Ectopic Lipids and hepatokines: interaction between movement behaviours and cardiometabolic health

Abstract

Ectopic fat and insulin resistance are pathophysiological determinants of obesity-related metabolic disease. High liver fat is particularly detrimental for cardiometabolic risk, with hepatic lipid composition (saturated, unsaturated, polyunsaturated) potentially mediating risk severity. The studies in this thesis examined associations between movement behaviours and cardiorespiratory fitness (CRF) with ectopic fat and adipose tissue insulin resistance. In men with non-alcoholic fatty liver disease (NAFLD), associations between glycaemic control and hepatic lipid composition were also examined, as well as the effect of exercise training on hepatic lipid composition.

Study 1 (Chapter 3) shows that, in community volunteers, device-based measured sedentary time is independently (positively) associated with adipose tissue insulin resistance (Adipo-IR) and visceral fat (V A T). Additionally, CRF was independently (inversely) associated with V A T and subcutaneous abdominal adipose tissue (ScAT). In the same population, Study 2 (Chapter 4) demonstrated that CRF was independently (inversely) associated with circulating concentrations of the hepatokines leukocyte cell- derived chemotaxin 2 (LECT2) and fibroblast growth factor 21 (FGF21). Study 3 (Chapter 5) showed that in men with NAFLD, hepatic lipid saturation is higher in those with impaired versus healthy glycaemic regulation. Circulating cytokeratin-18 (M65) concentration, a marker of liver injury, were also higher in men with IGR and correlated positively with hepatic lipid saturation. Finally, the randomised controlled trial in Study 4 (Chapter 6) demonstrated that 6-weeks of aerobic exercise training does not influence hepatic lipid composition (saturation, unsaturation, polyunsaturation) in men with NAFLD and impaired glycaemic regulation.

Collectively, the studies in this thesis demonstrate that higher levels of sedentary time are associated with ectopic lipid accumulation and adipose tissue dysfunction. Conversely, higher levels of CRF are linked to favourable adiposity and circulating hepatokine profiles. Finally, poorer glycaemic control is associated with greater hepatic lipid saturation in men with NAFLD, but 6-weeks of exercise training does not alter hepatic lipid composition.