Time-Restricted Eating, Cardiometabolic Health in Obesity and The Optimal Length of the Eating Window

According to chronobiology, throughout evolution, living organisms developed adaptive physiological mechanisms in response to selective pressures imposed by environmental phenomena, such as the alternation of light and darkness and fluctuations in temperature. These adaptations enabled organisms to anticipate and synchronize their biological functions with the environment changes daily, monthly, or yearly, thereby enhancing survival and ensuring optimal physiological functioning [24].

The term biological rhythms refers to cyclical patterns of biological activity that repeat at regular intervals. These rhythms are broadly categorized into three main types based on their periodicity. First, circadian rhythms, approximately 24h cycles. Second, ultradian rhythms, cycles with a period shorter than 24h and, therefore, occurring more than once per day (e.g., hormonal pulsatility, sleep cycles); and third infradian rhythms, cycles with a period longer than 24h and, therefore, occur less frequently than once per day, such as menstrual cycles or seasonal behaviors [24].

Among these, circadian rhythms are the most extensively studied due to their essential role in maintaining physiological processes and their strong association with the pathophysiology of several chronic diseases, including obesity, diabetes, cardiovascular disorders and cancer [25]. Given their central role in physiology and disease, circadian rhythms are orchestrated by a hierarchical system of central and peripheral clocks, as discussed in the following section.

Circadian rhythms are endogenous biological processes that exhibit a repeating pattern of approximately 24h which enable organisms to synchronize a broad spectrum of physiological and behavioral processes with external conditions. Through this synchronization, circadian regulation enhances metabolic, hormonal and cognitive functions and the body’s overall homeostasis [26].

The regulation of circadian rhythms is orchestrated by a hierarchical timekeeping system centered in the SCN of the hypothalamus. Acting as the master circadian pacemaker, the SCN governs rhythmicity across multiple levels of biological organization, ranging from the molecular regulation of gene expression to the coordinated functioning of peripheral organs. In addition to the central pacemaker, circadian regulation depends on peripheral clocks, which are self-sustained molecular oscillators present in virtually all organs and tissues, coordinated by the SCN and that drive tissue-specific rhythmicity across a wide array of physiological processes [27].

The central clock is synchronized primarily by light, detected by photosensitive retinal ganglion cells (pRGCs) containing melanopsin, which transmit photic information to the SCN via the retinohypothalamic tract (RHT). Upon receiving light input, the SCN conveys temporal signals to peripheral oscillators through neural, hormonal, and behavioral pathways, thereby aligning internal physiological processes with the external light-dark cycle [10, 28].

Although light is considered the predominant external cue for circadian synchronization, other environmental stimuli, known as zeitgebers (from the German term for “time giver”), also play critical roles in the regulation of biological clocks. These include ambient temperature, physical activity, feeding-fasting patterns, and, to a lesser extent, sound exposure [9]. At the molecular level, both central and peripheral clocks are governed by transcriptional-translational feedback loops (TTFLs), which constitute the core machinery of circadian regulation, as described in the following section.

At the molecular level, both central and peripheral clocks rely on a cell-autonomous TTFLs mechanism involving the core clock genes and their respective proteins. Figure 1 illustrates the entrainment of central and peripheral clocks, driven primarily by light-dark cycle and external cues such as feeding-fasting patterns, along with the transcriptional-translational feedback mechanism underlying circadian rhythms.

The primary transcriptional activators include Circadian Locomotor Output Cycles Kaput (CLOCK), its paralogue Neuronal PAS Domains Protein 2 (NPAS2) and Brain and Muscle ARNT-Like protein-1 (BMAL1). These form heterodimers CLOCK-BMAL1 and NPAS2-BMAL1, whose peak expression in mammals occurs early in the morning, and that bind to E-box elements in the promoters of target genes to drive its transcription. These genes are Period (Per1 and Per2) and Cryptochrome (Cry1 and Cry2), whose transcripts accumulate during the afternoon [29].

Following translation, PER and CRY repressor proteins progressively accumulate in the cytoplasm throughout the late afternoon and evening, where they dimerize, and subsequently translocate into the nucleus. Once inside, they inhibit the transcriptional activity of the CLOCK: BMAL1 complex, thereby repressing their own expression [29].

As repression proceeds, Per and Cry gene expressions decline, as well as PER and CRY protein levels, due to ubiquitin-proteasome mediated degradation. This degradation relieves inhibition of the CLOCK-BMAL1 complex, allowing it to reinitiate its transcription the following morning, completing a new cycle. This delayed negative feedback generates oscillations with a period of nearly 24h, constituting the molecular basis of circadian rhythmicity [27].

Beyond regulating Per and Cry, the CLOCK-BMAL1 complex also induces the transcription of Nuclear Receptor Subfamily 1 Group D Member 1 (Nr1d1) and Member 2 (Nr1d2), RAR-related Orphan Receptor alpha (Rorα) and beta (Rorβ). These genes encode auxiliary nuclear receptors REV-ERBα/β (NR1D1/NR1D2) and RORα/β, which act as stabilizing regulators of the circadian machinery. REV-ERBs and RORs exert opposing effects on Bmal1 transcription, by competitively binding to ROR response elements (ROREs) within its promoter. RORs activate Bmal1 transcription, whereas REV-ERBs repress it. This interlocked feedback loop confers additional robustness and stability to circadian oscillations [10].

From an evolutionary perspective, organisms have developed metabolic adaptations that align EI with the highest metabolic demand periods, thereby optimizing nutrient absorption and energy storage during feeding, and energy mobilization during fasting [30]. The circadian system thus orchestrates energy homeostasis by temporally regulating hormonal secretion, neuronal signaling, and behaviors related to food intake and expenditure [30].

Food intake follows a circadian rhythm, regulated by a multi-oscillatory system that integrates signals from the central clock in the SCN with secondary food-entrainable clocks located in metabolic centers of the hypothalamus and the brainstem to coordinate the timing of food intake [30]. This “food clock” is account for driving anticipatory and behavioral responses to scheduled feeding, known as food-anticipatory activity (FAA) [30, 31]. In addition, peripheral clocks are entrained by food-derived signals, such as circulating nutrients and hormones, which convey energy status and nutrient availability to the brain, and contribute to feeding-related rhythms [30, 32].

Feeding, while under circadian control, also functions as a potent zeitgeber, particularly in metabolically active tissues such as the liver and pancreas. In this context, mealtime can shift the phase of peripheral circadian oscillators independently of the SCN, highlighting its critical role in circadian regulation [10, 33]. Evidence from animal and human studies shows that late-night eating or irregular feeding patterns disrupts the synchrony between central and peripheral clocks [8, 9, 33]. Such misalignment compromises metabolic coordination, leading to poor appetite regulation, weight gain, impaired glucose tolerance, dyslipidemia and systemic inflammation [10, 33–36].

In this context, TRE, which consolidates EI into a limited daily eating window aligned with the circadian rhythms, has been supported by the scientific community as a dietary approach to counteract metabolic disturbances caused by chrononutritional misalignment [10].

Fasting, defined as voluntary abstinence from foods and beverages for a specified period beyond the physiological overnight fast, has been practiced for millennia across civilizations for cultural, religious, ethical and health-related purposes [37]. Initially supported by empirical observations, this therapeutic use has, in recent decades, become the focus of scientific investigation. Evidence now links fasting to benefits such as improved metabolic regulation, enhanced insulin sensitivity, activation of autophagy and potential extension of lifespan. This has shifted its perception from a primarily spiritual or empirical practice to a potential evidence-based dietary strategy [38, 39].

In this context, intermittent fasting (IF) has attracted increasing interest as an alternative to continuous ER, with potential applications in obesity prevention and treatment [40]. Unlike ER, IF alternates periods of feeding and fasting, potentially conferring comparable metabolic benefits, although current evidence remains inconclusive [40, 41]. Among the IF protocols studied in humans, three approaches predominate: Alternate Day Fasting (ADF), the 5:2 Diet and TRE [41].

The ADF protocol alternates fasting days, either complete or limited to about 25% of daily energy needs, with days of unrestricted food intake [42]. The 5:2 diet consists of five days of unrestricted eating and two nonconsecutive or consecutive fasting days per week, usually with 500 and 1.000 kcal/day [43]. TRE, however, has gained prominence for its alignment of EI with circadian rhythms [41]. Table 1 summarizes the main characteristics, advantages, and limitations of the most common IF protocols.

TRE is an IF regimen in which food intake is confined to a consistent daily time window, typically ranging from 6 to 12h, without necessarily reducing total EI. Unlike other IF protocols that involve full-day fasting, TRE emphasizes daily rhythmicity and synchronization with the circadian clock, making it a potentially sustainable and physiologically aligned dietary strategy [41].

The concept TRE derives from TRF, a term originally applied in preclinical studies. A landmark investigation by Hatori et al. (2012) showed that mice fed a high-fat diet (HFD) within an 8h TRF window were protected from adverse diet-induced obesity and associated metabolic disturbances. In addition, these mice exhibited improved glucose tolerance and reduced hepatic steatosis, despite consuming similar calories as the ad libitum-fed control [44, 45].

Human studies evidence for TRE was first provided by Gill and Panda (2015). Their pilot study revealed that United States adults had an average eating window of 14–15h per day, which often extended on weekends due to social and lifestyle factors [46]. In the subsequent intervention phase, overweight individuals with baseline eating windows longer than 14h adopted a 10–11h TRE schedule and experienced weight loss, alongside improvements in sleep quality and overall well-being [46]. Since then, multiple studies have reported beneficial effects of TRE in diverse populations, ranging from healthy individuals to those with overweight, obesity, or metabolic disorders [15, 20, 47].

Although advances have been made in the field of TRE, the physiological and molecular mechanisms underlying its metabolic effects remain incompletely understood. Current evidence indicates that the benefits of TRE likely arise from a multifactorial interplay between circadian alignment, extended fasting periods and behavioral modifications related to eating patterns [22]. Figure 2 illustrates the potential mechanisms through which TRE exerts its effects. A central mechanism proposed is the synchronization of food intake with the active phase of the circadian cycle. Key metabolic processes, including glucose and lipid metabolism, insulin sensitivity, mitochondrial function and secretion of appetite-regulating hormones, are regulated by circadian rhythms and operate more efficiently during the active phase of the day [13]. Aligning eating within this period may therefore optimize metabolic efficiency and energy balance [13]. Nonetheless, the direct effects of TRE on circadian systems in humans remain unclear, highlighting the need for further investigation [16, 17, 48].

Another important mechanism is the activation of fasting-associated metabolic pathways. Restricting food intake to a defined window prolongs fasting periods, which promotes the depletion of hepatic glycogen stores and a metabolic shift toward increased fatty acid oxidation, lipolysis and ketone body production, ultimately reducing hepatic fat accumulation [49]. In parallel, fasting activates nutrient-sensing pathways such as AMP-activated protein kinase (AMPK), while inhibiting the mechanistic target of rapamycin (mTOR), promoting metabolic efficiency, reducing oxidative stress, enhancing autophagy processes and improving insulin signaling [39, 45, 48, 50].

Emerging data suggest that fasting signals may also modulate peripheral circadian clocks via intracellular metabolic sensors such as AMPK and SIRT1. These sensors contribute to resetting the molecular clock by modulating transcription of core clock genes, which in turn govern the rhythmic expression of clock-controlled genes (CCGs) that regulate essential processes such as glucose and lipid metabolism and mitochondrial biogenesis [16].

Finally, behavioral modifications may further enhance TRE´s effects. Confining EI to a consistent window often eliminates late-night eating, a behavior strongly linked to weight gain and impaired glycemic control. Moreover, many individuals practicing TRE spontaneously reduce total EI without deliberate restriction, contributing to weight loss and improved cardiometabolic outcomes [20, 46]. While the precise contribution of each mechanism remains to be fully clarified, their combined effects likely underline the improvements reported in experimental and clinical studies.

Short eating windows restrict EI to 4–6h with fasting periods of 18–20h per day. This is the most restrictive TRE approach and induces profound metabolic changes, including a shift from glucose to lipid utilization, increased fat oxidation, ketogenesis and stimulation of autophagy. These adaptations reduce insulin levels, improve mitochondrial function, attenuate chronic inflammation and promote favorable changes in body composition, particularly in individuals with overweight or obesity [39, 45, 51–54]. Despite these positive findings, they are derived from trials with small sample sizes and short intervention periods, making this TRE schedule the most frequently associated with adverse events and poorer long-term adherence due to its extensive fasting duration, which may compromise its feasibility and reproducibility [55].

In a randomized clinical trial, Cienfuegos et al. [54] showed that both 4h and 6h TRE led to similar reductions in body weight, insulin resistance and oxidative stress in comparison to the control group. All the results below were expressed as mean and [standard deviation]. For body weight, 4h and 6h of TRE produced greater reductions (both ∆ = -3.2% [0.4%]) in comparison with the control group (∆ = 0.1% [0.4%]). Fasting insulin (FI) was significantly decreased in both 4h and 6h of TRE (∆ = − 2.3 [1.5] mlU/mL and ∆ = -1.9 [1.1] mIU/mL, respectively) in comparison with controls (∆ = 3.5 [1.4] mIU/mL). Similarly, IR decreased by 29% and 12% in the 4h and 6h TRE groups, respectively. Regarding 8-isoprostane, a key marker of oxidative stress, 8 weeks of 4h and 6h TRE significantly reduced its levels (∆ = -13 [6] pg/mL and ∆ = -12 [4] pg/mL, respectively) compared with controls (∆ = 3 [3] pg/mL).

In the study conducted by Sutton et al. [13], eight men with prediabetes followed a 6h TRE protocol for five weeks, resulting in reductions in FI (-3.4 [1.6] mU/L), mean insulin (-26 [9] mU/L), and peak insulin (-35 [13] mU/L) levels, along with an increase in the insulinogenic index, a marker of β cell responsiveness (14 [7] U/mg). Regarding systolic and diastolic blood pressure (SBP and DBP, respectively), 5 weeks of 6h TRE protocol resulted in reductions for both parameters (-11 [4] and − 10 [4] mm, respectively), similarly to oxidative stress markers, in which 6h TRE group experienced a decrease of about 14% in comparison to controls.

Despite these promising results, extended fasting periods are often associated with a higher incidence of adverse events, including hunger, fatigue and irritability, as well as the difficulties in maintaining social eating habits, which all may limit long-term feasibility [55, 56]. Moreover, sustained adherence to more restrictive eating windows may increase the risk of nutritional inadequacy or disordered eating behaviors [55]. Consistent with this, Nie et al. (2023) reported no significant metabolic benefits were observed when comparing different eating window durations, suggesting that short eating windows are not metabolically superior to moderate eating windows.

Moderate eating windows, which encompass daily mealtime periods of 8–10h, have been suggested to be associated with greater sustainability, fewer adverse effects (e.g. irritability and fatigue) and improvements in mood [51, 57–60]. In this context, although much of available evidence derives from heterogeneous, short-term and limited sample-sizes studies, this strategy may represent a balance between metabolic efficiency and long-term adherence, and may therefore be considered the most pragmatic option between eating windows schedules.

In a 12 weeks study, Gabel et al. (2018) found that adults with obesity practicing an 8h TRE schedule experienced greater weight loss (-2,6% [5]) and reductions in SBP compared with the control group. Chow et al. [12] also reported an approximate 3% body weight reduction after 12 weeks of 8h TRE, with decreases in fat mass and visceral adiposity, however, these effects lost significance when adjusted for body weight loss. In adults with metabolic syndrome (MetS), a 10h TRE intervention for 12 weeks reduced body weight (-3.3 kg), body fat, LDL, cholesterol, and both SBP and DBP, while showing favorable trends in glycemic control [20].

In a randomized clinical trial, Wilkinson et al. [20] reported that adults with MetS who followed a 10 h TRE schedule for 12 weeks experienced reductions in body weight (-3.3 [3.2] kg), body fat (-1.01 [0.91] %), total cholesterol (-13.16 [24.29] mg/dL), low-density lipoprotein (LDL) (-11.94 [19.01] mg/dL), as well as SBP (-5.12 [9.51] mmHg) and DBP (-6.47 [7.94] mmHg). Favorable trends were also observed for fasting blood glucose (FBG, p = 0.081), FI (p = 0.064) and HbA1c (p = 0.058).

Moderate eating window aligns food intake with circadian metabolism, as most meals are consumed during the active phase of the day. This alignment enhances insulin sensitivity, improves lipid and glucose metabolism, and may reduce oxidative stress depending on dietary quality [19, 20, 61]. Furthermore, moderate eating periods often lead to reduced overall EI, contributing to improvements in body composition even without explicit ER [20, 57]. Nevertheless, Chaix et al. (2019) and Clavero-Jimeno et al. (2025) emphasize a need for studies that count for additional variables, such as meal timing, diet quality and sleep duration and quality, to fully establish the effectiveness of moderate TRE windows.

The long eating window is the most common dietary pattern, in which daily EI is spread over 12–14h. It is frequent among individuals with irregular routines, disorganized sleep habits, and unrestricted food access [46]. In fact, more than 50% of adults eat for 14.75h or longer per day, and this is often accompanied by a HFD, which is directly associated with health problems such as diabetes, cardiovascular diseases, hypertension and other preventable conditions [46].

Peeke et al.. (2021) compared the effects of 12h vs.14h of TRE in body weight and FBG of individuals with obesity. After 8 weeks, the least squares (LS) mean change in body weight was − 10.7 kg (8.5%) in the 14h group and − 8.9 kg (7.1%) in the 12h (both p < 0.001). The between-group LS mean difference was − 1.9 kg (1.4%), indicating a significantly greater reduction in the 14h group. For FBG, the LS mean change from baseline was 7.6 mg/dL in the 14h group (p < 0.05) and − 3.1 mg/dL in the 12h group, the latter not reaching statistical significance, with no significant difference between groups [62].

The long eating window often overlaps with circadian misalignment, as EI commonly occurs in the evening or night, periods characterized by reduced insulin sensitivity and metabolic efficiency, leading to impaired glycemic control and increased risk of obesity, IR and MetS [13, 63, 64]. Moreover, the absence of fasting periods can disrupt physiological processes such as autophagy, oxidative stress regulation and neuroendocrine balance. Although a long eating window is associated with higher adherence and consistency, which may improve mood, it may not provide significant health benefits [65].

In the general population, this pattern is highly prevalent and often linked to excess EI. However, when the quantity and quality of the food are controlled, it may still support an adequate diet and health [65]. Compared to this approach, moderate eating windows appear feasible and sustainable, promoting metabolic and cardiovascular benefits, particularly in glucose regulation, provided food quality is adequate [56]. Conversely, a short eating window extends fasting periods and may lead to rapid improvements in cardiometabolic markers and insulin sensitivity, but they are generally associated with poorer sleep and mood [55, 56]. The main characteristics and results of studies assessing cardiometabolic outcomes of varying eating windows in individuals with obesity included in this study are presented in Tables 2 and 3.

The authors declare no competing interests.

No datasets were generated or analysed during the current study.