Project Summary/ Abstract Background: Time restricted feeding (TRF) has greatly increased in popularity in recent years. TRF typically involves confining the eating window to 6-8 h, and fasting for the remaining hours of the day. During the eating window, individuals are not required to monitor energy intake. One of the reasons why TRF is so popular, is because it does not require individuals to count calories in order to lose weight. This feature of TRF may greatly improve long-term adherence to this diet, and in turn produce lasting weight control. Despite its growing popularity, only four human trials have examined the effect of TRF on body weight. While these preliminary studies show promise for TRF as a weight loss intervention, these previous trials are limited by short duration (2-4 months), lack of a control group, and no comparison to traditional dieting (daily calorie restriction; CR). We recently conducted a pilot study to compare the weight loss efficacy of 6-h TRF versus daily CR in adults with obesity and prediabetes. Our findings show that TRF produced greater adherence, energy restriction, and weight loss (-5%) versus CR (-3%) over 3 months. TRF also produced more pronounced reductions in insulin resistance, blood pressure, and oxidative stress, versus CR. What remains unknown, however, is whether these improvements by TRF would become more pronounced over longer periods of time (12-months), and if TRF can be implemented to help individuals maintain weight loss and sustain reductions in metabolic disease risk. The mechanisms (microbiome, appetite, gut peptides) that underlie the superior effects of TRF on body weight and adherence, also remain unknown. Methods: A 12-month randomized, controlled, parallel-arm trial, divided into: (1) 6-month weight loss period; and (2) 6-month maintenance period, will be implemented. Adults with obesity and prediabetes (n = 120) will be randomized to 1 of 3 groups: (1) 6h-TRF (n = 40) ad libitum food intake from 1-7 pm, fasting from 7-1pm daily, (2) CR (n = 40), 25% energy restriction daily; or 3) control (n = 40), ad libitum food intake daily. Hypotheses: The present proposal will test the following hypotheses: (Hyp1) The TRF group will be more adherent with the intervention versus CR, which will result in greater energy restriction, weight loss and weight loss maintenance; (Hyp2) The TRF group will experience greater improvements in insulin sensitivity (measured by clamp), plasma lipids, blood pressure, inflammation, and oxidative stress versus CR; (Hyp3) The TRF group will produce greater improvements in the composition, structure, and metabolic activity of the gut microbiota, as well as in appetite and gut peptides, vs CR, which will be related to superior adherence and weight loss. Significance: This study will be the first to show that TRF can be implemented as an alternative to traditional dieting (i.e. daily calorie restriction) for long-term weight management. This study will also show that TRF can be used as an effective non-pharmacological therapy to improve insulin sensitivity and decrease metabolic disease risk in individuals with prediabetes and obesity. The mechanisms (gut microbiome and appetite) that underlie the beneficial effects of TRF will also be elucidated.