Intermittent fasting—The new lifestyle?

Obesity has become a pandemic that affects all populations of all ages living in countries of all income levels.1 Attributed to sedentary lifestyle and energy dense diet, obesity is a risk factor for cardiovascular disease, insulin resistance, type 2 diabetes and even some types of cancer.2 These comorbidities also affect the immune system adversely and can exacerbate infectious diseases as observed in the most recent case of pandemic COVID-19.3, 4 The need for effective solutions is urgent and diet is one of the most important targets for intervention,1 alongside education,1, 2 behavioural therapy,2, 5 exercise2, 6-8 and bariatric surgery.2, 9, 10 Dieting trends have indeed been many and varied. One such trend that has gained popularity in the past decade is intermittent fasting (IF).11 Not a novel concept in itself, IF has been followed all over the world in one form or the other since time immemorial.11 It is a broad term encompassing a wide range of protocols with one underlying principle—abstaining from food intake for longer periods than the usual overnight fast. Popular IF protocols fall in the following three categories: whole day fasting (WDF), alternate day fasting (ADF) and time-restricted feeding (TRF). WDF protocols call for complete abstinence from food for 1 or 2 days per week with ad libitum food intake the rest of the week. ADF involves alternating 24 hours periods of fasting and ad libitum food intake while TRF involves following a routine every day where certain hours are designated as eating periods and the remaining hours as fasting periods (eg 8 hours eating period, 16 hours fasting period).12 IF is considered an easier alternative to traditional continuous energy restriction methods since it does not involve tedious calorie counting. This ease has been proposed to improve adherence to the diet regimen which in case of continuous energy restriction is known to decline within 1-4 months irrespective of results.13 During IF, glucose levels decrease followed by the depletion of glycogen reserves in the liver. This triggers gluconeogenesis which leads to the release and catabolism of fats from adipocytes accompanied by a decrease in insulin secretion along with an increase in glucagon secretion.14 The role played by glucagon in the circadian rhythm of pancreatic islet cells was recently described by Petrenko et al15 Circadian rhythms are biological clocks that operate in all light sensitive organisms and are responsible for temporal coordination of physiological processes.16-18 They are a fundamental anticipatory mechanism that enable organisms to adapt to environmental changes.17 One of the factors that have a major effect on circadian rhythms and associated anticipatory behaviour is meal timings. For example, mice on a TRF regimen show an increased activity 1-3 hours before the regular eating window.19 This effect of IF was initially thought to be controlled by both the central circadian clock (suprachiasmatic nucleus (SCN) of the hypothalamus) as well as the peripheral circadian clock viz. the endocrine signals from the liver, pancreas, intestine, muscles and adipose tissue.17, 20 That is, when food is provided during daytime, the SCN controls the metabolic activity and behaviour while the peripheral oscillators are in charge when food is provided during night-time.20 However, an SCN-independent feeding entrained oscillator in the form of dorsal striatum dopamine has recently been described. Briefly, when food is available for regular but time restricted intervals, the food entrained oscillator takes precedence over the SCN in controlling food anticipatory activity.19 It is important to note that short term disruptions of the circadian rhythm in humans were shown to decrease insulin sensitivity which is a risk factor for type 2 diabetes.21 In another study involving mice, synchronization of feeding windows with the circadian rhythm prevented weight gain even when fed with a high fat diet. Their counterparts, however, when fed ad libitum with the same diet gained weight. Interestingly, there was no difference in the total energy intake between the two groups.11 Another factor that plays a bidirectional role in maintaining circadian rhythms is gut microbiota.5 The circadian clock of the host brings about diurnal oscillations in the function and composition of the gut microbiota while signals from the microbiota in turn regulate the circadian rhythms of the host.22 In mice, IF was shown to reshape the gut microbiota which in turn promoted the browning of adipose tissue. The role played by the microbiota was confirmed by the absence of this phenotype in germ-free mice and its induction after they received a microbiota transfer.23 Brown adipose tissue, specifically the activity of uncoupling protein 1 therein, mediates a process called non-shivering thermogenesis which has been shown to counteract excessive energy intake by reinstating energy balance. Hence, IF mediated browning of adipose tissue could be an effective therapy for obesity and related metabolic diseases.23 In human studies, IF has shown moderate weight loss and was as effective as traditional continuous energy restriction.13 Both ADF and WDF showed a weight loss of ~3%-9% within 12-24 weeks while data on TRF are not available. A reduction in total cholesterol (~5-21%), triglycerides (~14%-50%) as well as a reduction in the levels of low-density lipoproteins was also observed.12 Plasma levels of adiponectin are often reduced in obese individuals.24 IF has been shown to reverse this trend.14 Moreover plasma levels of leptin, which positively correlate with increasing adipose tissue mass,25 decrease during IF.14 Adiponectin and leptin are cytokines secreted by adipocytes (adipokines) that regulate body weight by controlling glucose uptake, lipid accumulation and appetite.26 IF also leads to lowered levels of inflammatory markers such as interleukine-6, homocysteine and C-reactive protein.14 These changes along