Effect of intermittent fasting and meal timing on metabolic health

Abstract

Calorie restriction (CR) provides health and longevity benefits in rodents. However, CR rodents are typically fed once per day, and consume all of their food within 2-4 hours. Therefore, it remains unclear whether it is CR per se or the self-imposed prolonged fasting that underpins these health benefits. Intermittent fasting (IF) diets cycle between fasting and unrestricted eating periods. Most trials in humans have reported equivalent health outcomes in IF versus CR, and a handful reported superior benefits of IF to induce greater weight loss, insulin sensitivity and/or lipid profiles, as reviewed in Chapter 1. This thesis aimed to examine the effectiveness, mechanisms and behaviour change patterns following either IF or CR diets. In a previous trial conducted by our lab, 8-week IF was superior to CR in reducing body weight and blood lipids. The IF participants spontaneously restricted energy intake further than prescribed, likely explaining greater weight loss. In Chapter 2, I reported an exploratory analysis of IF versus CR on growth differentiation factor 15 (GDF15), a novel cytokine that suppresses food intake in animals. Although there was modest rise in GDF15 following IF versus CR, the magnitude appeared to be insufficient to explain the spontaneous energy restriction. Accumulating evidence highlights the importance of meal timing in mediating the benefits of CR. We proposed a novel diet, intermittent fasting plus early time restricted eating (iTRE) that requires people to eat between 8am-12pm with 20-h fast for three days/week. I conducted a parallel-group, randomised controlled trial with 6-month intervention plus 12-month follow-up among people at high risk of developing type 2 diabetes, to compare iTRE versus energy-matched CR. The primary outcome of the iTRE versus CR trial is reported in Chapter 3. Compared to CR, iTRE resulted in greater improvements in post-prandial glucose area under the curve (AUC) at 6 months. I also observed greater reductions in insulin AUC, independent from weight and fat losses. As reported in Chapter 4, after averaging the data following both fasting (20-h fast) and refeeding (12-h fast) days of iTRE, the superiority for glucose tolerance was lost, but the greater improvement in insulin sensitivity and reductions in novel hepatokines implicated in diabetes risk were maintained. In Chapter 5, I observed higher mean morning salivary cortisol in iTRE versus CR, when assessed after a 12-h fast in a sub-group of men. There were no differences in adipose tissue lipolytic gene expression, but reduced expression of lipogenic genes after 20-h fasting in iTRE versus CR, which may indicate suppressed adipose tissue de novo lipogenesis. In Chapter 6, I performed a qualitative exploration of the barriers and enablers to adherence to the iTRE and CR diets. There were similar behaviour change patterns in the two groups. Participants who successfully maintained the diet developed strong internal motivations and self-efficacy, which was facilitated by the “feedback system” built by the health professionals undertaking the study. In conclusion, my research supported that iTRE is a viable alternative to CR that provided modest but superior benefits in postprandial glycaemic control. Critically, efforts should be made to assist behaviour change for long-term acceptability and sustainability of both CR and iTRE.