The influence of meal frequency and timing on health and disease has been a topic of interest for many years. While epidemiological evidence indicates an association between higher meal frequencies and lower disease risk, experimental trials have shown conflicting results. Furthermore, recent prospective research has demonstrated a significant increase in disease risk with a high meal frequency (≥6 meals/day) as compared to a low meal frequency (1–2 meals/day). Apart from meal frequency and timing we also have to consider breakfast consumption and the distribution of daily energy intake, caloric restriction, and night-time eating. A central role in this complex scenario is played by the fasting period length between two meals. The physiological underpinning of these interconnected variables may be through internal circadian clocks, and food consumption that is asynchronous with natural circadian rhythms may exert adverse health effects and increase disease risk. Additionally, alterations in meal frequency and meal timing have the potential to influence energy and macronutrient intake.A regular meal pattern including breakfast consumption, consuming a higher proportion of energy early in the day, reduced meal frequency (i.e., 2–3 meals/day), and regular fasting periods may provide physiological benefits such as reduced inflammation, improved circadian rhythmicity, increased autophagy and stress resistance, and modulation of the gut microbiota

Keywords: time-restricted feeding, fasting, meal frequency, meal timing, obesity, cardiovascular health, diabetes
“Eat like a king in the morning, a prince at noon, and a peasant at dinner”

(Moses ben Maimon or Maimonides. 1135-1404)
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1. A Brief Historical Introduction
In Western culture, it is a common idea that the daily food intake should be divided into three square meals: breakfast, lunch, and dinner. Often dieticians suggest adding two snacks (morning and afternoon) to help appetite control, and indeed the mainstream media message is to eat “five to six times a day”. However, the number of meals is not a universal standard, and the traditional three square meals are, somewhat surprisingly, a recent behaviour. As an example, the Ancient Romans had only one substantial meal, usually consumed at around 16:00 h (coena), and they believed that eating more than once per day was unhealthy. Although they also ate in the morning (ientaculum) and at noon (prandium), these meals were frugal, light and quick [1]. Later, Monastic rules influenced common peoples’ eating behaviour. The term breakfast means “break the night’s fast”, pointing out that it is the first meal after the evening/night devoted to prayer [2]. In the early medieval times, monks were obliged to remain silent during meals while one of them read aloud a religious text. One of the most-read texts was the Collationes (compilation) by Giovanni Cassiano, and it is worth mentioning that the Italian term for breakfast is “colazione”, which is derived precisely from the Latin word “collationes” [3]. Breakfast also became important during the industrial revolution as a meal consumed before going to work. Dinner in its current form and timing became popular after the widespread use of artificial light, which facilitated eating before dawn and after dark [3].

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2. Meal Frequency
2.1. Epidemiological Studies about the Effects of Meal Frequency on Cholesterol, Body Weight and Diabetes
The origin of the firm belief that eating three meals per day is the better healthy choice is a mix of cultural heritage [4,5,6] and early epidemiological studies [7]. The available epidemiological studies have not primarily investigated cardiovascular diseases (CVDs), but rather some risks factors such as cholesterol and body weight [8,9]. These studies observed a worsening of blood lipids associated with a “gorging” (a reduced meal frequency, one or two meals daily) diet compared to “nibbling” (the consumption of frequent smaller meals or snacks). In these early studies, authors stated that a reduced meal frequency is associated with an increased risk of cardiovascular disease [10]. Subsequent studies seemed to confirm these previous findings, reporting a lower age-adjusted total and LDL (low-density lipoprotein) cholesterol in subjects who reported eating four or more meals daily, compared to those reporting one or two [11]. The association was also confirmed after adjustment for alcohol, smoking, systolic blood pressure, anthropometric measurements as WHR (waist to hip ratio) and BMI (body mass index), and macronutrient intake. In a 1989 paper, authors compared a very high frequency of meals (17) to a lower frequency (3) and found an improvement of total and LDL cholesterol with the higher frequency; however, this particular approach is clearly atypical in ordinary life [12]. A recent study within the European Prospective Investigation into Cancer (EPIC) project showed a lower concentration of total and LDL cholesterol in subjects reporting a higher (≥6 times/day) meal frequency compared to those who ate 1 or 2 times a day, even when adjusted for age, BMI, physical activity, smoking, total energy intake, and macronutrient distribution [13]. Again, a recently published cross-sectional analysis within the prospective Seasonal Variation of Blood Cholesterol Study in Worcester County, Massachusetts (SEASONS) showed that a frequency higher than four times per day leads to a lower risk of obesity compared to a frequency lower than three times per day, even after adjustment for age, sex, physical activity, and total energy intake [14].

Another large cohort study, the Malmo Diet and Cancer study, reported that eating more than six meals per day reduces the risk of obesity compared to less than three meals daily; moreover, after adjustment for diet and lifestyle, frequent eaters had lower waist circumference [15]. Regarding diabetes, a 16-year follow-up study showed an increased risk of type 2 diabetes mellitus in men who ate 1–2 times a day compared to those who ate three meals a day (relative risk RR 1.26) after adjustments for age, BMI, and other relevant factors [16]. These data are in contrast to another study that found no correlation between increased meal frequency and type 2 diabetes risk in women after six years follow up (3 times a day: RR 1.09, ≥6 times a day: RR 0.99) [17]. Despite the numerous studies examining risk factors, only one prospective cohort study investigated the relationship between meal frequency and coronary heart disease (CHD) risk. Cahill et al. [18] found that men eating 1–2 meals per day hadan RR for CHD of 1.10, men eating 4–5 meals per day hadan RR of 1.05, and men eating ≥6 times hadan RR 1.26, as compared to who ate three times a day after adjustment for total energy intake, diet composition, and other risk factors. In general, conflicting results are depending on the outcome investigated and the methodology used.

However, as also suggested by other authors [19,20], the correlation between a reduced meal frequency and a higher risk of CHD in these studies appears to be weak considering the cross-sectional nature of these studies, making it difficult to establish the causality or temporality of this association.

2.2. Meal Frequency and Weight Control: One, Two, Three, or More Meals?
Obesity is a rapidly growing epidemic worldwide; its prevalence has nearly doubled in more than 70 countries since 1980. In 2015, a total of 107.7 million children and 603.7 million adults were obese [21]. Seventy-five percent of the world’s population live in countries where overweight and obesity kills more people than underweight [22]. Obesity is one of the main risk factors for cardiovascular disease, along with dyslipidemia and hypertension [23]. As a part of the strategies proposed for reducing energy intake (diets, drugs, and bariatric surgery) [24] and for increasing energy output (exercise and non-exercise movement) [25], meal timing and frequency could exert a significant influence on weight control and weight loss. [26,27]

A very recent and extensive study published by Kahleova and colleagues [28] investigated 50,660 adult members of Seventh-day Adventist churches in the United States and Canada. The results showed that eating one or two meals daily was associated with a relatively lower BMI compared with three meals daily. Interestingly, they found a positive relationship between the number of meals and snacks (more than three daily) and increases in BMI. Furthermore, the change in BMI was related to the length of the overnight fast: the longer the overnight fast, the lower the BMI. Authors suggested that the positive effects of such nutritional regimen are due to the combination of timing, meal frequency, and long overnight fasting; they hypothesised different underlying reasons as an effect of satiety hormones (leptin or ghrelin), an improvement of peripheral circadian clock (and therefore an improvement of key metabolic regulators such as cAMP response element-binding protein), and a reduction of oxidative damage together with a higher stress resistance [28]. These data suggest that 1–2 meals are better than three or more, but how can we integrate these results with previous, older research? Both older studies [9,10,12,29,30] and more recent research [31] seem to suggest that a higher meal frequency can reduce weight gain risk; however, recent large prospective studies seem to support that frequent snacking increases the risk of weight gain [32,33] and type 2 diabetes [16,17]. Additionally, research investigating acute metabolic responses to differing meal frequencies may support the benefits of a lower meal frequency. Taylor and Garrow evaluated the effects of isocaloric diets consisting of two or six meals per day on energy expenditure measured in a metabolic chamber. The results showed no differences during the day whilst night expenditure was significantly higher with two meals compared with six meals [34]. On the contrary, other studies demonstrated a significantly higher basal energy expenditure in the morning compared to the evening [35,36,37]. However, diurnal differences in the total energy expenditure are not consistently found in all studies [38]. Other studies suggest that weight gain and its metabolic consequences with a higher meal frequency are due to not only to the higher sugar derived energy intake [39] and associated metabolic issues, but also to increased food stimuli, hunger and desire to eat [40,41]. Thus, a regular meals pattern has potential positive effects on health outcomes regardless of meal frequency.

Often infrequent meal pattern, i.e. a reduced meal frequency, is associated with an irregular eating approach that could cause weight gain, increase hunger-related hormones, and ultimately lead to a metabolic disturbance that may increase cardiovascular risk [42]. On the contrary, a lower frequency but with regular timing may decrease weight gain risk [28].

2.3. Intervention Studies and Reciprocal Influences of Meal Frequency and Macronutrients
In addition to the effects of changing meal frequency per se, it must be considered that these changes could also modify the overall macronutrient intake. This was demonstrated by McGrath and Gibney, who convinced subjects who usually eat six times daily to reduce their frequency while persuading lower frequency eaters (three times daily) to increase their frequency to six times. The increase of meal frequency induced a significant reduction of total and LDL cholesterol but was coupled with a reduction of carbohydrate intake [30].

The reductions of cholesterol observed by McGrath and Gibney can be considered in light of the current debate about the real relationship between traditional disease markers such as total cholesterol and LDL cholesterol and CHD [43], as some have challenged the common idea that higher blood levels of cholesterol increase stroke and other cardiovascular events [44]. It is reasonable to assume that the mechanisms involved in cholesterol reduction may be related to cholesterol synthesis mechanisms. We now know that insulin activates a key enzyme in cholesterol biosynthesis, hydroxymethylglutaryl-CoA (HMGCoA) reductase (the target for statins) [45]. Even though the discussion about the mechanisms underlying this control (AMP-activated protein kinase, increased rate of transcription, or insulin-induced genes) [46,47,48], exceeds the aims of this review, it appears consequential that an increase in blood glucose and, of consequence, of insulin will lead to increased endogenous cholesterol synthesis [49,50,51]. It was demonstrated that a higher meal frequency (nibbling) reduced insulin concentrations as compared to three meals daily [12], likely caused by a reduction in cholesterol synthesis [29].