Project Summary/Abstract Data from both epidemiological and sleep intervention studies have shown that insufficient sleep causes metabolic dysfunction and is associated with an increased risk of developing obesity and metabolic diseases, such as type 2 diabetes (T2D). However, a comprehensive assessment of the potential therapeutic benefits of sleep extension have not been evaluated in people. The overall goal of this proposal is to determine the effect of sleep extension on multi- system metabolic function and the potential mechanisms responsible for the link between insufficient sleep and metabolic dysfunction, including circadian misalignment, increased oxidative stress, plasma metabolomics and both systemic and adipose tissue inflammation in people with metabolically unhealthy obesity (MUO) who habitually maintain chronic short sleep schedules. Accordingly, we have assembled a transdisciplinary research team with expertise in metabolism (S. Klein, G. Smith at Washington University School of Medicine [WUSM]), sleep (K. Wright, J. Broussard at University of Colorado Boulder and B. Lucey [WUSM]), circadian biology and molecular science (J. Yoshino [WUSM]), and metabolomics (M. Jain at University of California San Diego) to conduct a randomized controlled trial to assess a 6-wk sleep extension intervention in people with MUO, who habitually sleep ≤6.0 h/night. We will determine the effect of sleep extension, on: 1) multi-organ insulin sensitivity (assessed by using the two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracers), 2) 24h plasma glucose, free fatty acids and hormone profiles, and 3) intrahepatic triglyceride content (assessed by using magnetic resonance imaging) and the potential cellular mechanisms responsible for insufficient sleep-induced metabolic dysfunction, by targeted (circadian misalignment, clock genes, inflammation, and oxidative stress) and non-targeted (mass spectroscopy-driven metabolome) approaches. The results from this transdisciplinary collaboration will provide important insights into understanding the physiological and molecular interactions between sleep and metabolic function, and could provide evidence for sleep extension as a countermeasure to improve metabolic health in people at high risk for developing metabolic diseases.