Lucinda K. M. Summers

Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity.

Abstract.Aims/hypothesis: British dietary recommendations are to decrease total fat intake to less than 30 % of daily energy intake and saturated fat to less than 10 %. In practice, it is difficult for people to make these changes. It may be easier to encourage people to switch from a diet rich in saturated fatty acids to one rich in polyunsaturated fatty acids. Methods: A total of 17 subjects – six people with Type II (non-insulin-dependent) diabetes mellitus, six non-obese and five obese people without diabetes – were randomised to spend two 5-week periods on a diet rich in saturated or in polyunsaturated fatty acids, in a crossover design. At the start of the study and after each dietary period, we assessed abdominal fat distribution using magnetic resonance imaging, insulin sensitivity using hyperinsulinaemic-euglycaemic clamps and fasting lipid parameters. Results: Dietary compliance, assessed by weekly 3-day dietary records and measurement of biochemical markers, was good. Energy and fat intake appeared to be reduced on the diet rich in polyunsaturated fatty acids although body weights did not change. Insulin sensitivity and plasma low density lipoprotein cholesterol concentrations improved with the diet rich in polyunsaturated fatty acids compared with the diet rich in saturated fatty acids. There was also a decrease in abdominal subcutaneous fat area. Conclusion/interpretation: If this result is confirmed in longer-term studies, this dietary manipulation would be more readily achieved by the general population than the current recommendations and could result in considerable improvement in insulin sensitivity, reducing the risk of developing Type II diabetes. [Diabetologia (2002) 45: 369–377]

Impaired postprandial tissue regulation of blood flow in insulin resistance: a determinant of cardiovascular risk?

The insulin resistant state is a major risk factor for coronary artery disease. This increased risk is likely to be due to associated lipid and coagulation abnormalities rather than just abnormalities in glucose metabolism or hyperinsulinaemia alone. Exaggerated postprandial lipaemia is a well-recognised associate of insulin resistance and postprandial hypertriglyceridaemia is particularly important in the development of coronary atheroma. It seems likely that insulin is one of the hormonal regulators of adipose tissue and skeletal muscle blood flow. The reduced blood flow and blunting of the postprandial rise of peripheral blood flow in insulin resistance may decrease chylomicron-triglyceride delivery to muscle in subjects with insulin resistance. This, in turn, will lead to increased production of atherogenic particles. We propose that impaired postprandial vasodilation, already recognised as a key feature of glucose intolerance, is also the cause of impaired lipid metabolism in insulin resistant subjects and predisposes them to cardiovascular disease.

The effect of triacylglycerol fatty acid positional distribution on postprandial metabolism in subcutaneous adipose tissue

We hypothesized that fatty acids at the sn-2 position of chylomicron triacylglycerol are preferentially released into the venous plasma (rather than being taken up and stored in the adipocytes) after hydrolysis by lipoprotein lipase (EC 3.1.1.34) in adipose tissue. Arteriovenous differences across adipose tissue were studied in eight healthy subjects on two occasions for 6 h after ingestion of different structured triacylglycerols rich in palmitic acid either at the sn-2 or the sn-1,3 positions. In particular the specific fatty acids making up lipoprotein fractions and plasma non-esterified fatty acids were analysed. After the different meals there were no differences between either postprandial arterialized or venous plasma metabolite concentrations. Chylomicron triacylglycerol extraction in adipose tissue was the same following the two types of fat. There was no difference between the specific fatty acid composition of the postprandial non-esterified fatty acid release from adipose tissue after ingestion of the two triacylglycerols, indicating that there was no preferential release of a saturated fatty acid at the sn-2 position.

Adipose tissue metabolism in the postprandial period: microdialysis and arteriovenous techniques compared.

We investigated whether two different methods of studying metabolism in adipose tissue, microdialysis and the arteriovenous technique, produced comparable results during the postprandial period. Interstitial glycerol concentrations measured by microdialysis are usually used as an index of intracellular lipolysis, and it is not known whether they also reflect the intravascular action of lipoprotein lipase in the postprandial period. The two techniques were compared in 10 healthy subjects fed mixed meals. Interstitial glycerol concentrations reflected those measured in adipose tissue venous plasma. However, the calculation of the rate of glycerol release from adipose tissue using the microdialysis data differed systematically from that using arteriovenous difference measurement. The former method gave, on average, 40% lower values than the latter one. The difference is probably due to the assumptions that had to be made for the calculation of glycerol release. The two techniques have complementary places in the study of postprandial adipose tissue metabolism, with microdialysis reflecting intracellular hormone-sensitive lipase action rather than intravascular lipoprotein lipase.We investigated whether two different methods of studying metabolism in adipose tissue, microdialysis and the arteriovenous technique, produced comparable results during the postprandial period. Interstitial glycerol concentrations measured by microdialysis are usually used as an index of intracellular lipolysis, and it is not known whether they also reflect the intravascular action of lipoprotein lipase in the postprandial period. The two techniques were compared in 10 healthy subjects fed mixed meals. Interstitial glycerol concentrations reflected those measured in adipose tissue venous plasma. However, the calculation of the rate of glycerol release from adipose tissue using the microdialysis data differed systematically from that using arteriovenous difference measurement. The former method gave, on average, 40% lower values than the latter one. The difference is probably due to the assumptions that had to be made for the calculation of glycerol release. The two techniques have complementary places in the study of postprandial adipose tissue metabolism, with microdialysis reflecting intracellular hormone-sensitive lipase action rather than intravascular lipoprotein lipase.

The acylation-stimulating protein pathway and regulation of postprandial metabolism

Much has recently been learned about the processes involved in postprandial triacylglycerol clearance. As discussed previously, important differences in the metabolism of chylomicrons and VLDL have become apparent. The ASP pathway has also been recognized and appears to play a critical role in chylomicron metabolism. The ASP pathway is activated in order to trap the fatty acids released from chylomicrons by the action of LPL and there is now unequivocal in vivo evidence in human subjects that ASP is generated by adipocytes in the postprandial period. These findings match the in vitro data showing that chylomicrons, but not the other plasma lipoproteins or fatty acids, activate the generation of ASP by cultured human adipocytes. An inverse relationship appears to exist between the proportion of fatty acids taken up by adipocytes and that released into the general circulation. Too great a release into the general circulation because of diminished trapping of fatty acids released from chylomicrons appears to be critical in the pathogenesis of the dyslipoproteinaemias associated with hyperapo B or FCHL and omental obesity. Evidence has been presented that dysfunction of the ASP pathway may be one of the causes of this disorder. Put differently, the ASP pathway is essential for the normal clearance and disposition of dietary fatty acids. Binding of chylomicrons to capillary endothelium followed by lipolysis by LPL results in the sudden liberation of fatty acids, and in the marked generation of ASP by adipocytes. The ASP that is generated is essential if LPL is to continue to form fatty acids at a normal rate. It is essential also if the fatty acids which are formed are to enter the adipocyte rather than exit into the general circulation. The transport vehicle, the chylomicron, therefore stimulates the formation of the peptide, ASP, which is responsible for its successful metabolism. Thus, the ASP pathway provides the metabolic coordination between the chylomicron and the adipocyte, which we describe as microenvironmental metabolic regulation and which we believe is essential for the normal clearance of dietary triacylglycerol from plasma.

Peripheral fat metabolism during infusion of an exogeneous triacylglycerol emulsion

OBJECTIVE: To test the hypothesis that intravenous infusion of lipid would bring about changes in adipose tissue metabolism, which would tend to spare net fat mobilization, and to attempt to identify the mediators of such responses.DESIGN: The triacylglycerol (TG) emulsion, Intralipid, was infused and metablic changes in subcutaneous adipose tissue and forearm muscle were assessed by measurements of arterio-venous differences.SUBJECTS: Six normal male subjects aged 21–37 y, with body mass index (BMI) 23.0–25.9 kg/m2.RESULTS: Plasma TG and non-esterified fatty acid (NEFA) concentrations rose during infusion as expected. The rise in systemic plasma NEFA concentration occurred despite decreased NEFA release from adipose tissue. Intralipid infusion resulted in a suppression of intracellular lipolysis in adipose tissue, by mechanisms which are not clear. Plasma leptin concentrations, measured in a search for the regulator of lipolysis, showed consistent leptin release from adipose tissue which did not change significantly with time.CONCLUSION: The suppression of intracellular lipolysis in adipose tissue during Intralipid infusion is a new observation and may reflect a novel mechanism for regulation of fat storage.

Visceral fat in relation to health: is it a major culprit or simply an innocent bystander?

Seidell and Bouchard 1 discuss the associations between visceral fat accumulation and obesity-related diseases, and conclude that it is difficult at present to be sure whether these are simply associations or whether there is causality involved. As these authors point out, the ‘visceral fat’ hypothesis for obesityrelated diseases has gained rapid acceptance, although it is necessary to maintain a sceptical attitude until proof of causality is established. When associations such as these are described, it is always easier to believe in causality when a plausible mechanism can be identified. In this case, such a mechanism is not difficult to envisage. Many of the adverse metabolic consequences of obesity, could be mediated through increased delivery of non-esterified fatty acids (NEFA) to the liver. These would include excessive VLDL-triacylglycerol secretion, stimulation of hepatic glucose production and impaired hepatic insulin clearance (hence, systemic hyperinsulinaemia). 2,3 This makes a very attractive hypothesis, especially in the light of consistent demonstrations that ‘visceral fat’ is more responsive to lipolytic stimuli in vitro than subcutaneous fat. 4 Recently this has been termed the ‘portal theory’. 3 However, following the warning from Seidell and Bouchard about the need for scepticism, we would like to offer the following thoughts about the portal theory. First, it is important to consider carefully, the idea that omental fat (whose lipolytic products are liberated into the portal vein) is more lipolytically active than subcutaneous fat. If this fat depot is consistently exporting fatty acids at a high rate, how is it supposed that it ever ‘accumulated’ in the first place? We believe that the only consistent interpretation is that this depot has a high rate of lipid turnover, with a high lipolytic capacity in times of stress or fasting, matched or exceeded at other times by a high capacity for fatty acid uptake and storage. Fatty acid uptake is likely to involve the lipoprotein lipase pathway. In that case, omental fat could be envisaged as protecting the liver from an influx of triacylglycerol-fatty acids in the postprandial period. This emphasises the difficulty of extrapolating from in vitro data on adipose tissue metabolism to in vivo situations. Secondly, therefore, we suggest that is important to look critically at in vivo evidence for the ‘portal

The effect on adipose tissue blood flow of isoenergetic meals containing different amounts and types of fat

OBJECTIVE: To investigate the factors regulating the increase in adipose tissue blood flow following meals.DESIGN: Eight subjects were fed three isoenergetic meals; two high-fat meals rich in either saturated or polyunsaturated fatty acids and one low-fat, high-carbohydrate meal.MEASUREMENTS: Blood samples were taken and adipose tissue blood flow was measured before and for 6 h after the meal. Plasma glucose, insulin, non-esterified fatty acid, total and chylomicron-triacylglycerol and catecholamine concentrations were measured.RESULTS: Adipose tissue blood flow rose to a peak after all three meals (P<0.05 for each). The three meals stimulated adipose tissue blood flow at similar times. There was a marked and statistically significant similarity in the time course of changes in blood flow and insulin concentrations. In contrast, noradrenaline concentrations peaked later than adipose tissue blood flow (P=0.014).CONCLUSION: Adipose tissue blood flow may be ‘carbohydrate-stimulated’ rather than ‘fat-stimulated’, with insulin having a vasodilatory role in adipose tissue as in skeletal muscle.