Aligning the timing of eating and exercise with circadian rhythms for improved metabolic health

Obesity is increasing in prevalence worldwide and is associated with cardio-metabolic complications, such as diabetes or myocardial infarction. Weight loss is the cornerstone of management, but lifestyle modifications (a healthy diet, physical activity) have limited efficacy and are hard to maintain long term in the current food environment, and hence patients and clinicians seek alternative options. Time-restricted eating (TRE) is a form of intermittent fasting where eating is limited to a specified time window of the 24h clock. In addition, physical activity might be more efficient in the afternoon and evening, thus leading the idea of timed exercise bouts.Animal and human studies support the emerging concept of 'circadian misalignment' where a mismatch between the internal circadian clocks and external rhythms of (a) food intake and (b) physical activity can disrupt metabolic processes. (a) TRE is interesting compared to other forms of dietary restrictions because altering meal times could realign the eating rhythms with other biological rhythms: TRE can lead to 3-4% weight loss, lower blood pressure, glucose and lipid profile, albeit not consistently. (b) In studies of resistance exercise, the peak force was 3-18% higher when exercise was timed in the afternoon and evening vs. in the morning, but the results were unclear with moderate and long-duration exercise. The phase and amplitude of molecular circadian rhythms in skeletal muscle are modulated by physical activity. (c) Finally, adverse events are not well described. Thus, we cannot advise TRE and timed exercise to a broad population, even less so in diabetes with the risk of hypo/hyperglycemia or ketosis.Objectives and specific aims. Our objective is to improve the metabolic benefits of TRE by refining its implementation and timing in relation to activity and sleep, and then to develop a personalized intervention combining TRE and timed exercise in patients at metabolic risk such as overweight, obesity and diabetes.- Aim 1. To build an international TRE consortium pooling data of previous TRE studies and determine the predictors of weight loss and improved metabolic outcomes, including the food environment and socio-economic status.- Aim 2. To personalize TRE implementation and exercise timing (2a) to maximize weight loss in patients with obesity and other components of the metabolic syndrome, (2b) to improve the glucose profile in insulin-treated diabetes, and (2c) to assess and minimize the adverse events of TRE, e.g. hypoglycemia or loss of bone mass.Methods. For aim 1, we will build an international TRE consortium of researchers who have performed previous TRE studies. In this consortium, we will pool individual participant data (i.e. demographics, clinical and lab measurements, eating timing before and after TRE, activity and sleep times) and explore the potential predictors of response to TRE in univariate and multivariate analyses. For studies with geolocation data, the food environment and socio-economic status of each participant will be determined by geocoding their home address and consumed food + drinks. We will assess the association of the food environment and socio-economic status with TRE efficacy. For aim 2, we will extend the TRE intervention (2a) by comparing TRE alone (which focuses on eating timing only) vs. TRE combined with timed exercise sessions in a randomized controlled trial. (2b) For patients with insulin-treated diabetes, we will test how TRE could decrease glucose excursion and insulin requirements, increase glucose time-in-range and improve the glucose profile. In addition to these two trials focusing on TRE efficacy, (2c) we will carefully record the adverse events of TRE overall and specifically in diabetes and on bone mass.Expected results and impact. Obesity and its cardio-metabolic complications are the leading cause of morbidity and mortality. To complement standard lifestyle modifications, intermittent fasting and TRE have gained a lot of interest in the public, the media, and the scientific community. We propose to personalize the TRE intervention with timed exercise to best match individual characteristics and improve their metabolic health outcomes.