Metabolic Effects of Circadian-Based Dinner Time

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Obesity and its metabolic complications are leading causes of morbidity and mortality in the world. Evidence is mounting that inappropriate timing of food intake contributes to obesity. Late eating is associated with obesity and metabolic syndrome, suggesting that circadian misalignment may be the mechanism underlying the adverse metabolic consequences of late eating. We hypothesize that meal timing in relation to the endogenous circadian rhythm, rather than to clock hour, determines metabolic outcomes. In this study, we will use dim light melatonin onset (DLMO), the gold-standard for ascertaining central circadian output, to assess individual circadian rhythms. We will use DLMO to prospectively assign “early” (DLMO-3h) vs “late” (DLMO+1h) dinner while maintaining the same sleep times (DLMO+2h to +10h) to evaluate whether acute metabolic dysfunction can be reliably induced or prevented by setting dinner times around DLMO. We will use hourly blood sampling for detailed glucose and insulin profiles, oral [2H31] palmitate tracer to quantify dietary fat oxidation, and whole-room indirect calorimetry to measure total fat oxidation. We will enroll both normal-weight healthy adults (NWH) and adults with obesity and prediabetes (OPD), as the latter population is particularly vulnerable to metabolic diseases and could derive immediate benefit from our findings. The specific aims are to: 1) Quantify the impact of DLMO-based “early” vs. “late” dinner time on post-prandial and overnight glucose and insulin levels in NWH and OPD adults, 2) Measure the impact of DLMO-based “early” vs. “late” dinner time on (a) exogenous/dietary and (b) total fat oxidation in NWH and OPD adults, and 3) Examine the utility of circadian phase markers to predict susceptibility to late eating-induced metabolic dysfunction. For Aims 1 and 2, we will crossover-randomize 16 NWH adults (8 men, 8 women) and 16 OPD adults (8 men, 8 women) to the 2 dinner times with isocaloric feeding in a metabolic chamber. For Aim 3, we will leverage validated circadian metrics derived from actigraphy and ingestible thermosensors to predict effects of late dinner. Dr. Daisy Duan’s long-term career goal is to become an independent clinician investigator leveraging novel mechanistic insights that underly the intersection between the circadian system and metabolism to design and validate interventions for the prevention and treatment of obesity and its metabolic complications. She seeks a K23 mentored career development award to gain critical skills and experience in order to effectively lead an independently-funded research program. The goals during the award period include developing expertise in the design and implementation of in vivo metabolic studies and in the principles, practice, and analytical methods in sleep and circadian phenotyping techniques, through a combination of mentored research experience, focused coursework, hands-on learning in research methodology, participation in local and national conferences, grant writing, and leadership training and experience. The proposed study will lay the foundation for novel, circadian- based meal timing as a precision medicine approach to obesity and metabolic dysfunction.