Impact of time restricted feeding on glucose metabolism and metabolic health

Abstract

Lifestyle induced metabolic diseases such as obesity, type 2 diabetes and cardiovascular diseases are often associated with increased energy intake, and reduced levels of physical activity. However, accumulating evidence suggests that when we eat may be a contributing factor to chronic disease progression. Eating out of phase with daily circadian rhythms induces metabolic desynchrony in peripheral metabolic organs in mice, and may increase chronic disease risk. Time restricted feeding (TRF, also known as time restricted eating) is a novel dietary tool that limits the duration of the daily food intake window to 6-12 hours, without altering calorie intakes or diet quality. In preclinical models, TRF reduced diet-induced weight gain and hepatosteatosis, improved glucose tolerance, mitigated age-induced decline in cardiac function and improved muscle function, and protected from the metabolic milieu of diverse nutritional challenges, including high-fat-diet (HFD) and high-fat-high-sucrose diet. In human trials, that are currently limited in size and number, TRF also reduced body weight and fasting glucose, improved glucose tolerance, reduced blood pressure, and reduced atherogenic lipids in people with overweight and obesity. However, the majority of TRF interventions in animal models and in humans have been initiated early in the active phase. Implementing TRF initiated early in the morning may be challenging in the general population both biologically and socially. Hunger is lowest in the morning due to a circadian nadir in ghrelin. Furthermore, family and communal get togethers are essential factors to increase social bonding capable of providing social and emotional support, however many social events are typically geared towards evening. Delaying the initiation time of TRF (i.e. allowing food consumption for identical time lengths later in the day) may overcome both of these issues, but the metabolic consequences of delayed TRF are unclear. This thesis examined the impact of early and delayed TRF in humans and in mice. We carried out the first human trial (randomized cross-over) examining the acute effects of early versus delayed TRF in overweight men at the risk of type 2 diabetes. After baseline assessment for one week, participants were randomised to eat their habitual diets within a 9-hour period starting early (8am-5pm, TRFe) or delayed (12pm-9pm, TRFd), separated by a 2-week wash out period. One-week of TRF improved glucose tolerance, modestly reduced body weight, reduced fasting triglycerides, and reduced fasting glucose as measured by continuous glucose monitoring. These results were independent of gastric emptying or physical activity. Importantly, there was no statistically significant difference in any of above results between TRFe and TRFd. This study suggested that TRF improved markers of health, irrespective of whether it was initiated at 8am or 12pm. To further examine the long-term effects of early versus delayed TRF on metabolic phenotypes and circadian rhythms in peripheral organs, we carried out an 8-week early versus delayed TRF study in chow or high-fat diet fed mice. After four weeks of ad libitum feeding with chow or high-fat diet, mice on each diet were randomized to one of three interventions: i) continue ad libitum, ii) 10-hour TRF initiated at ZT12 (TRFe), and iii) 10-hour TRF initiated at ZT16 (TRFd) for a further 8-weeks. This study showed that both forms of TRF reduced weight and fat gain, improved glucose tolerance, reduced hepatosteatosis, and increased metabolic flexibility. We measured the mRNA levels of key genes involved in circadian regulation in the liver as an index of peripheral circadian rhythm. We observed that both forms of TRF increased the amplitude of genes involved in circadian regulation and markers of nicotinamide adenine dinucleotide (NAD) metabolism in liver compared to ad libitum. TRFd marginally limited the benefits in weight and fat gain compared to TRFe, and induced a phase delay in body temperature, and clock genes and markers of NAD metabolism in liver. However, a phase delay in key circadian genes in liver did not adversely impact the improvement in metabolic phenotypes in TRFd, as well as there was no statistically significant difference in measured metabolic phenotypes and amplitudes of circadian genes in liver between TRFe and TRFd. Additionally, we explored whether intermittent fasting (IF) impacted markers of NAD metabolism in skeletal muscle, and whether this was associated with metabolic switching from fed to fasting day in overweight women and chow or high-fat diet fed mice. We demonstrated that insulin sensitivity was transiently reduced in overweight women on the fasting day during IF, which may help to spare glucose. At the molecular level, the rise in NAMPT expression on fasting day may facilitate the lipid oxidation pathways in skeletal muscle. In conclusion, this research showed that TRF improves metabolic health whether initiated early or delayed (akin to skipping breakfast), when there are equidistant transitions between fasting-feeding cycles. Uniquely, we demonstrate the metabolic benefits of TRFd occur alongside a phase delay in hepatic clocks and metabolic markers, but with increases in the amplitude and/or mean of genes involved in nutrient signalling and circadian regulation. Flexibility to initiate TRF a few hours later in the day could increase the translational potential of this promising dietary tool in the general population. Further, a transient reduction in insulin sensitivity and rise in skeletal muscle NAMPT expression in response to the fasting day may facilitate metabolic switching from glucose to fat oxidation in intermittent fasting.