Influence of Fasting until Noon (Extended Postabsorptive State) on Clock Gene mRNA Expression and Regulation of Body Weight and Glucose Metabolism

Abstract

The trend of fasting until noon (omission or delayed breakfast) is increasingly prevalent in modern society. This eating pattern triggers discordance between endogenous circadian clock rhythms and the feeding/fasting cycle and is associated with an increased incidence of obesity and T2D. Although the underlying mechanism of this association is not well understood, growing evidence suggests that fasting until noon, also known as an "extended postabsorptive state", has the potential to cause a deleterious effect on clock gene expression and to disrupt regulation of body weight, postprandial and overall glycemia, skeletal muscle protein synthesis, and appetite, and may also lead to lower energy expenditure. This manuscript overviews the clock gene-controlled glucose metabolism during the active and resting phases and the consequences of postponing until noon the transition from postabsorptive to fed state on glucose metabolism, weight control, and energy expenditure. Finally, we will discuss the metabolic advantages of shifting more energy, carbohydrates (CH), and proteins to the early hours of the day.

Keywords: circadian clock genes; diet induced thermogenesis; fasting until noon; overall glycemia; weight loss.

Figure 1

Mechanism of the molecular clock. The above illustration shows that the early-timed breakfast at dawn activates the CLOCK: BMAL1 complex associated with SIRT1 and the transcription of PERs and CRYs. The resulting proteins PER (P) and CRY (C) form PER: CRY (C-P) dimers in the cytoplasm. Subsequently, PER: CRY dimers translocate back to the nucleus to repress CLOCK: BMAL1. The blockage of CLOCK: BMAL1 is reversed by casein kinase I epsilon (CKIε). NAD+ activates SIRT1, which interacts with the CLOCK: BMAL1. In addition, AMPK positively interacts with SIRT1. CLOCK: BMAL1-driven transcription of PERs, CRYs, REV-ERBα, RORα genes, and PGC-1α promotes the expression of tissue-specific clock-controlled genes. It leads to the upregulation of β-cell insulin secretion, L-cell postprandial incretin GLP-1 response, and the increase of GLUT4 activity and muscle glucose uptake. The clock gene-driven nocturnal hepatic glucose production promotes glycogenolysis and gluconeogenesis in the first and second part of the nocturnal resting phase. PGC-1α plays a role in lipid metabolism (lipogeneses and nocturnal lipolysis.

Figure 2

Central and peripheral clocks alignment. The illustration shows the central clock in SCN, responsive to light input, and peripheral clocks, activated by meal timing, both in synchrony. On the right side are some examples of the peripheral CGs outputs, i.e., the hepatic glucose production; ghrelin secretion in the stomach; b-cell insulin secretion; the intestinal K-cell secretion of GIP and L-cell secretion of GLP-1 and GLP-2; leptin and adiponectin in adipose tissue; GLUT4 driven muscle glucose uptake; and the muscle protein breakdown/synthesis.

Figure 3

Clock-controlled postprandial and postabsorptive glucose metabolism. The illustration shows on the left side the clock-controlled glucose metabolism during overnight fast (postabsorptive state), consisting of nocturnal hepatic glycogenolysis and gluconeogenesis. The postprandial state is shown on the right side. It begins upon early-timed breakfast and consists mainly of muscle glucose uptake.

Figure 4

Effect of early-timed high energy breakfast diet (Bdiet) versus high energy dinner diet (Ddiet) on postprandial glycemia, insulin, intact GLP-1, and hunger scores in T2D. In the upper part is shown the caloric content for Breakfast (B), Lunch (L), and Dinner (D) on Bdiet day (pink) and Ddiet day (blue). The line charts show an all-day graph for overall postprandial glycemia, insulin, intact GLP-1, and hunger VAS in Bdiet vs. Ddiet group. * p < 0.05 “Reproduced and adapted with permission” [18].

Figure 5

Clock Genes (AMPK, BMAL1, PER1 and RORα) mRNA expression and glucose, insulin, and intact GLP-1 blood levels, at fasting, before lunch and after lunch in YesB and NoB day in T2D. (A) Clock gene expression: Blood samples were collected in YesB (purple) and NoB day (blue), at fasting (time point 0 min), before lunch (time point 210 min), and 3.5 h after lunch (time point 420 min). Asterisks denote statistical differences (p < 0.05) between time points 210- and 420 min. B: Line charts of glucose, insulin, and intact GLP-1 postprandial responses in YesB and NoB days. Breakfast (B) was given to the YesB group at time point 0. Lunch (L) was given to both groups at a time point of 210 min. Asterisks denote statistical differences between YesB and NoB at a specific time point. Data are means ± SE. “Reproduced and adapted with permission” [22].

Figure 6

Effect of prolonged fast until noon (NoB) vs. breakfast consumption (YesB) on glucose, insulin, and intact GLP-1 (iGLP-1). The blood samples were taken at fasting and postprandial responses after breakfast or no breakfast, lunch, and dinner at the same time points. Statistics were between the NoB and the YesB. Data are means ± SE. Asterisks denote statistical differences between YesB and NoB at a specific time point. * p < 0.001. B: Breakfast; L: Lunch; D: Dinner. NoB: purple lines; YesB: blue lines “Reproduced and adapted with permission” [44].