women, we hypothesize that eight weeks of IN OXT (24 IU qid) compared to placebo will result in (a) weight loss, (b) increased resting energy expenditure; and (c) reduced total body, visceral and liver fat. Building on our prior findings indicating that OXT may achieve weight reduction in part by modulating reward and impulse control neural pathways to curb eating, we further hypothesize that OXT will result in reduced caloric intake at a test meal, independent of change in weight, compared to placebo, mediated by (a) reduced fasting and post- prandial fMRI activation of reward-related food motivation brain regions (ventral tegmental area, basal ganglia) using a visual food stimuli paradigm; and (b) increased impulse control accompanied by increased fMRI activation and functional connectivity of impulse control brain regions (anterior cingulate, dorsolateral prefrontal cortex) during a validated task requiring the engagement of impulse control to suppress impulsive responses. This study will demonstrate the efficacy and increase our understanding of the underlying mechanisms of IN OXT as a potential weight loss drug -- critical steps in the translation of preclinical findings to humans and optimizing therapies for patients with obesity.

Public Health Relevance

Obesity is a major public health concern that is associated with comorbidities and premature mortality, and has limited treatment options. Oxytocin, a hypothalamic hormone that regulates appetite and energy metabolism, is a promising therapy for obesity. This randomized placebo-controlled investigation will study the effects and underlying mechanisms of eight weeks of intranasal oxytocin on weight in obese adults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK109932-01A1
Application #
9309526
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2017-05-01
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114