Tracing the fate of dietary fatty acids: metabolic studies of postprandial lipaemia in humans

Most postprandial studies have investigated the response of a single meal, yet the ingestion of sequential meals is more typical in a Western society. The aim of this review is to explain how natural and stable isotope tracers of fatty acids have been used to investigate the metabolism of dietary fat after single and multiple meals, with a focus on in vivo measurements of adipose tissue metabolism. When stable isotope tracers are combined with arteriovenous difference measurements, very specific measurements of metabolic flux across tissues can be made. We have found that adipose tissue is a net importer of dietary fat for 5 h following a single test meal and for most of the day during a typical three-meal eating pattern. When dietary fat is cleared from plasma, some fatty acids ‘spillover’ into the plasma and contribute up to 50 % of postprandial plasma non-esterified fatty acid concentrations. Therefore, plasma non-esterified fatty acid concentrations after a meal reflect the balance between intracellular and extracellular lipolysis in adipose tissue. This balance is altered after the acute ingestion of fructose. The enzyme lipoprotein lipase is a key modulator of fatty acid flux in adipose tissue and its rate of action is severely diminished in obese men. In conclusion, in vivo studies of human metabolism can quantify the way that fatty acid trafficking modulates plasma lipid concentrations. The magnitude of fatty acid flux from adipose tissue has implications for ectopic fat deposition in tissues such as the liver and muscle. The immediate fate of dietary fat is important to health. Indeed, atherogenesis has been described as a postprandial phenomenon (1), and postprandial lipaemia (the rise in plasma triacylglycerol (TAG) concentrations after a meal) is thought to be involved (2,3). Although the exact mechanisms that link postprandial lipaemia remain to be elucidated, small chylomicron remnants have been implicated in the progression of coronary artery disease (4). Postprandial lipaemia has also been shown to be associated with oxidative stress and inflammation as recently reviewed (5). Therefore it is important to understand factors that influence the duration and magnitude of postprandial lipaemia. A key tissue in the disposal of meal fatty acids is adipose tissue. The importance of adipose tissue in this respect is outlined in the so called adipose tissue expandability hypothesis (6). This hypothesis proposes that ‘a failure in the capacity for adipose tissue expansion, rather than obesity per se is the key factor linking positive energy balance and type 2 diabetes’. With increasing adiposity in some individuals, it is proposed that the capacity of adipose tissue to store further TAG is reduced, and lipids begin to accumulate in other tissues. The aim of this paper is to summarise the metabolic studies in humans performed by ourselves and others that have helped to understand the way in which adipose tissue metabolises and stores dietary fat. The single meal model A typical protocol for studying postprandial lipaemia is to study volunteers after an overnight fast followed by a single meal. Whilst fasting, the role of adipose tissue is to release fatty acids into the systemic plasma in order to supply tissues with a high requirement for fatty acids, such as skeletal muscle and the heart. Thus fasting plasma NEFA concentrations are high (Figure 1). After a test meal is given, adipose tissue metabolism is coordinated in order to deal with the nutrient load that is given. A typical metabolic response to a high fat meal in a healthy non-obese male is shown in Figure 1. As fat enters the bloodstream in the form of chylomicron-TAG, the concentration of plasma TAG increases. The increase in plasma TAG is also partly due to an increase in the concentration of endogenous TAG in very low density lipoprotein (VLDL, sythesised in the liver) (7) and plasma taken after a meal containing fat is often cloudy because these large lipoproteins scatter light. The concentration of plasma TAG starts to fall as it is cleared from the plasma (Figure 1). This is largely mediated by the action of adipose tissue lipoprotein lipase (LPL) (8), situated at the capillary endothelium. LPL hydrolyses chylomicron-TAG, releasing fatty acids to be taken up by adipose tissue. This pathway is upregulated by insulin, which increases rapidly in response to the carbohydrate content of the meal (Figure 1). It has long been known that LPL is inhibited by apoCII but it has recently been shown that LPL is also inhibited physiologically by angiopoietin-like protein (Angptl)-4 (9). The expression of this protein appears to be decreased in response to food, thus lifting the inhibition and allowing TAG hydrolysis to proceed at a higher rate. Studies from knock-out mice have shown that LPL also appears to require GPIHBP1, a cell-surface glycoprotein synthesised by the endothelium (10). In contrast to the increase in concentration of plasma TAG after a mixed meal, the concentration of plasma NEFA rapidly decreases, but often rebounds above postabsorptive values at the end of the postprandial period (Figure 1). The initial decrease is due to the action of plasma insulin on the suppression of intracellular lipases. Thus insulin is a key mediator of changes in adipose tissue fatty acid trafficking in the transition from fasting to fed states; any meal given with no carbohydrate (eg pure fat load) would fail to illicit the metabolic responses that depend on the increase in plasma insulin concentrations. However, adipose tissue is very sensitive to insulin. Therefore, even a small insulin excursion can reduce plasma insulin concentrations (Figure 2, after fructose ingestion).