Late isocaloric eating increases hunger, decreases energy expenditure, and modifies metabolic pathways in adults with overweight and obesity

Abstract

Late eating has been linked to obesity risk. It is unclear whether this is caused by changes in hunger and appetite, energy expenditure, or both, and whether molecular pathways in adipose tissues are involved. Therefore, we conducted a randomized, controlled, crossover trial (ClinicalTrials.gov NCT02298790) to determine the effects of late versus early eating while rigorously controlling for nutrient intake, physical activity, sleep, and light exposure. Late eating increased hunger (p < 0.0001) and altered appetite-regulating hormones, increasing waketime and 24-h ghrelin:leptin ratio (p < 0.0001 and p = 0.006, respectively). Furthermore, late eating decreased waketime energy expenditure (p = 0.002) and 24-h core body temperature (p = 0.019). Adipose tissue gene expression analyses showed that late eating altered pathways involved in lipid metabolism, e.g., p38 MAPK signaling, TGF-β signaling, modulation of receptor tyrosine kinases, and autophagy, in a direction consistent with decreased lipolysis/increased adipogenesis. These findings show converging mechanisms by which late eating may result in positive energy balance and increased obesity risk.

Keywords: adipose; early eating; energy expenditure; energy intake; gene expression; ghrelin; hunger; late eating; leptin; meal timing.

Figure 1.

CONSORT Flow Diagram

Figure 2.

Experimental design: (A) Each of the two laboratory stays was preceded by a pre-laboratory lead-in with a regular sleep/wake cycle for 2–3 weeks, and dietary office-prepared, eucaloric meals during the indicated time intervals (arrows indicate the range) during the last 3 days. Laboratory visits for the (B) early and (C) late meal schedule protocol began with two adaptation days. Beginning on day 3, late and early eating protocols were established. Study day 3 and 6 served as Test Day 1 and 2, respectively. Subcutaneous adipose tissue was biopsied (in a subset of participants) on in-laboratory day 5.

Figure 3.

Effects of late eating schedule on daily profiles in: (A) self-reported hunger; (B) serum leptin concentration; (C) plasma acylated (active) ghrelin concentration; and (D) acylated ghrelin:leptin ratio. Data shown as mean±SEM; each data point is expressed as the percentage of the mean of all timepoints collected during the early eating protocol for that same participant. Left panels, Test Day 1; middle panels, Test Day 2; right panels, effects of late eating (late eating schedule minus early eating schedule) averaged across test days with asterisks indicating significant differences (*,p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001). Vertical black dashed and red solid lines, timing of meals in early and late eating schedule, respectively. Horizontal black bars along X-axes, scheduled sleep episodes. Gray bars, semi-recumbent posture.

Figure 4.

Effects of late eating schedule on daily profiles in: (A) energy expenditure; (B) carbohydrate oxidation; (C) lipid oxidation; and (D) CBT. Data show as mean±SEM; panels A-C show data normalized to early-meal schedule mean (as in Fig. 3), and panel D shows absolute levels. Symbols as in Fig. 3.

Figure 5.

(A) Heat map indicating direction and magnitude of change of gene expression (late divided by early eating) capped at +/− 2 standard deviations of the mean of all data. Fuchsia color indicates decreased gene expression with late eating; yellow, increased gene expression; gray, no change; white, missing data. (B) Network diagram summarizing pathways altered by late eating schedule. Network diagram was generated by running an over-representation analysis on the filtered list of genes that were significantly differentially expressed. Node pathway clusters were named based upon the narrowest ontological category that could define all the pathway nodes included within it. This diagram is based on databases accessed on November 1, 2020. (C) Genes from pathway analysis and their direction of change with late eating; fuchsia down-arrow, decrease; yellow up-arrow, increase.