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Biomedical subjects

Keith N Frayn

Publications and source records attributed to Keith N Frayn.

At least 19 recordsLinked to original sources
PubMed2007

Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period.

Despite consistent evidence that abnormalities of fatty acid delivery and storage underlie the metabolic defects of insulin resistance, physiological pathways by which fat is stored in adipose tissue and skeletal muscle are not clear. We used a combination of stable isotope labeling and arteriovenous difference measurements to elucidate pathways of postprandial fat deposition in adipose tissue and skeletal muscle in healthy humans. A test meal containing [U-(13)C]palmitate was combined with intravenous infusion of [(2)H(2)]palmitate to label plasma fatty acids and VLDL-triglyceride. Both dietary (chylomicron) and VLDL-triglyceride were cleared across adipose tissue and muscle, though with greater fractional extraction of the chylomicron-triglyceride. In adipose tissue there was significant uptake of plasma nonesterified fatty acids (NEFAs) in the postprandial but not the fasting state. However, this was minor in comparison with chylomicron-triglyceride fatty acids. We modeled the fate of fatty acids released by lipoprotein lipase (LPL). There was clear preferential uptake of these fatty acids compared with plasma NEFAs. In muscle, there was unexpected evidence for release of LPL-derived fatty acids into the plasma. With this integrative physiological approach, we have revealed hidden complexities in pathways of fatty acid uptake in adipose tissue and skeletal muscle.

Abdomen↗
PubMed2006

Dietary fatty acids make a rapid and substantial contribution to VLDL-triacylglycerol in the fed state.

Exaggerated postprandial lipemia is associated with coronary heart disease and type II diabetes, yet few studies have examined the effect of sequential meals on lipoprotein metabolism. We have used 13C-labeled fatty acids to trace the incorporation of fatty acid derived from a meal into apolipoprotein B-100 (apoB-100)-containing lipoproteins and plasma nonesterified fatty acids (NEFA) following two consecutive meals. Healthy volunteers (n=8) were given breakfast labeled with [1-(13)C]palmitic acid, eicosapentaenoic acid, and docosahexaenoic acid, followed 5 h later by lunch containing [1-(13)C]oleic acid. Blood samples were taken over a 9-h period. ApoB-100-containing lipoproteins were isolated by immunoaffinity chromatography. Chylomicron-triacylglycerol (TG) concentrations peaked at 195 min following breakfast but at 75 min following lunch (P<0.001). VLDL-TG concentrations, in contrast, rose to a broad peak after breakfast and then fell steadily after lunch. Breakfast markers followed chylomicron-TG concentrations and appeared in plasma NEFA with a similar profile, whereas [1-(13)C]oleic acid peaked 2 h after lunch in plasma TG and NEFA. Breakfast markers appeared steadily in VLDL, peaking 1-3 h after lunch, whereas [1-(13)C]oleic acid was still accumulating in VLDL at 9 h. Around 17% of VLDL-TG originated from recent dietary fat 5 h after breakfast, and around 40% at the end of the experiment. We conclude that there is rapid flux of fatty acids from the diet into endogenous pools. Further study of these processes may open up new targets for intervention to reduce VLDL-TG concentrations and postprandial lipemia.

Adult↗
PubMed2006

Fatty acid metabolism in adipose tissue, muscle and liver in health and disease.

Fat is the largest energy reserve in mammals. Most tissues are involved in fatty acid metabolism, but three are quantitatively more important than others: adipose tissue, skeletal muscle and liver. Each of these tissues has a store of triacylglycerol that can be hydrolysed (mobilized) in a regulated way to release fatty acids. In the case of adipose tissue, these fatty acids may be released into the circulation for delivery to other tissues, whereas in muscle they are a substrate for oxidation and in liver they are a substrate for re-esterification within the endoplasmic reticulum to make triacylglycerol that will be secreted as very-low-density lipoprotein. These pathways are regulated, most clearly in the case of adipose tissue. Adipose tissue fat storage is stimulated, and fat mobilization suppressed, by insulin, leading to a drive to store energy in the fed state. Muscle fatty acid metabolism is more sensitive to physical activity, during which fatty acid utilization from extracellular and intracellular sources may increase enormously. The uptake of fat by the liver seems to depend mainly upon delivery in the plasma, but the secretion of very-low-density lipoprotein triacylglycerol is suppressed by insulin. There is clearly cooperation amongst the tissues, so that, for instance, adipose tissue fat mobilization increases to meet the demands of skeletal muscle during exercise. When triacylglycerol accumulates excessively in skeletal muscle and liver, sometimes called ectopic fat deposition, then the condition of insulin resistance arises. This may reflect a lack of exercise and an excess of fat intake.

Adipose Tissue↗
PubMed2005

Obesity and metabolic disease: is adipose tissue the culprit?

Obesity is a risk factor for the development of type 2 diabetes and CVD. Is adipose tissue the culprit in the relationship between obesity and metabolic disease? It is certainly possible to argue that adipose tissue function is disturbed in obesity in such a way that adverse consequences may follow. For instance, lipolysis is down regulated, the sensitivity of lipolysis to insulin is reduced and there are disturbances in the regulation of adipose tissue blood flow. However, when examined critically these changes can be seen as adaptations to the increased adipose tissue mass, making the situation better rather than worse. In terms of the many peptide and other factors now known to be secreted from adipose tissue, it is easier to argue that adipose tissue is the culprit. However, for no single 'adipokine' is there as yet unequivocal evidence of a link between adipose tissue secretion and adverse metabolic events in other tissues. The best documented of these adipokines in relation to insulin resistance is adiponectin. Here, unusually, adiponectin confers insulin sensitivity, and its secretion is down regulated in obesity. It could be again that adipose tissue has down regulated its function in an attempt to compensate for its increased mass, although certainly that down-regulation is too extreme. On balance, it is clear that adipose tissue is a link in the chain of events leading to metabolic disease, but in many respects it is an innocent intermediary trying to deal with the consequences of positive energy balance, the real culprit.

Adiponectin↗
PubMed2005

Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism.

BACKGROUND: Resistant starch may modulate insulin sensitivity, although the precise mechanism of this action is unknown. OBJECTIVE: We studied the effects of resistant starch on insulin sensitivity and tissue metabolism. DESIGN: We used a 4-wk supplementation period with 30 g resistant starch/d, compared with placebo, in 10 healthy subjects and assessed the results by using arteriovenous difference methods. RESULTS: When assessed by euglycemic-hyperinsulinemic clamp, insulin sensitivity was higher after resistant starch supplementation than after placebo treatment (9.7 and 8.5 x 10(-2) mg glucose x kg(-1) x min(-1) x (mU insulin/L)(-1), respectively; P = 0.03); insulin sensitivity during the meal tolerance test (MTT) was 33% higher (P = 0.05). Forearm muscle glucose clearance during the MTT was also higher after resistant starch supplementation (P = 0.03) despite lower insulin concentrations (P = 0.02); glucose clearance adjusted for insulin was 44% higher. Subcutaneous abdominal adipose tissue nonesterified fatty acid (NEFA; P = 0.02) and glycerol (P = 0.05) release were lower with resistant starch supplementation, although systemic NEFA concentrations were not significantly altered. Short-chain fatty acid concentrations (acetate and propionate) were higher during the MTT (P = 0.05 and 0.01, respectively), as was acetate uptake by adipose tissue (P = 0.03). Fasting plasma ghrelin concentrations were higher with resistant starch supplementation (2769 compared with 2062 pg/mL; P = 0.03), although postprandial suppression (40-44%) did not differ significantly. Measurements of gene expression in adipose tissue and muscle were uninformative, which suggests effects at a metabolic level. The resistant starch supplement was well tolerated. CONCLUSION: These results suggest that dietary supplementation with resistant starch has the potential to improve insulin sensitivity. Further studies in insulin-resistant persons are needed.

Adipose Tissue↗
PubMed2005

Adipose tissue fatty acid metabolism and cardiovascular disease.

PURPOSE OF REVIEW: Fatty acid and triacylglycerol metabolism in adipose tissue may be involved in the generation of risk factors for cardiovascular disease and type 2 diabetes. Pharmaceutical companies are targeting adipocyte metabolism in their search for drugs for treating, or reducing the risk of, these conditions. We review new developments in adipose tissue fatty acid metabolism and how that might relate to cardiovascular disease. RECENT FINDINGS: Fatty acid release from human adipose tissue is oscillatory, with a period of about 12 min. Remarkably, oscillatory fatty acid release is also seen in isolated adipocytes. Further evidence has emerged that not all adipose depots are equal, and that lower-body adipose tissue may exert protective effects against cardiovascular disease. There have been a number of developments in the area of fatty acid handling by adipocytes. Fatty acid binding proteins are clearly important in regulating fatty acid metabolism, with striking protection against atherosclerosis in mice deficient in both the binding proteins expressed in adipocytes. The demonstration that adipocytes lacking hormone-sensitive lipase still display lipolysis has led to the identification of novel lipases that may play crucial roles in adipose tissue fatty acid metabolism. Further evidence has accrued of the interaction between hormone-sensitive lipase and perilipin, the protein that coats the adipocyte lipid droplet. SUMMARY: Recent developments in our understanding of adipose tissue fatty acid metabolism open up the possibility of new pharmaceutical targets. However, interference with adipose tissue fatty acid metabolism is not to be undertaken lightly and needs a clear understanding of the normal role of adipocyte lipolysis.

Adipose Tissue↗
PubMed2005

Oscillations of fatty acid and glycerol release from human subcutaneous adipose tissue in vivo.

We sought evidence for pulsatility of lipolysis in human subcutaneous adipose tissue in vivo. Arterialized and adipose tissue venous blood samples were drawn at 2-min intervals from nine healthy subjects. This procedure was repeated during hyperinsulinemic-euglycemic clamp to remove insulin pulsatility. We found evidence for pulsatile release of both nonesterified fatty acids (NEFAs) (seven of nine subjects) and glycerol (five of six subjects) with a period of approximately 12-14 min. This pulsatility was maintained even during the hyperinsulinemic clamp. Checks were made for spurious pulse detection, including the creation of "mock" venoarterialized differences by subtracting one subject's arterialized concentrations from another's venous; the peaks detected were less consistent in character than with real data (peak width, P = 0.006; peak interval, P < 0.004). Significant cross-correlations between NEFA and glycerol release also provided evidence of a real effect. Arterialized norepinephrine concentrations were also pulsatile, but the period did not match that of NEFA and glycerol release. Insulin concentrations were pulsatile with a typical period of 12 min, but this was not significantly cross-correlated with lipolysis. We conclude that release from adipose tissue of the products of lipolysis is pulsatile in humans.

Adipose Tissue↗
PubMed2005

Rosiglitazone increases indexes of stearoyl-CoA desaturase activity in humans: link to insulin sensitization and the role of dominant-negative mutation in peroxisome proliferator-activated receptor-gamma.

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and delta6- and delta5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and delta5-desaturase but not delta6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPARgamma carrier, SCD and delta5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPARgamma mutation supports a pivotal role of PPARgamma function in SCD regulation.

Diabetes Mellitus, Type 2↗
PubMed2004

The nicotinic acid receptor--a new mechanism for an old drug.

CONTEXT: Non-esterified fatty acids in plasma originate from adipose tissue. Delivery of fatty acids to the liver provides the substrate for VLDL triglycerides. Insulin-sensitive organs, overburdened by high concentrations of non-esterified fatty acids, may develop resistance to insulin action. In addition, insulin secretion from pancreatic beta-cells may be impaired by long-standing elevation of concentrations of non-esterified fatty acid in plasma. Normally, such concentrations fluctuate over the day depending on the transient suppression of lipolysis from adipose tissue by insulin released after meals. Diurnal concentrations of non-esterified fatty acid are often elevated in obesity, in particular in male-pattern upper-body fat accumulation. Nicotinic acid is the only drug that primarily lowers concentrations of non-esterified fatty acids and thereby lowers VLDL triglycerides. Nicotinic acid, or its analogues, seems to alleviate insulin resistance in the short-term whereas, paradoxically, the long-term effect is often the opposite. Suppression of lipolysis by nicotinic acid gives rise to a prominent rebound and the degree to which this occurs might explain this paradox. STARTING POINT: The exact cellular mechanism by which nicotinic acid exerts its antilipolytic effects has not been known until the recent discovery of a distinct G-protein coupled receptor. Nicotinic acid is a high affinity ligand, but the endogenous ligand is still unknown. Recently, Tina Rubic and colleagues (Biochem Pharmacol 2004; 67: 411-19) proposed a mechanism in which nicotinic acid stimulates cholesterol mobilisation from macrophages, thereby providing a potential link between regression of atherosclerosis and use of nicotinic acid. WHERE NEXT: Research on signalling through the nicotinic acid receptor might give rise to novel and more effective methods to interfere with fatty-acid metabolism, with insulin resistance, hyperlipidaemia, and atherosclerosis as target diseases.

Adipose Tissue↗
PubMed2004

Lipid metabolism.

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Cardiovascular Diseases↗
PubMed2003

Nitric oxide and beta-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans.

BACKGROUND: Blood flow mediates the metabolic and endocrine roles of adipose tissue. We have previously shown that the postprandial adipose tissue blood flow (ATBF) increase is dependent on insulin sensitivity. However, subcutaneous local insulin delivery had no demonstrable effect on either preprandial or postprandial ATBF. We hypothesized that insulin may act indirectly via sympathetic activation, mainly in the postprandial period, and that nitric oxide may be an overall major regulator of subcutaneous ATBF. METHODS AND RESULTS: We investigated the endogenous preprandial and postprandial regulation of ATBF by applying local tissue blockade of beta-adrenergic (propranolol), alpha-adrenergic (phentolamine and yohimbine), and nitric oxide (NG-monomethyl-L-arginine, L-NMMA) regulation of blood flow. Healthy subjects (body mass index, 18 to 31 kg/m2) were challenged with 75 g glucose for endogenous stimulation of ATBF. We used the novel "microinfusion" technique, which allows for simultaneous local delivery of pharmacological agents (or contralateral saline) and measurement of ATBF with the 133Xe washout method. Compared with control, the preprandial ATBF was not affected by propranolol but was increased by 21% (P<0.013) and 15% (P=0.004) with phentolamine and yohimbine, respectively. A decrease of 42% (2.97+/-0.33 versus 4.75+/-0.47 mL x min(-1) x 100 g tissue(-1), P<0.01) was seen with L-NMMA. The postprandial response was blunted by 58% (0.81+/-0.42 versus 1.90+/-0.44 mL x min(-1) x 100 g tissue(-1), P<0.004) with propranolol, but neither phentolamine, yohimbine, or L-NMMA altered this response. CONCLUSIONS: Nitric oxide seems to determine the absolute level of ATBF, whereas a major proportion of the postprandial enhancement of ATBF is under beta-adrenergic regulation in vivo in humans.

Adipose Tissue↗
PubMed2003

Selective partitioning of dietary fatty acids into the VLDL TG pool in the early postprandial period.

Circulating triacylglycerol (TG) arises mainly from dietary fat. However, little is known about the entry of dietary fat into the major TG pool, very low-density lipoprotein (VLDL) TG. We used a novel method to study the specific incorporation of dietary fatty acids into postprandial VLDL TG in humans. Eight healthy volunteers (age 25.4 +/- 2.2 years, body mass index 22.1 +/- 2.3 kg/m2) were fed a mixed meal containing 30 g fish oil and 600 mg [1-13C]palmitic acid. Chylomicrons and VLDL were separated using immunoaffinity against apolipoprotein B-100. The fatty acid composition of lipoproteins was analyzed by gas chromatography/mass spectrometry. [1-13C]palmitic acid started to appear in VLDL TG 3 h after meal intake, and a similar delay was observed for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Approximately 20% of dietary fatty acids entered the VLDL TG pool 6 h after meal intake. DHA was clearly overincorporated into this pool compared with [1-13C]palmitic acid and EPA. This seemed to depend on a marked elevation of this fatty acid in the nonesterified fatty acid pool. In summary, the contribution of dietary fatty acids to early postprandial VLDL TG is substantial. The role of DHA in VLDL TG production will require further investigation.

Adult↗
PubMed2003

Lipid metabolism.

Explore the source record for details and available documents.

Acyltransferases↗
PubMed2002

Physiological, metabolic, and performance implications of a prolonged hill walk: influence of energy intake.

We aimed to examine the effects of different energy intakes on a range of responses that are relevant to the safety of hill walkers. In a balanced design, 16 men completed a strenuous self-paced mountainous hill walk over 21 km, under either a low-energy (2.6 MJ; 616 kcal) intake (LEI) or high-energy (12.7 MJ; 3,019 kcal) intake (HEI) condition. During the hill walk, rectal temperatures were measured continuously, and blood samples for the analysis of metabolites and hormones were drawn before breakfast and immediately after the walk. Subjects also completed a battery of performance tests that included muscular strength, reaction times, flexibility, balance, and kinesthetic differentiation tests. During the LEI, mean blood glucose concentrations leveled off at the low-middle range of normoglycemia, whereas, on the HEI, they were significantly elevated compared with the LEI. The maintained blood glucose concentrations, during the LEI, were probably mediated via the marked fat mobilization, reflected by a two- to fivefold increase in nonesterified fatty acids, 3-hydroxybutyrate, and glycerol concentrations. The LEI group showed significantly slower one- and two-finger reaction time, had an impaired ability to balance, and were compromised in their ability to maintain body temperature, when compared with the HEI group. The modestly impaired performance (particularly with respect to balance) and thermoregulation during the LEI condition may increase susceptibility to both fatigue and injury during the pursuit of recreational activity outdoors.

Adult↗
PubMed2002

Novel experimental protocol to increase specific plasma nonesterified fatty acids in humans.

This study reports a novel protocol to increase plasma monounsaturated, polyunsaturated, and saturated nonesterified fatty acids (NEFA) in eight healthy volunteers (age 29-54 yr, body mass index 23-26 kg/m(2)). This was achieved by feeding small boluses of fat at different time points (35 g at 0 min and 8 g at 30, 60, 90, 120, 150, 180, and 210 min) in combination with a continuous low-dose heparin infusion. Olive oil, safflower oil, or palm stearin were used to increase monounsaturated, polyunsaturated, or saturated NEFAs, respectively. Plasma NEFA concentrations were increased for 2 h, when fat and heparin were given (olive oil: 745 +/- 35 micromol/l; safflower oil: 609 +/- 37 micromol/l, and palm stearin: 773 +/- 38 micromol/l) compared with the control test (no fat and no heparin: 445 +/- 41 micromol/l). During the heparin infusion, 18:1 n-9 was the most abundant fatty acid for the olive oil test compared with 18:2 n-6 for the safflower oil test and 16:0 for the palm stearin test (P < 0.01). The method described here successfully increases several types of plasma NEFA concentrations and could be used to investigate differential effects of elevated individual NEFAs on metabolic processes.

Adult↗