PROJECT ABSTRACT Obesity in adolescence and young adulthood is epidemic, leading to increased metabolic risk later in life. The extent of weight loss through lifestyle interventions is variable and difficult to sustain. Existing medical therapies for adults, which are often not FDA-approved in children, may lead to modest weight loss, but effects are difficult to sustain, and these medications are limited by their tolerability. Oxytocin (OXT), a hypothalamic hormone that regulates food intake and energy metabolism, is an exciting potential novel therapeutic in this population. Intranasal (IN) OXT induced marked weight loss and was well tolerated in a small 8-week study of adults with obesity. Our preliminary data show reduction in BMI SDS with excellent tolerability with 6-months of IN OXT in 5-18-year-old children across a range of BMIs. Data in rodent and nonhuman primates indicate that OXT drives weight loss by reducing food consumption and increasing energy expenditure. Importantly, OXT also has the potential to reduce metabolic risk through reduction in visceral and hepatic fat, reduced inflammation, and improved lipids. In fact, OXT has recently been shown to reduce neuroinflammation, and hypothalamic inflammation in rodent models with obesity. We propose a randomized, placebo-controlled study of twelve weeks of IN OXT vs. placebo to determine whether OXT reduces weight and metabolic risk markers in adolescents with obesity as it does in diet-induced obese animal models. We will also investigate underlying mechanisms driving OXT effects using cutting-edge imaging and metabolic assessments. In a study of 75 adolescents with obesity, we hypothesize that twelve weeks of IN OXT compared to placebo will result in (1) reduced BMI SDS from (a) decreased food intake in the fasting state and in the absence of hunger, and (b) increased resting energy expenditure and diet-induced thermogenesis, mediated by reduced measures of hypothalamic inflammation; and (2) reduced visceral and intrahepatic fat with relative preservation of lean/muscle mass, associated with reduced systemic inflammation and an improved lipid profile. This study will be the first to systematically investigate the efficacy and safety of OXT as a novel therapeutic agent to induce weight loss and improve indicators of metabolic risk in adolescents with obesity.