Figure 3.

Diet composition produces diverse zeitgebers for the clock. Typical food items for the so-called “western diet”, which is generally composed of foods high in saturated fat combined with high sugar content, and a so-called “Mediterranean diet”, which is generally considered to contain a higher percentage of plant-based foods and a substitution of some saturated fats with mono and poly-unsaturated fats. Each of these diets produces macromolecules and metabolites known to function as zeitgebers for the circadian clock in various tissues and cell types. While lipids and cholesterol are known to modulate PPARγ, RORα, LXR, and RORβ, fats (particularly those which affect insulin sensitivity over time), and high glucose likely modulates BMAL1 activity in a GSK3β-dependent manner. Stearic acid has been observed to modulate the sirtuin protein SIRT6 (which binds directly to CLOCK:BMAL1). Under different dietary conditions, there is an increase in potential clock zeitgebers including vitamin A (known to activate RAR and RXR), polyphenols such as resveratrol (activator of SRIT1) and proanthocyanidins (regulators or modulators of Bmal1, Nampt, and several other clock genes). Additional ligands or modulators of clock-related proteins or rhythmic nuclear receptors include polyamines (regulators of the PER2:CRY1 complex), MUFA and PUFAs (modulators of SIRT6, PPARγ, RXR, and PPARα), and phytosterols (modulators of LXR).