Role of circadian clock gene expression in metabolic adaptation upon switching from high to low carb diets with replacement by fat

Background and aims: The circadian clock coordinates numerous behavioural and physiological processes including feeding, energy metabolism and inflammatory responses. In turn, metabolic processes feed back onto the circadian clock. However, there is little information about the effect of nutrition on circadian mechanisms in humans. To address this, we analysed daily expression profiles of clock genes, LPS response and fat metabolism genes in human blood monocytes after 6 weeks high carbohydrate – low fat (HC/LFD, 55% carbohydrate, 30% fat) followed by 6 weeks of low carbohydrate – high fat (LC/HFD, 40% carbohydrate, 45% fat) isocaloric diet interventions.

Materials and methods: 30 non obese healthy participants of the NUtriGenomics Analysis in Twins (NUGAT) study were metabolically characterized and gene expression was measured at three time points (in the morning, at noon and in the afternoon). Three investigation days were dated after 6 weeks HC/LFD and after 6 and 42 days of the LC/HFD.

Results: We demonstrated that clock genes (PER1, PER2, PER3, CRY1, CRY2, BMAL1, REV-ERBα, DBP and TEF), genes contributing to the LPS response (CD14, IKBα, CD180, ERK1, IL1b, IL10, TNFa, CCL3) and fat metabolism (FASN, CPT1a) as well as a key gene of NAD+ biosynthesis, NAMPT, exhibited significant daily variation in human monocytes. The LC/HFD induced an increase of the expression of the Period genes PER1, PER2 and PER3 and TEF after one and six weeks of intervention (p < 0.05) and alterations of the synchronisation state within the clock gene system. Moreover, the LC/HFD affected the expression of the LPS response genes CD14, IKBα and IL8, fat metabolism genes ACOX3 and IDH3A as well as genes related to the NAD+ salvage pathway NAMPT and SIRT1. The expression levels of Period genes and TEF significantly correlated with blood cholesterol levels and with the expression of energy and fat metabolism genes in monocytes. Clock gene expression levels as well as LC/HFD-induced expression changes were highly concordant within monozygotic twin pairs.

Conclusion: Our results suggest that the dietary fat and carbohydrate content regulates genes contributing to inflammation and fat metabolism in part by altering clock gene expression in humans. The rapid onset after few days and the hereditary pattern emphasizes a causal role of clock genes in mediating nutritionally induced changes of human metabolism and inflammation.