Daily Eating Patterns and Their Impact on Health and Disease

Abstract

Cyclical expression of cell-autonomous circadian clock components and key metabolic regulators coordinate often discordant and distant cellular processes for efficient metabolism. Perturbation of these cycles, either by genetic manipulation, disruption of light/dark cycles, or, most relevant to the human population, via eating patterns, contributes to obesity and dysmetabolism. Time-restricted feeding (TRF), during which time of access to food is restricted to a few hours, without caloric restriction, supports robust metabolic cycles and protects against nutritional challenges that predispose to obesity and dysmetabolism. The mechanism by which TRF imparts its benefits is not fully understood but likely involves entrainment of metabolically active organs through gut signaling. Understanding the relationship of feeding pattern and metabolism could yield novel therapies for the obesity pandemic.

Keywords: diabetes; dyssynchrony; eating; entrainment; fasting; gut; hepatic; high-fat diet; liver; microbiome; oscillation; time-restricted feeding; transcriptome.

Figure 1

Central Circadian Control of Endocrine Signals. Specialized retinal ganglion cells in the retina detect ambient light and send this information to the suprachiasmatic nucleus (SCN) through the retinohypothalamic tract. The SCN contains the central circadian clock. This area also receives information about light input indirectly thorough the thalamus. Sleep/wake homeostasis constitutes another oscillatory network. This system has an ‘hourglass’ oscillation that is dependent on the amount of neural sleep factor S (together with other sleep factors) that build up over time. The central circadian clock and the sleep/wake homeostasis systems are tightly regulated through unknown mechanisms. Melatonin from the pineal gland is one compound that can help to synchronize these two systems. Neural and chemical signaling from the SCN to the hypothalamus induces circadian release of multiple releasing hormones [e.g., corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), growth hormone releasing hormone (GHRH)]. These in turn cause the pituitary to release several hormones in a circadian manner [adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH)]. The circadian release of these hormones has an effect on peripheral tissues, but they respond differently to nutrients or stressors depending on the time of the day. For examples, blood glucose oscillates with time, rising above average in the late evening, early night, peaking in the middle of the night, and then at a nadir in the morning. The central circadian clock in the SCN also can modulate circadian cycles in the peripheral organs, although the process is not well understood. Abbreviations: CLC, cardiotrophin-like cytokine; TGF-α, transforming growth factor α.

Figure 2

Green arrows indicate findings published in the literature. Red arrows signify potential pathways. Mice on a diet-induced obesity (DIO) protocol have ad libitum access to a high-fat diet (HFD). These mice have changes in the gut microbiome, stool metabolomics, and hepatic gene expression. There are presumed changes in gut signaling, particularly in the bile acid signaling pathway. As a result, these mice are particularly predisposed to obesity and dysmetabolism. With TRF, cyclical fluctuation is restored in the gut microflora, luminal metabolites, and hepatic gene expression. Presumably TRF also restores oscillations in gut signaling. As a result, TRF protects against obesity and dysmetabolism. Abbreviations: CYP7A1, cytochrome P450 7A1; FGF15, fibroblast growth factor 15; FXR, farnesoid X receptor; LIPC, hepatic lipase.