Dietary intervention and tissue remodelling

Abstract

Increased macrophage infiltration and extracellular matrix deposition in adipose tissue and skeletal muscle are observed in obesity and associated with insulin resistance. Daily calorie restriction (DR) and intermittent fasting (IF) are two dietary approaches to treat obesity. A handful of studies have compared the effects of DR versus IF on metabolic health in humans. However, the impact of these dietary interventions on adipose tissue and skeletal muscle remodelling are poorly investigated. This thesis focuses on the adipose tissue and skeletal muscle remodelling following 8-weeks of DR or IF in humans, and also examines metabolic characteristics and adipose tissue remodelling in lean and diet-induced obese mice following IF. The study reported in Chapter 3 is the first randomised controlled study to compare continuous and intermittent intake patterns at two energy levels (at energy balance, or 30% energy restriction). This study showed that IF induced greater reductions in body weight, fat mass, homeostatic model assessment of insulin resistance and total cholesterol. However, the mode of dietary restriction did not impact overall insulin sensitivity by the clamp method, and fasting for 24-hours induced transient insulin resistance. In Chapter 4, weight loss by DR and IF reduced fat cell size and stimulated markers of extracellular matrix remodelling, but did not reduce markers of inflammation. In contrast, IF transiently elevated markers of inflammation in adipose tissue and muscle, which was associated with increases in non-esterified fatty acids (NEFA). To further examine the metabolic profiles and adipose tissue remodelling in response to IF, C57BL/6J mice were fed chow or high-fat diet ad libitum for 8-weeks, then subjected to ad feeding or IF for another 8-weeks. The study in Chapter 5 suggests IF promoted fat mass loss and improved glucose tolerance in chow and high-fat diet fed mice, but decreased body weight, and visceral adipose tissue inflammation and fibrosis in high fat diet fed mice only. In contrast to humans, IF did not increase macrophages in adipose tissue in mice, despite marked increases in NEFA. The mechanisms underlining improved metabolic phenotype in chow and high fat diet fed mice following IF was documented in Chapter 6. Our data shows that IF increased energy expenditure and promoted subcutaneous and visceral adipose tissue browning in both chow and high fat diet fed mice. However in humans, eight weeks of IF did not alter mRNA levels of uncoupling protein 1, a marker of white adipose tissue browning. The adipose tissue and skeletal muscle remodelling in response to acute overfeeding was described in Chapter 7. This study suggests extracellular matrix remodelling in adipose tissue is an early event in response to over-nutrition, and occurs prior to altered insulin sensitivity by clamp. In conclusion, this research highlights that energy restricted intermittent fasting promotes greater weight and fat loss, but does not induce greater improvements in insulin sensitivity by clamp versus daily calorie restriction. This thesis also suggests intermittent fasting results in favourable adipose tissue remodelling in mice, and distinct tissue adaptations versus daily calorie restriction in humans.