Timing of energy intake and the therapeutic potential of intermittent fasting and time-restricted eating in NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents a major public health concern and is associated with a substantial global burden of liver-related and cardiovascular-related morbidity and mortality. High total energy intake coupled with unhealthy consumption of ultra-processed foods and saturated fats have long been regarded as major dietary drivers of NAFLD. However, there is an accumulating body of evidence demonstrating that the timing of energy intake across a the day is also an important determinant of individual risk for NAFLD and associated metabolic conditions. This review summarises the available observational and epidemiological data describing associations between eating patterns and metabolic disease, including the negative effects of irregular meal patterns, skipping breakfast and night-time eating on liver health. We suggest that that these harmful behaviours deserve greater consideration in the risk stratification and management of patients with NAFLD particularly in a 24-hour society with continuous availability of food and with up to 20% of the population now engaged in shiftwork with mistimed eating patterns. We also draw on studies reporting the liver-specific impact of Ramadan, which represents a unique real-world opportunity to explore the physiological impact of fasting. By highlighting data from preclinical and pilot human studies, we present a further biological rationale for manipulating timing of energy intake to improve metabolic health and discuss how this may be mediated through restoration of natural circadian rhythms. Lastly, we comprehensively review the landscape of human trials of intermittent fasting and time-restricted eating in metabolic disease and offer a look to the future about how these dietary strategies may benefit patients with NAFLD and non-alcoholic steatohepatitis.

Keywords: DIABETES MELLITUS; ENERGY METABOLISM; LIVER METABOLISM; NONALCOHOLIC STEATOHEPATITIS; OBESITY.

Figure 1

Timing of food intake as a risk factor for NAFLD and metabolic dysfunction. Timing of energy intake across the day–night cycle is an important determinant of individual risk for NAFLD. Skipping breakfast, chaotic meal patterns and night-time eating are all associated with metabolic dysfunction and disruption to natural circadian rhythms (symbolised by blue line). Conversely, shifting energy intake toward the beginning of the day, standardised meal patterns and fasting during Ramadan are all associated with benefits to metabolic and liver health. γGT, γ-glutamyl transferase; B, breakfast; CVD, cardiovascular disease; D, dinner; L, lunch; LDL, low-density lipoprotein cholesterol; NAFLD, non-alcoholic fatty liver disease. Figure made with biorender.com.

Figure 2

IF and TRE strategies. Commonly employed IF and TRE strategies. Figure made with biorender.com. IF, Intermittent fasting; TRE, time-restricted eating.

Figure 3

Mechanistic basis for improved metabolic outcomes following fasting and TRF/TRE. The benefits of fasting (right) and TRF/TRE (left) are well conserved across simple organisms, rodent models and humans. Fasting has pleiotropic effects, including anti-inflammatory properties, weight loss through adipose browning and exerts a beneficial impact as a result of metabolic switching from glucose to fatty acids and ketones as a source of fuel. Time-restricted calorie intake introduces additional benefits by aligning circadian rhythms across multiple tissue types. 5:2, 5 days eating 2 days fasting; ADF, alternate day fasting; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; LSM, liver stiffness measurement; NASH, non-alcoholic steatohepatitis; TRE, time-restricted eating; TRF, time-restricted feeding. Figure made with biorender.com.

Figure 4

Rationale for the application of TRE in NAFLD. Multiple strands of evidence point toward the therapeutic potential of TRE in NAFLD and NASH. Timing of energy intake, circadian rhythms and metabolic phenotype are all intrinsically linked. These interactions can be positively influenced by TRE which has been shown to restore the rhythmicity of metabolic pathways and is known to improve major drivers of liver disease progression, including obesity and insulin resistance. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; TRE, time-restricted eating. Figure made with biorender.com.