Intermittent fasting: review of effects on weight

BODNĂRESCU-COBANOGLU Mihaela1, LEȚI Maria-Mădălina *2 IONITA Corina3, ZETU Cornelia1, POP Anca Lucia 1,3

1National Institute of Diabetes, Nutrition and Metabolic Diseases “Prof. Dr. N. Paulescu” Romania

2Clinical Hospital of Psychiatry”Prof. Dr. Alexandru Obregia”, Romania

3University of Medicine and Pharmacy “Carol Davila” Bucharest, Romania

*Corresponding author: mariamadalinaleti@gmail.com, 

Abstract

Intermittent fasting diet (IFD) has been shown as a promising dietary approach for the management of overweight and obesity in adults over 18 when compared with other methods of weight loss (continuous daily restricted calorie diets) in some studies, but the results are still controversial. IFD describes a variety of eating patterns and fasting that range from 12 hours to several days. The objective of this paper is to review the most recent data about the types of intermittent fasting regimens as well as a summary of evidence regarding weight loss obtained through intermittent fasting and to discuss physiological mechanisms by which metabolism leads to weight loss. Data sources: A search and review of scientific literature methodology were performed to identify peer-reviewed research articles in the following databases: PubMed, BMC Public Health, Global Health, CrossRef, Scopus, Web of Science, Google Scholar and Medline using the terms: “intermittent fasting,” “fasting,” “time-restricted feeding”. Study selection: We analyzed relevant papers from the reference lists of research papers, as well as reviews of fasting regimens; we didn’t perform a formal review or a meta-analysis: the studies couldn’t be combined because they are markedly dissimilar regarding the interventions, the comparison groups (or lack thereof), sample composition, study design, and intervention duration. From a variety of studies identified through a literature search, we finally selected nine articles. Results: When applying TRF both observational and RCT studies reported a significant reduction in body weight, with a more evident effect in the former (~2 kg less) than in RCTs (~0.4 kg less).

Keywords: circadian rhythm, intermittent fasting, obesity; glucose metabolism, Chrono nutrition

Introduction

Since the time of ancient Chinese, Greek, and Roman physicians fasting for medical purposes has been practiced parallel with the religious one [1]. On the other hand, all around the world, almost two billion people were overweight five years ago and over half a billion people were obese.  representing approximately 39% of the world’s population [2]. There is a steady increase in the obesity rates irrespective of age, sex, race, geographical locality, ethnicity, or socioeconomic status, being greater in women and old people. A multifactorial ethiopatogeny of obesity is analyzed nowadays, generating a chronic positive energy imbalance generating conversion and triglycerides synthesis and adipose tissue stacking generating hypertrophy and hyperplasia of this storage tissue [3]. The increase of low nutrient high caloric cheap food immediately available, more processed and affordable food, and promote passive overconsumption from energy-dense, nutrient-poor foods and beverages have been identified as a major driver of the obesity epidemic, although a decrease in physical activity owing to the modernization of lifestyles is also likely involved.

Data sources

A search and review of scientific literature methodology was performed to identify peer-reviewed research articles in the following databases: PubMed, BMC Public Health, Global Health, CrossRef, Scopus, Web of Science, Google Scholar and Medline using the terms: “intermittent fasting,” “fasting,” “time-restricted feeding”. This was not a formal review or a meta-analysis: the studies could not be merged because they are markedly dissimilar concerning the interventions, the comparison groups, sample structure, study design, and duration of intervention.  Besides, we analyzed relevant papers from the reference lists of research papers, as well as reviews of fasting regimens. From a variety of studies identified through a literature search, we finally selected nine articles (Table I) and three main topics – the Physiology of fasting, Chrono nutrition, types of intermittent fasting.

How fasting results in fat burning? (Physiology of fasting)

The theory of “fasting physiology” is that biochemical processes associated with fasting are triggered once stored energy is being utilized and the onset of the metabolic switch is triggered (Fig.1) – the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake). [4]

Fig. 1. Pathways of the metabolic switch (after Anthon & al., 2018)

The glycogenolysis path is targeted on great fasting period, eating at the usual four hours meal gap will never get the human body to the metabolic switch from glycogenolysis – when glycogen stores in hepatocytes are depleted and accelerated adipose tissue lipolysis produces increased fatty acids and glycerol [5, 6] – towards keto state, thus the ketone levels remain continuously low. The metabolic switch typically occurs between 12 to 36 hours after cessation of food consumption depending on the liver glycogen content at the beginning of the fast, and on the amount of the individual’s energy expenditure/exercise during the fast. The adipocytes triacylglycerol and diacylglycerol are metabolized to free fatty acids (FFAs), that are released into the blood (Fig.1) and used as energy fuel.

Other cell types are starting to generate ketones, i.e. the astrocytes in the brain. FFAs are transported into hepatocytes where they are metabolized by β-oxidation to produce the ketones β-OHB and acetoacetate, which may in turn induce mitochondrial biogenesis [7]. The ketones used in high amounts into cells with high metabolic activity (muscle cells and neurons) where they are metabolized to acetyl coenzyme A, which then enters the tricarboxylic acid (TCA) cycle to generate ATP. In this way, ketones serve as an energy source to sustain the function of muscle and brain cells during fasting and extended periods of physical exertion/exercise [8].

The circadian clock is highly connected with nutrient-sensing pathways. The absence of the fasting periods during the day/night, the continuous eating – disturbs the normal counter-regulatory metabolic state that occurs during fasting. Activation of the insulin-pAKT-mTOR pathway drives downstream gene activities promoting anabolic processes during the feeding period. Fasting for over 4 hours activate the triggers of healing and catabolic processes through AMPK. Pararelly AMPK-mediated inhibition of mTOR activity (Inoki et al., 2011) [9, 31] and downstream anabolic pathways ensures separation of catabolic and anabolic processes. In addition to well-characterized anabolic targets, the mTOR pathway also phosphorylates casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), both of which phosphorylate the circadian clock component PER, altering its stability [10] so the feeding pattern affects the circadian clock.  

Fig. 2 The human circadian rhythm regulates eating, sleeping, hormones, physiologic processes, and coordinates metabolism and energetics [11]

Fasting enables the organisms to enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources.

Intermittent fasting generates adaptive cellular responses integrated between and within organs in a manner that improves glucose regulation, increases stress resistance and suppresses inflammation by a mechanism evolutionarily conserved. During the fasting the cells activate pathways that intensify intrinsic defenses against oxidative and metabolic stress and those that remove or repair injured molecules [12]. The two intermittent and periodic fasting result in benefits that rank from prevention to the intensified treatment of diseases. When the feeding time is limited to certain hours of the day is considered Time-restricted feeding (TRF) with a daily fasting period that lasts >12 h [13]. Understanding the mechanism between nutrients and the fasting benefits is bringing to the identification of fasting-mimicking diets (FMDs) that achieve changes alike to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMD, the two basic science and translational research are a future way to develop fasting-associated interventions into effective and inexpensive treatments that can have the potential to improve the healthspan (the period of one’s life that one is healthy)[14].

Besides the effect on weight loss, many studies presented that through IF we can expect a powerful effect of improvement of glucose metabolism by lowering insulin resistance [15].

Inside the liver, TRF reprograms metabolic flux through gluconeogenesis by switching pyruvate metabolism to the TCA cycle and glucose-6P metabolism by way of the pentose phosphate pathway. These two pathways aid to increase the expression of Cyp7A, which redirects the production of cholesterol to bile acids. TRF also increases activity levels of brown adipose tissue (thus rising the metabolic rate], increases fatty acid β–oxidation, and decreases hepatic glucose production [16, 17, 18]. In the white adipose tissue, TRF lowers macrophage infiltration and resulting inflammation. Repeated flipping of the metabolic switch aside from providing the ketones that are necessary to fuel cells during the fasting period also elicits highly orchestrated systemic and cellular responses that carry over into the fed state to bolster mental and physical performance, as well as disease resistance [19, 32]. It also promotes T cells cytotoxicity on cancer cells as immune-based therapies (IBT) and the number of cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) mediated by heme-oxygenase 1[33].

Types of intermittent fasting identified

Different types of diets have been used to study the effects of intermittent fasting. Here we describe all types found in current literature:

    1. Alternate-day fasting (ADF): Involves alternating fasting days (no energy-containing foods or beverages consumed) with eating days (foods and beverages consumed ad libitum).  The sparse data on alternate-day fasting suggest that this regimen can result in modest weight loss and lead to improvements in some metabolic parameters. However, reports of extreme hunger while fasting indicate that this may not be a feasible public health intervention [20, 21].
    2. Alternate-day modified fasting (ADMF): Allows consumption of 20–25% of energy needs on scheduled fasting days; the basis for the popular 5:2 diet, which involves severe energy restriction for 2 non-consecutive days per week and ad libitum eating for the other 5 days. [22, 23, 24]
    3. Time-restricted fasting: Allows ad libitum energy intake within specific time frames, inducing regular, extended fasting intervals (usually between 8-12 hours/day); studies of <3 meals per day are indirect examinations of a prolonged daily or nightly fasting period [25].
    4. Periodic fasting: The human circadian rhythm regulates eating, sleeping, hormones, physiologic processes, and coordinates metabolism and energetics.

Synthesis

A big part of scientific evidence regarding the effects on the health of intermittent fasting comes from studies made in rodents. In terms of human studies, the data has been limited to observational studies of religious fasting (e.g Ramadan, Members of the Church of Jesus Christ of Latter-Day Saints, Some Seventh-day Adventists), cross-sectional studies of eating patterns associated with health outcomes and experimental studies with small sample sizes.

A review of all relevant clinical trials evaluating chronic calorie restriction in the 20–50% range (CR) and intermittent fasting, shows that CR (caloric restriction) is superior in causing weight loss compared to IF, but both interventions have the same effects on the reduction of visceral fat, serum insulin levels and insulin resistance (Barnosky et al., 2014).  Nevertheless, nor calorie restriction and neither intermittent fasting do not clinically impact glycemia levels [27] limiting the applications in the prevention of metabolic non-communicable diseases (NCD) backed by low compliance to either severe and chronic CR or severe restrictions limiting calorie consumption to 500 – 600 kcal/day on average between 9 and 15 times per month.

The study showed that two months of alternate-day fasting lead to a significant reduction in inflammatory markers in patients suffering from asthma so the IF may improve the symptoms in asthma. [26]. Limiting access to high-fat food to only 8–12 hours per day it’s not reducing overall caloric intake (in comparison to animals fed ad libitum), but has a beneficial effect on circadian rhythms and helps prevent or reverse metabolic diseases [28, 29, 30]. In a meta-analysis made by Pellegrini et al. 2020, pooled data from 11 studies (485 subjects) showed a consistent effect of TRF on weight loss (WMD: −1.07 kg, 95%CI: −1.74 to −0.40; p = 0.002; I2 = 56.2%) [31].

Conclusions:

It appears that modified fasting regimens promote weight loss and may improve metabolic health. There is evidence to support the hypothesis that eating patterns that minimize or eliminate nighttime eating and extend nightly fasting intervals can result in sustained improvements in human health. IF regimens are assumed to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep [30]. If shown to be efficacious, these eating regimens are promising nonpharmacological methods to improve health at the population level, with many public health benefits. When applying time-restricted feeding in both observational and RCT studies were reported an important reduction in body weight, with a more evident effect in the observational (~2 kg less) than in RCTs (~0.4 kg less). Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and the magnitude of negative energy balance during the fasting period. 

Study limitations: in the present review we didn’t perform a formal systematic review or a meta-analysis: the studies couldn’t be combined being different in the interventions, the control groups (or lack thereof), study group, study design, intervention duration.

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