All organisms have evolved to survive in the changing environment of the 24 hour light–dark cycle. The time to eat and sleep can be crucial factors for survival. Various behavioral and physiological pathways are constrained to periods of approximately 1 day, following a cycle known as the circadian rhythm.
In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus, which contains approximately 20,000 neurons, is the primary generator of endogenous circadian rhythms and functions as a master clock to regulate the peripheral systems. The transcription–translation feedback loops in the cells establish circadian rhythms by regulating membrane electrical activity and intracellular mechanisms [1
]. The SCN obtains input from the photosensitive ganglion cells in the retina to entrain the master clock to environmental solar cycles. Outputs from the SCN synchronize the rhythms in other brain regions and in the peripheral organs [3
]. The molecular clock loops are also present in cells of the pancreas, liver, adipose tissue, and immune system [4
], and feedback loops have crucial roles in peripheral metabolism. Previous studies have reported that dysfunctions in peripheral clock genes can lead to deleterious changes in lipid metabolism [8
], glucose homeostasis [9
], and inflammatory pathways.
Communication between the master and peripheral clocks operates via rhythmic neuronal and humoral signals. The SCN outputs influence rhythms in other brain regions via neuronal connections. The peripheral clocks are entrained by autonomic innervation and by glucocorticoid hormones from the central nervous system. The hypothalamus obtains humoral signals from peripheral organs in the form of gut-derived ghrelin, glucagon-like peptide-1 (GLP-1), and adipocyte-derived leptin [10
]. The SCN also appears to directly accept input signals from peripheral organs, given that receptors for metabolic hormones such as insulin, ghrelin, and leptin are expressed in the SCN [15
]. While the SCN is primarily synchronized by light, peripheral clocks are mainly dependent on feeding time. Feeding–fasting cycles are the major synchronizers for peripheral oscillators. Thus, irregular feeding times can induce a shift in the peripheral clock and internal desynchronization through the decoupling of peripheral clocks, resulting in health consequences such as metabolic syndrome. This type of internal desynchronization has been shown to cause higher levels of postprandial glucose intolerance and decreased insulin sensitivity to glucose [18
]. Prolonged desynchrony between the endogenous clock and feeding/fasting cycles can cause the impairment of β
cell function [9
]. Therefore, the concept of timed food intake in coordination with the circadian rhythm has received medical attention; thus, the therapeutic effects of time-restricted feeding on metabolic syndrome have been studied.
Eating strategies to prevent obesity and metabolic syndrome are classified into three types: calorie restriction (CR), intermittent fasting (IF), and time-restricted eating (TRE). CR involves a 25% reduction in the daily caloric intake with the usual timing of mealtimes. In IF, the eating period is restricted, with an unintentional reduction in calorie intake. TRE involves consuming all calories within a consistent 8–12 h daily timespan. While IF emphasizes the ratio of fasting/feeding durations, TRE emphasizes the timing of eating within a limited duration without involving CR. As the timing of eating is essential to synchronize the peripheral clock to the central clock, the restriction of the timing and duration of eating may reduce desynchronization between the central and peripheral clocks and recover impaired metabolic pathways. Thus, TRE may be a more effective strategy for combating metabolic syndrome. Recent papers based on small-scale pilot studies reported that TRE reduced body weight and the risks of metabolic diseases and showed beneficial effects on metabolic dysfunctions [23
]. However, no prospective large-scale study has been conducted on the benefits of TRE. A meta-analysis provides objective and strong integrative evidence in medical research [24
]. In this study, we aim to investigate the effects of TRE intervention on metabolic parameters such as body weight, glucose metabolism, blood pressure, and lipid profiles in adults via a systemic review and meta-analysis.
To determine the beneficial effects of TRE, we selected 19 clinical studies by a systemic review and performed a meta-analysis. The results of this analysis showed that TRE is an effective treatment strategy for patients who are overweight and obese. Participants using a TRE schedule lost bodyweight and showed a decrease in fat mass. TRE significantly lowered systolic blood pressure and glucose concentration. TRE also changed the lipid profiles of participants. Although LDL-C and HDL-C levels did not show significant differences, triglyceride levels were significantly decreased after TRE.
To overcome the heterogenic nature of our participants’ metabolic profiles (some are healthy young, others are unhealthy obese), we performed subgroup analysis. In the metabolic unhealthy participants, TRE showed a significant reduction in body weight. In the healthy participants, TRE did not show weight reduction, but still showed beneficial effects such as fat mass reduction. This means TRE has beneficial effects on participants with or without metabolic dysfunction.
At the molecular level, circadian rhythms are generated by cell-autonomous transcription–translation feedback loops composed of multiple genes such as Clock
, period (per
), and cryptochrome (cry
]. The Clock
heterodimers bind to the E-box in the promoter regions of per
, resulting in the expression of Per and Cry proteins. They also form heterodimers in the cytoplasm to suppress the transcription of Clock
back in the nucleus. Bmal1
gene expression is activated by retinoic acid receptor-related orphan receptors (RORs) and suppressed by REV-ERBα/β. This negative feedback loop repeats approximately every 24 h, and an abnormal rate of gene expression induces shorter or longer circadian periods [47
]. A Clock
mutation in mice can lengthen the circadian period to as much as 27 h [48
Mutations in clock genes in peripheral tissues can cause metabolic dysfunctions. Adiponectin and leptin levels are controlled by the molecular circadian rhythm of adipocytes. Mice with adipocyte-specific mutations in the Clock
gene showed increased body weight, fat composition, and adipocyte size, as well as impaired lipolysis during fasting periods [8
]. Intestinal lipogenesis also shows circadian variations, and hypertriglyceridemia and obesity are observed in Bmal1
knock out mice [9
]. Mice with both Clock
gene mutation and Bmal1
deletion showed impaired glucose homeostasis with hyperglycemia and hypoinsulinemia [19
Glucose homeostasis also oscillates in a daily rhythm. Decreased insulin sensitivity and glucose oxidation in the evening are caused by higher levels of postprandial free fatty acid levels in the evening compared to those in the morning [18
]. Late lunch eaters show significantly less weight loss than early eaters due to decreased glucose tolerance and insulin functions during the evening [49
In several murine animal models, feeding time changed the circadian oscillators in the peripheral tissues [50
]. A recent clinical study also suggested that mealtime might change the central circadian clock [36
]. These results emphasize the importance of the “Right Time to Eat” in health. TRE reduces body weight and improves metabolic dysfunction by repairing the disrupted circadian rhythm in people who are overweight and obese [50
TRE is a new treatment strategy for weight control without calorie reduction. This method is a potentially easier way than CR to maintain optimal body weight and health for a longer time because patients do not need to reduce total food intake or to calculate total daily kcal intake. Clinical studies have confirmed the effectiveness of this strategy. Dorothea et al. reported that TRE was predominantly well accepted by participants [32
]. In their study, 86% of participants achieved their weight target during the 3 month study period [32
]. Research in animal models has shown the beneficial effects of TRE on obesity, diabetes, fatty liver, cardiometabolic dysfunctions, and lifespan [19
]. Several pilot studies have reported the beneficial effects of TRE in humans [19
Intriguingly, in our study, TRE did not reduce total mass. This implies that TRE reduces fat mass selectively without muscle loss. This result may explain why TRE improves metabolic dysfunction in patients who are overweight or obese, particularly because muscle mass is an important factor in controlling body weight and maintaining a metabolically healthy state [53
Our data suggest that TRE is a better strategy than CR diet to lose weight. According to a recent review [54
], the contribution of fat-free mass loss often exceeded 35% of the total weight loss in persons with normal weight and 20%~30% of the total weight loss in persons who are overweight or obese on a CR diet. Therefore, researchers recommend that persons on a CR diet should increase physical activity and protein intake to preserve muscle mass [54
]. Conversely, TRE restored muscle function in Drosophila melanogaster
(common fruit fly), a species of two-winged flies commonly used for circardian rhythm study, under the conditions of obesity or circadian disruption [55
]. Moreover, TRE has not been shown to reduce muscle strength in clinical studies [38
Aging is associated with a gradual loss of fat-free mass and a gain of excess body fat. We refer to this condition involving high fat mass with low fat-free mass as sarcopenic obesity [57
]. TRE reduces this ratio; thus, TRE may be a good therapeutic strategy to treat obesity in elderly patients. Animal research has provided evidence on the beneficial effects of TRE. TRE reduced intramuscular fat deposits and suppressed obesity-induced myofibril and mitochondrial defects in Drosophila
]. TRE has been shown to reduce whole-body fat accumulation, improve glucose homeostasis, restore cholesterol homeostasis, and improve muscle function in mouse studies [58
This study had some limitations. First, most included studies had small sample sizes, and several studies had high risk of bias. Therefore, further large studies are necessary to clarify the effect of TRE in the general population. Second, most studies were performed over a short duration. Therefore, we could not analyze the long-term benefits and safety of TRE in terms of cardiovascular disease, type 2 diabetes, and mortality. Third, we could not analyze blood parameters related to obesity and metabolic dysfunction such as adiponectin, leptin, and insulin levels because of lack of data. Last, although TRE is one form of intermittent fasting, we could not compare TRE to other types of intermittent fasting because of lack of data.
In conclusion, TRE significantly reduces body weight and fat and improves metabolic parameters associated with cardiometabolic health. Further studies are needed to confirm the long-term outcomes of TRE.