Leanne Hodson

Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake.

Accurate assessment of fat intake is essential to examine the relationships between diet and disease risk but the process of estimating individual intakes of fat quality by dietary assessment is difficult. Tissue and blood fatty acids, because they are mainly derived from the diet, have been used as biomarkers of dietary intake for a number of years. We review evidence from a wide variety of cross-sectional and intervention studies and summarise typical values for fatty acid composition in adipose tissue and blood lipids and changes that can be expected in response to varying dietary intake. Studies in which dietary intake was strictly controlled confirm that fatty acid biomarkers can complement dietary assessment methodologies and have the potential to be used more quantitatively. Factors affecting adipose tissue and blood lipid composition are discussed, such as the physical properties of triacylglycerol, total dietary fat intake and endogenous fatty acid synthesis. The relationship between plasma lipoprotein concentrations and total plasma fatty acid composition, and the use of fatty acid ratios as indices of enzyme activity are also addressed.

Stearoyl-CoA desaturase: rogue or innocent bystander?

Different lipid fractions in humans have characteristic fatty acid profiles and these are maintained partly through diet and to a lesser extent through endogenous synthesis. The enzyme stearoyl-CoA desaturase (SCD; EC 1.14.99.5) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids such as palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9). These are the two most abundant monounsaturated fatty acids in human plasma lipids, membranes and adipose tissue. Although in quantitative terms, the endogenous synthesis of fatty acids in humans is not great in most circumstances, it is becoming increasingly evident that SCD plays important structural and metabolic roles. In addition, 16:1 n-7 has been purported to act as a beneficial lipokine in an animal model. Research in humans has relied on indirect measurements of SCD1 activity and therefore, much of our understanding has come from work on animal models. However, results have been somewhat counterintuitive and confusing, so the purpose of this review is to try to summarise our current understanding of this fascinating enzyme.

Fasted to Fed Trafficking of Fatty Acids in Human Adipose Tissue Reveals a Novel Regulatory Step for Enhanced Fat Storage

CONTEXTnAbsence or excess of adipose tissue are both associated with metabolic complications, implying the importance of well-functioning adipose tissue present in normal amounts. Adipose tissue sequesters dietary fat and thus protects other tissues from excess fat exposure, especially after meals.nnnOBJECTIVEnThe objective of the study was the use of an integrative physiological technique to quantify trafficking of fatty acids (FAs) in adipose tissue over a 24 h period.nnnMETHODSnAdipose tissue FA handling was studied in response to three meals in eight healthy men by the combination of arteriovenous blood sampling, tissue blood flow, and specific labeling of FA tracing of exogenous and endogenous fat by stable isotope methodology.nnnRESULTSnThe efficiency of adipose tissue FA uptake increased robustly with each meal. Chylomicron-triglyceride was the dominating source of FA. Adipose tissue fractional extraction of chylomicron-triglyceride increased from 21 +/- 4 to 47 +/- 8% (P = 0.03) between the first and last meal. Although adipose tissue lipoprotein lipase action increased with time (2-fold), there was an even greater increase in FA reesterification (3-fold), which led to a reduced spillover of chylomicron-derived FA, from 77 +/- 15 to 34 +/- 7% (P = 0.04) comparing the end of the first and the third meal period. Increased uptake of very low-density lipoprotein-derived FA was observed, but spillover of very low-density lipoprotein-derived FA was seen only in the fasting state.nnnCONCLUSIONnHuman adipose tissue has a significant potential to up-regulate fat storage during a normal day that goes beyond increased lipoprotein lipase activation. The adaptation toward increasing fat storage may provide an explanation for the beneficial properties of normal amounts of adipose tissue.

Chronic Palmitate Exposure Inhibits Insulin Secretion by Dissociation of Ca2+ Channels from Secretory Granules

Summary Long-term (72 hr) exposure of pancreatic islets to palmitate inhibited glucose-induced insulin secretion by >50% with first- and second-phase secretion being equally suppressed. This inhibition correlated with the selective impairment of exocytosis evoked by brief (action potential-like) depolarizations, whereas that evoked by long (∼250 ms) stimuli was unaffected. Under normal conditions, Ca2+ influx elicited by brief membrane depolarizations increases [Ca2+]i to high levels within discrete microdomains and triggers the exocytosis of closely associated insulin granules. We found that these domains of localized Ca2+ entry become dispersed by long-term (72 hr), but not by acute (2 hr), exposure to palmitate. Importantly, the release competence of the granules was not affected by palmitate. Thus, the location rather than the magnitude of the Ca2+ increase determines its capacity to evoke exocytosis. In both mouse and human islets, the palmitate-induced secretion defect was reversed when the β cell action potential was pharmacologically prolonged.

The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women: Studies in the Postprandial State

OBJECTIVE—We aimed to determine differences in the postprandial contributions of different fatty acid sources to VLDL triglycerides (TGs) in healthy men and women with varying degrees of insulin resistance. RESEARCH DESIGN AND METHODS—Insulin-resistant (n = 11) and insulin-sensitive (n = 11) men and women (n = 6) were given an intravenous infusion of [2H2]palmitic acid to investigate systemic nonesterified fatty acid (NEFA) incorporation into VLDL TGs. Participants were also fed a mixed meal containing [U-13C]palmitic acid to investigate the contribution of dietary fatty acids to VLDL TG production. Blood samples were taken over the following 6 h. Separation of VLDL was performed by density gradient ultracentrifugation and immunoaffinity techniques specific to apolipoprotein B-100. RESULTS—Insulin-resistant and insulin-sensitive men had similar postprandial chylomicron and chylomicron remnant TG concentrations, but insulin-resistant men had higher postprandial VLDL TG concentrations (median [range]; area under the curve 485 μmol/l [123–992] vs. 287 μmol/l [162–510]; P < 0.05). At 360 min, most of the difference in VLDL TGs was accounted for by an additional contribution from splanchnic fat (means ± SE; 331 ± 76 μmol/l vs. 89 ± 25 μmol/l; P < 0.01). The contribution of fatty acids from endogenous systemic NEFAs was similar across the groups, as were dietary fatty acids. There was no difference in the VLDL TG concentration or the contribution of different fatty acid sources between insulin-sensitive men and women. CONCLUSIONS—In the postprandial period, the only sources of fatty acids for VLDL TG production to differ in the insulin-resistant compared with the insulin-sensitive men are those derived from splanchnic sources.

Gluteofemoral Adipose Tissue Plays a Major Role in Production of the Lipokine Palmitoleate in Humans

The expansion of lower-body adipose tissue (AT) is paradoxically associated with reduced cardiovascular disease and diabetes risk. We examined whether the beneficial metabolic properties of lower-body AT are related to the production and release of the insulin-sensitizing lipokine palmitoleate (16:1n-7). Using venoarterial difference sampling, we investigated the relative release of 16:1n-7 from lower-body (gluteofemoral) and upper-body (abdominal subcutaneous) AT depots. Paired gluteofemoral and abdominal subcutaneous AT samples were analyzed for triglyceride fatty acid composition and mRNA expression. Finally, the triglyceride fatty acid composition of isolated human preadipocytes was determined. Relative release of 16:1n-7 was markedly higher from gluteofemoral AT compared with abdominal subcutaneous AT. Stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in endogenous 16:1n-7 production, was more highly expressed in gluteofemoral AT and was associated with greater enrichment of 16:1n-7. Furthermore, isolated human preadipocytes from gluteofemoral AT displayed a higher content of SCD1-derived fatty acids. We demonstrate that human gluteofemoral AT plays a major role in determining systemic concentrations of the lipokine palmitoleate. Moreover, this appears to be an inherent feature of gluteofemoral AT. We propose that the beneficial metabolic properties of lower-body AT may be partly explained by the intrinsically greater production and release of palmitoleate.

Differences in partitioning of meal fatty acids into blood lipid fractions: a comparison of linoleate, oleate, and palmitate

There has been much interest in the health effects of dietary fat, but few studies have comprehensively compared the acute metabolic fate of specific fatty acids in vivo. We hypothesized that different classes of fatty acids would be variably partitioned in metabolic pathways and that this would become evident over 24 h. We traced the fate of fatty acids using equal amounts of [U-13C]linoleate, [U-13C]oleate, and [U-13C]palmitate given in a test breakfast meal in 12 healthy subjects. There was a tendency for differences in the concentrations of the tracers in plasma chylomicron-triacylglycerol (TG) (oleate > palmitate > linoleate). This pattern remained in plasma nonesterified fatty acid (NEFA) and very low-density lipoprotein (VLDL)-TG (P ≤ 0.01 and P ≤ 0.02 for [U-13C]oleate vs. both [U-13C]palmitate and [U-13C]linoleate for NEFA and VLDL-TG, respectively). There was significantly more [U-13C]linoleate than the other two tracers in plasma cholesteryl ester and phospholipid (PL). Using the values for isotopic enrichment in the different lipid fractions compared with the test meal, we calculated the contribution of meal fatty acids to the respective fractions. At 24 h, 10% of plasma PL-linoleate originated from the breakfast test meal. This was significantly greater than for oleate and palmitate (both 3 ± 0.3%; P < 0.05). This pattern was also true for erythrocyte PL fatty acids. The marked rapid incorporation of linoleate from a single meal into blood PL fractions may have functional consequences such as maintenance of membrane fluidity and may explain why linoleate is a useful biomarker of dietary intake.

Substrate Utilization by the Failing Human Heart by Direct Quantification Using Arterio-Venous Blood Sampling

Metabolic substrate utilization of the human failing heart is an area of controversy. The purpose of this study is to directly quantify myocardial substrate utilization in moderately severe heart failure, type 2 diabetes and healthy controls using simultaneous coronary sinus and arterial blood sampling. Patients with heart failure (nu200a=u200a9, mean NYHA 2.7±0.5), with type 2 diabetes (nu200a=u200a5) and with normal heart function (nu200a=u200a10) were studied after an overnight fast in connection with electrophysiological investigations/treatments. A systemic infusion of [2H2]palmitate allowed for the calculation of absolute palmitate extraction across the heart. Blood samples were analysed for non-esterified fatty acids, triacylglycerol, glycerol, glucose, pyruvate, lactate, 3-hydroxybutyrate, and blood gases after simultaneous sampling of arterial and coronary sinus blood. Arterio-coronary sinus metabolite concentration differences and fractional extractions for all substrates were similar between the groups. The absolute NEFA uptakes assessed by [2H2]palmitate extraction were also similar between the groups. Using direct measurements of metabolic substrate uptake by arterio-venous difference technique, the compensated human failing heart does not appear to have reduced myocardial fatty acid uptake.

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Background Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low‐density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre‐ and postmenopausal women. Methods and Results We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 versus 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 versus 142±13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride‐enriched (production ratio of VLDL 2‐ triglyceride:apolipoprotein B 30±5.3 versus 19±1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (r s=−0.49, P=0.006), de novo lipogenesis (r s=0.55, P=0.003), and desaturation (r s=0.48, P=0.012) were closely correlated with abdominal obesity‐driven large VLDL‐triglyceride secretion rate. Conclusions In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.

Preeclampsia is associated with compromized maternal synthesis of long chain polyunsaturated fatty acids leading to offspring deficiency

Obesity and excessive lipolysis are implicated in preeclampsia (PE). Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with PE (n=62) or intrauterine growth restriction (n=23) compared with healthy pregnancies (n=164). Markers of lipid metabolism and erythrocyte fatty acid concentrations were measured. Maternal adipose tissue fatty acid composition and mRNA expression of adipose tissue fatty acid–metabolizing enzymes and placental fatty acid transporters were compared. Mothers with PE had higher plasma triglyceride (21%, P<0.001) and nonesterified fatty acid (50%, P<0.001) concentrations than controls. Concentrations of major n−6 and n−3 long-chain polyunsaturated fatty acids in erythrocytes were 23% to 60% lower (all P<0.005) in PE and intrauterine growth restriction mothers and offspring compared with controls. Subcutaneous adipose tissue &Dgr;−5 and &Dgr;−6 desaturase and very long-chain fatty acid elongase mRNA expression was lower in PE than controls (respectively, mean [SD] control 3.38 [2.96] versus PE 1.83 [1.91], P=0.030; 3.33 [2.25] versus 1.03 [0.96], P<0.001; 0.40 [0.81] versus 0.00 [0.00], P=0.038 expression relative to control gene [square root]). Low maternal and fetal long-chain polyunsaturated fatty acid concentrations in PE may be the result of decreased maternal synthesis.