Interaction Between Early Meals (Big-Breakfast Diet), Clock Gene mRNA Expression, and Gut Microbiome to Regulate Weight Loss and Glucose Metabolism in Obesity and Type 2 Diabetes

Abstract

The circadian clock gene system plays a pivotal role in coordinating the daily rhythms of most metabolic processes. It is synchronized with the light-dark cycle and the eating-fasting schedule. Notably, the interaction between meal timing and circadian clock genes (CGs) allows for optimizing metabolic processes at specific times of the day. Breakfast has a powerful resetting effect on the CG network. A misaligned meal pattern, such as skipping breakfast, can lead to a discordance between meal timing and the endogenous CGs, and is associated with obesity and T2D. Conversely, concentrating most calories and carbohydrates (CH) in the early hours of the day upregulates metabolic CG expression, thus promoting improved weight loss and glycemic control. Recently, it was revealed that microorganisms in the gastrointestinal tract, known as the gut microbiome (GM), and its derived metabolites display daily oscillation, and play a critical role in energy and glucose metabolism. The timing of meal intake coordinates the oscillation of GM and GM-derived metabolites, which in turn influences CG expression, playing a crucial role in the metabolic response to food intake. An imbalance in the gut microbiota (dysbiosis) can also reciprocally disrupt CG rhythms. Evidence suggests that misaligned meal timing may cause such disruptions and can lead to obesity and hyperglycemia. This manuscript focuses on the reciprocal interaction between meal timing, GM oscillation, and circadian CG rhythms. It will also review studies demonstrating how aligning meal timing with the circadian clock can reset and synchronize CG rhythms and GM oscillations. This synchronization can facilitate weight loss and improve glycemic control in obesity and those with T2D.

Keywords: big-breakfast diet; circadian clock genes; gut microbiome; type 2 diabetes; weight loss.

Figure 1

Interactions among meal timing, circadian clock genes, and gut microbiome. The timing of food intake significantly impacts how the GM regulates the expression of circadian CGs and energy and glucose metabolism. As we can see in the illustration, the meal timing coordinates the rhythm of the GM and the release of GM-derived metabolites such as short-chain fatty acids (SCFAs), lipopolysaccharides (LPSs), bile acids (BAs), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and other cytokines. These metabolites in turn can influence circadian CG expression and the body’s hormonal and metabolic response to meal timing.

Figure 2

Mechanism of meal timing interactions with molecular CGs and the gut microbiome. The illustration shows on the left how the meal timing and light at dawn activate the CLOCK–BMAL1 complex associated with SIRT1 and the transcription of PERs and CRYs to form PER (P) and CRY (C) proteins. PER and CRY proteins form dimers (CP) in the cytoplasm. Subsequently, the CP dimers translocate back to the nucleus to repress CLOCK–BMAL1. The blockage of CLOCK–BMAL1 is reversed by casein kinase I epsilon (CKIε), restarting a new cycle. In addition, AMPK positively interacts with SIRT1. CLOCK–BMAL1 complex-driven transcription of PERs, CRYs, REV-ERBα, and RORα genes, and PGC-1α, promote the expression of tissue-specific clock-controlled genes. This upregulates β-cell insulin secretion, L-cell postprandial incretin GLP-1 response, increase in muscle GLUT4 activity, and glucose uptake. The clock gene REVERBα-, RORα-, and SIRT1-driven nocturnal hepatic glucose production in the liver promotes glycogenolysis enzymes HG6-P and PEPCK of the gluconeogenesis pathway. In addition. BMAL1 transcription of PPARα and PGC-1α in adipose tissue plays a role in nocturnal lipolysis. On the right is a representation of how the GM, through the secretion of SCFAs, influences BA metabolism and gut permeability, and its influence on the release of LPSs and proinflammatory cytokines, including, TNF-α, Reg3γ, IL-1, and IL-6, may exert modulatory effect on CG expression and subsequently influence energy and glucose metabolism. Abbreviations: Glucose 6-phosphatase: HG6-P; phosphoenolpyruvate carboxykinase: PEPCK; short-chain fatty acids: SCFAs; bile acids: BA; lipopolysaccharides: LPSs; interleukin 1: IL-1; interleukin 6: IL-6; tumor necrosis factor α: TNFα; regenerating islet-derived protein III gamma: Reg3γ; Toll-like receptor: TLR.

Figure 3

Role of GM-derived SCFAs in obesity, metabolic syndrome, inflammation, and T2D. The diagram illustrates how butyrate, propionate, and acetate, the three main SCFAs, help reduce gut permeability and have an anti-inflammatory effect by decreasing the release of cytokines and lipopolysaccharides (LPSs). SCFAs also influence glucose metabolism by binding to specific cell-surface G protein-coupled GPR43/41 receptors in various tissues. They also increase muscle GLUT4, enhance muscular glucose uptake, and promote glycogen synthesis. Moreover, SCFAs improve insulin sensitivity and β-cell secretion while decreasing glycolysis and gluconeogenesis in the liver. Activation of GPR43/41 by SCFAs reduces lipogenesis in adipose tissue and stimulates the secretion of GLP-1. The effects of SCFAs disrupted in T2D are highlighted in red.

Figure 4

Effects of misalignment on circadian clock genes, gut microbiome, and energy and glucose metabolism. In this illustration, we observe on the left how eating and sleeping hours are not aligned with the circadian clock, i.e., small breakfast, big dinner, and sleeping during daylight lead to disrupted CG expression and GM dysbiosis. On the right, we observe several cellular mechanisms by which GM dysbiosis may cause insulin resistance, obesity, and hyperglycemia in T2D. First, GM dysbiosis leads to reduced release of SCFAs and binding to the cell-surface GPR43/41 receptor. This results in less secretion of GLP-1 from enteroendocrine L-cells and to increased insulin-mediated fat accumulation. GM dysbiosis causes a reduction in secondary BAs, deficient binding of BAs with FXR and TGR5 interaction, and a reduction in FGF19 secretion, diminished energy expenditure, and abnormal glucose homeostasis. Lower binding of secondary BAs to TGR5 to form the BA–TGR-5 complex may also lead to a reduction in GLP-1 secretion from intestinal L-cells and a reduction in glucose-stimulated insulin release from pancreatic β-cells. More importantly, GM dysbiosis enhances the secretion of cytokines, i.e., Il-6, IL-1, hs-CRP, LPSs, TNFα, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), all of which activate several pathways that worsen insulin resistance, obesity, and hyperglycemia.