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Results of a randomized controlled cross-over trial were recently published in the journal Cell Metabolism, detailing the effects of late versus early eating on a variety of outcomes, including hunger, hormone levels, energy expenditure, and more. The link between the circadian system and energy metabolism is both fascinating and incompletely understood, and there is considerable interest in this connection, particularly as it relates to glycemic control and weight management. Much of the data in this area of study is either based upon animal research or observational studies; this trial was an in-laboratory experiment (at the Brigham and Women’s Hospital Center for Clinical Investigation), meaning that substantial effort was made to control for all the relevant variables, including not just total calorie consumption, but physical activity and light exposure. In addition, the mechanisms underlying these links were evaluated in depth, using calorimetry-derived assessment of energy expenditure, polysomnographic analysis of sleep, subjective measures of hunger and appetite, profiles of leptin, ghrelin, and core body temperature, as well as fat biopsies to analyze gene expression in adipose cells.
The methods of this study are too detailed to include here, but the degree of variable control was extensive and much more comprehensive than typical randomized trials. Sixteen participants with overweight/obesity (5 with prediabetes) spent 6 days in-lab, following a 2-to-3-week lead-in period which verified a regular sleep/wake cycle; the participants’ mean age was approximately 34-40. They were randomized to either early or late-eating, with a difference of 250 minutes between the two. Specifically, the early-eating group had their first meal 1 hour after waking, vs. 5 hours and 10 minutes after waking in the late-eating group. The late-eating group had their final meal of the day 13.5 hours after waking, vs. 9 hours and 20 minutes after waking. It’s important to note that all meals were provided by the lab, and both the eucaloric and macronutrient-controlled meals (as well as sleep) in the lab were scheduled according to individualized existing patterns, with no difference in calorie intake between early vs. late-eating. Each participant had a washout period between being randomized to either the early or late eating protocols.
Some of the important takeaways; late-eating was associated with increased hunger. Specifically, it doubled the odds of hunger probability, from about 10% to about 20%. This included increases in having a strong desire to eat, as well as a desire to eat specific foods, including starchy and salty foods, meat, dairy, and vegetables. Late-eating also changed hunger/satiety hormone levels (measured on an hourly basis), which correlated with the increase in hunger. Leptin (satiety) decreased by 6% over a 24-hour period, and 16% during the wake period. The ratio of ghrelin (active) to leptin over the wake period also increased by 34%, though it was primarily leptin that changed and not ghrelin. Thus, the drive to eat was increased with late-eating, despite the same 24-hour nutritional intake.
Late-eating also decreased energy expenditure during the wake period, approximately 5% less than with early-eating. No differences were seen in either carbohydrate or lipid oxidation. Late-eating also decreased core-body temperature (CBT) over a 24-hour period, again primarily because of a drop during the wake period. This was speculated to be because of a decrease in thermogenesis and energy expenditure.
A subset of 7 participants also had subcutaneous adipose tissue biopsies during both the early and late-eating protocols, and differences in gene expression profiles were observed for multiple pathways, including those related to lipid metabolism, p38 MAPK signaling, tyrosine kinase receptors, TGF-b signaling, and autophagy, with the largest number of changes related to lipid metabolism. This included the downregulation of genes related to lipid breakdown, such as PLD6, DECR1, and ASAH1. For example, DECR1 (previously identified as a rate-limiting enzyme in an auxiliary pathway for polyunsaturated fatty acid β-oxidation), had a nearly 20% lower expression in the late-eating protocol. Similarly, reduced expression of ADHB5 was observed with late-eating, a gene regulated by PERILIPIN1, variants of which have previously been shown to predict variability in weight loss that is influenced by late-eating. Increased expression of genes related to lipid synthesis was also observed, including GPAM, ACLY, AACS, and CERK. GPAM, for example, has been shown to be involved in both triglyceride and cholesterol synthesis, and influences multiple other gene pathways, as well as NF-kappa B signaling. The most strongly down-regulated gene was THBS1 (Thrombospondin-1, aka TSP-1), which the authors suggest is indicative of increased adipogenesis. In general, late-eating altered adipose gene expression toward increased adipogenesis and decreased lipolysis, as well as reduced insulin sensitivity, most likely promoting an increase in total fat mass.
Although there are a number of limitations of this study, including small sample size, the indeterminate effect of late-eating on ad libitum intake, etc., this study provides well-controlled insight into both the effects and mechanisms of late-eating in an overweight/obese population, and expands our understanding of the role that timing of food intake has on energy metabolism and weight control.
Stay tuned for Part 2 of this blog, where we will take a closer look at time-restricted eating, and how it might (or might not) influence weight loss.
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