Increased postprandial fatty acid trapping in subcutaneous adipose tissue in obese women

The objective of this study was to test the hypothesis that increased fatty acid trapping by subcutaneous adipose tissue might contribute to the development and/or maintenance of obesity. To do so, venoarterial (V-A) gradients across subcutaneous adipose tissue for triglycerides, glycerol, nonesterified fatty acid (NEFA), and acylation-stimulating protein (ASP) were determined in eight lean females [body mass index (BMI), 22.2 ± 0.6] and eight obese females (BMI, 34.4 ± 3.4). Plasma insulin was also measured at intervals throughout this period. Fasting plasma triglyceride was significantly higher in the obese group and postprandial triglyceride was also significantly delayed. In contrast, both triglyceride clearance and fatty acid uptake by subcutaneous adipose tissue were significantly greater in the obese group compared with the lean group. Fasting insulin did not differ between the groups, but postprandial insulin values were significantly higher in the obese group. The pattern of ASP release from subcutaneous adipose tissue also appeared to differ in that it was significantly greater in the early postprandial period (0–90 min) in the obese group versus the lean group and this correlated with greater triglyceride clearance during this period. Moreover, there were strong, positive correlations between BMI and the V-A gradient for fasting ASP, the 0- to 90-min area under the curve (AUC) for ASP V-A gradient fasting insulin, and the 0- to 90-min AUC for fatty acid incorporation into adipose tissue. Taken together, these data demonstrate that fatty acid trapping by adipose tissue can be increased even when overall plasma triglyceride clearance is delayed. The postprandial pattern of insulin, in particular, was altered in the obese, although it is certainly possible that differences in ASP release or response could also contribute to increased fatty acid trapping in the obese. The data, therefore, suggest that increased fatty acid trapping by adipose tissue may be a feature of some forms of obesity.—Kalant, D., S. Phélis, B. A. Fielding, K. N. Frayn, K. Cianflone, and A. D. Sniderman. Increased postprandial fatty acid trapping in subcutaneous adipose tissue in obese women. J. Lipid Res. 2000. 41: 1963–1968. The objective of this study was to test the hypothesis that increased fatty acid trapping by subcutaneous adipose tissue might contribute to the development and/or maintenance of obesity. To do so, venoarterial (V-A) gradients across subcutaneous adipose tissue for triglycerides, glycerol, nonesterified fatty acid (NEFA), and acylation-stimulating protein (ASP) were determined in eight lean females [body mass index (BMI), 22.2 ± 0.6] and eight obese females (BMI, 34.4 ± 3.4). Plasma insulin was also measured at intervals throughout this period. Fasting plasma triglyceride was significantly higher in the obese group and postprandial triglyceride was also significantly delayed. In contrast, both triglyceride clearance and fatty acid uptake by subcutaneous adipose tissue were significantly greater in the obese group compared with the lean group. Fasting insulin did not differ between the groups, but postprandial insulin values were significantly higher in the obese group. The pattern of ASP release from subcutaneous adipose tissue also appeared to differ in that it was significantly greater in the early postprandial period (0–90 min) in the obese group versus the lean group and this correlated with greater triglyceride clearance during this period. Moreover, there were strong, positive correlations between BMI and the V-A gradient for fasting ASP, the 0- to 90-min area under the curve (AUC) for ASP V-A gradient fasting insulin, and the 0- to 90-min AUC for fatty acid incorporation into adipose tissue. Taken together, these data demonstrate that fatty acid trapping by adipose tissue can be increased even when overall plasma triglyceride clearance is delayed. The postprandial pattern of insulin, in particular, was altered in the obese, although it is certainly possible that differences in ASP release or response could also contribute to increased fatty acid trapping in the obese. The data, therefore, suggest that increased fatty acid trapping by adipose tissue may be a feature of some forms of obesity.—Kalant, D., S. Phélis, B. A. Fielding, K. N. Frayn, K. Cianflone, and A. D. Sniderman. Increased postprandial fatty acid trapping in subcutaneous adipose tissue in obese women. J. Lipid Res. 2000. 41: 1963–1968. It remains as unclear as ever whether any substantial proportion of those who become obese are metabolically programmed to do so. In particular, much remains to be learned in what ways, if at all, the obese differ from the nonobese with respect to the uptake and release of fatty acids from adipose tissue. In the postprandial period, dietary fatty acids are transported as chylomicron triglycerides (TG) and distributed among adipose tissue, muscle, and the liver. There is, necessarily, an inverse relationship between fatty acid trapping by adipose tissue and the delivery of fatty acids to the other two sites (1Sniderman A.D. Cianflone K. Arner P. Summers L. Frayn K. The adipocyte, fatty acid trapping, and atherogenesis.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 147-151Google Scholar). In particular, to the extent fatty acid trapping by adipose tissue is increased, delivery of fatty acids to the liver will be reduced and apolipoprotein B (apoB) secretion will be reduced as well. Therefore, in general, effective fatty acid trapping by adipose tissue is associated with normal plasma apoB. Until recently, attention has focused on insulin as the sole regulator of fatty acid trapping by adipose tissue. Moreover, there is a widely held view that obesity is associated with insulin resistance, although whether this applies to adipocytes as well as to glucose removal by skeletal muscle is not really clear (2Rabinowitz D. Some endocrine and metabolic aspects of obesity.Annu. Rev. Med. 1970; 21: 241-258Google Scholar, 3Howard B.V. Klimes I. Vasquez B. Brady D. Nagulesparan M. Unger R.H. The antilipolytic action of insulin in obese subjects with resistance to its glucoregulatory action.J. Clin. Endocrinol. Metab. 1984; 58: 544-548Google Scholar, 4Pei D. Chen Y.D. Hollenbeck C.B. Bhargava R. Reaven G.M. Relationship between insulin-mediated glucose disposal by muscle and adipose tissue lipolysis in healthy volunteers.J. Clin. Endocrinol. Metab. 1995; 80: 3368-3372Google Scholar). But insulin is not the only peptide that modulates adipose tissue fatty acid balance. Acylation-stimulating protein (ASP) is a 76-amino acid peptide that is the product of the interaction of three proteins secreted by adipose tissue: C3, adipsin, and factor B (5Baldo A. Sniderman A.D. St-Luce S. Avramoglu R.K. Maslowska M. Hoang B. Monge J.C. Bell A. Mulay S. Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis.J. Clin. Invest. 1993; 92: 1543-1547Google Scholar). In the initial reaction, a 77-amino acid peptide, C3a, is produced, after which the carboxy-terminal arginine is removed by carboxypeptidase B to produce C3adesArg or ASP. ASP stimulates adipocyte TG synthesis by increasing specific membrane transport of glucose and by increasing the activity of diacylglycerol acyltransferase, the enzyme that drives the last step in the synthesis of a TG molecule (6Germinario R. Sniderman A.D. Manuel S. Pratt S. Baldo A. Cianflone K. Coordinate regulation of triacylglycerol synthesis and glucose transport by acylation stimulating protein.Metabolism. 1993; 42: 574-580Google Scholar). ASP also reduces fatty acid release from human adipocytes by reducing hormone-sensitive lipase activity and by increasing re-esterification (7Van Harmelen V. Reynisdottir S. Cianflone K. Degerman E. Hoffstedt J. Nilsell K. Sniderman A. Arner P. Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation stimulating protein and insulin.J. Biol. Chem. 1999; 274: 18243-18251Google Scholar). Both effects, therefore, lead to greater entrapment of fatty acids in adipose tissue. Of importance, the effects of ASP are independent of, but additive to, those of insulin (8Cianflone K. Maslowska M. Sniderman A.D. Acylation stimulating protein (ASP), an adipocyte autocrine: new directions.Semin. Cell. Dev. Biol. 1999; 10: 31-41Google Scholar). Our initial study, which examined the in vivo release of ASP from normal human subcutaneous adipose tisssue, demonstrated that i) ASP was released after an oral fat load, ii) the release of ASP increased substantially in the second half of this period, and iii) TG clearance and fatty acid uptake paralleled the changes in ASP release (9Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google Scholar). Plasma insulin was also increased over this period and therefore both insulin and ASP could have contributed to the increase in fatty acid trapping by subcutaneous adipocytes that was evident in the postprandial period. Both insulin and ASP are increased in obesity and accordingly it seemed possible that obesity could be associated with increased fatty acid trapping. On the basis of the hypothesis outlined above, we reasoned that obese subjects with normal plasma apoB might manifest increased fatty acid trapping by adipose tissue. Therefore, the present study was designed to examine the effectiveness of postprandial fatty acid trapping in normal and obese females with normal plasma apoB. Sixteen female subjects were studied. Some data from some of the subjects have been included in other studies (10Summers L.K. Fielding B.A. Ilic V. Quinlan P.T. Frayn K.N. The effect of triacylglycerol-fatty acid positional distribution on postprandial metabolism in subcutaneous adipose tissue.Br. J. Nutr. 1998; 79: 141-147Google Scholar, 11Summers L.K. Fielding B.A. Herd S.L. Ilic V. Clark M.L. Quinlan P.T. Frayn K.N. Use of structured triacylglycerols containing predominantly stearic and oleic acids to probe early events in metabolic processing of dietary fat.J. Lipid Res. 1999; 40: 1890-1898Google Scholar). The subjects were divided into two groups: lean and obese, with a body mass index (BMI) cutoff of 25 kg/m2 for the lean (12Bray G.A. Pathophysiology of obesity.Am. J. Clin. Nutr. 1992; 55: 488S-494SGoogle Scholar). Their ages, BMI, and fasting lipid levels are shown in Table 1. All subjects fasted and drank only water for at least 12 h before the study. All studies were undertaken in a temperature-controlled room (23°C) and none of the subjects was taking any medication known to affect lipoprotein metabolism. All studies were approved by the Central Oxford Research Ethics Committee, and subjects gave their informed consent.TABLE 1.Fasting arterial values for lean and obese womenLean (n = 8)Obese (n = 8)PAge (years)42.0 ± 6.053.0 ± 3.0NSBMI22.2 ± 0.634.4 ± 3.40.0025ApoB (mg/dl)62.7 ± 4.686.0 ± 5.60.005Cholesterol (mM)4.4 ± 0.35.3 ± 0.40.05HDL cholesterol (mM)1.3 ± 0.11.0 ± 0.1NSASP (nM)58.1 ± 10.347.7 ± 6.9NSInsulin33.1 ± 2.143.4 ± 7.6NSTG (μM)885.0 ± 119.01,842.0 ± 373.00.025NEFA (μM)717.0 ± 78.0858.0 ± 26.0NSGlycerol (μM)71.7 ± 10.1104.7 ± 7.40.01All values were measured in arterial plasma except for glycerol, which was measured in whole blood. Values are reported as the mean ±standard error of the mean. Means were compared by unpaired t-testand the P values are indicated. Open table in a new tab All values were measured in arterial plasma except for glycerol, which was measured in whole blood. Values are reported as the mean ±standard error of the mean. Means were compared by unpaired t-testand the P values are indicated. Venoarterial (V-A) studies were conducted as previously described (13Frayn K.N. Coppack S.W. Humphreys S.M. Subcutaneous adipose tissue metabolism studied by local catheterization.Int. J. Obes. Relat. Metab. Disord. 1993; 17: S18-S21Google Scholar). In brief, a cannula was inserted retrogradely into a hand vein and the hand was warmed in a box at 60–70°C so that arterialized blood samples could be obtained. A 10-cm, 22-gauge catheter was then introduced over a guide wire into one of the superficial veins on the anterior abdominal wall and threaded toward the groin, so that its tip lay just superior to the inguinal ligament. Samples from this cannula represent the venous effluent from the subcutaneous abdominal adipose tissue, uncontaminated by muscle drainage and with only a minor contribution from skin. Both catheters were kept patent with saline and heparin was not administered. The subjects rested for at least 30 min after insertion of the catheters and before any samples were taken. They then ate a mixed meal containing 60 g of fat, 85 g of carbohydrate, and 13 g of protein and V-A blood samples were taken simultaneously at times 0, 30, 60, and 90 min as well as 2, 3, 4, 5, and 6 h after eating. The samples were centrifuged and plasma stored at –70°C. Plasma TG were measured enzymatically on an IL Monarch centrifugal analyzer (Instrumentation Laboratory, Warrington, Chesire, UK) with correction for free glycerol (14Humphreys S.M. Fisher R.M. Frayn K.N. Micromethod for measurement of sub-nanomole amounts of triacylglycerol.Ann. Clin. Biochem. 1990; 27: 597-598Google Scholar). Plasma total cholesterol was measured with a commercial enzymatic colorimetric Plasma nonesterified fatty acid was measured by an enzymatic apoB was measured by a apoB a commercial and and as previously described K. D. Sniderman A.D. The effect of acids on and secretion by Biol. Chem. Scholar). Plasma insulin was measured by a was measured in whole blood S.M. Frayn K.N. for of Chem. Scholar). ASP was as previously described (9Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google Scholar). The was the was acid incorporation into adipose tissue was as previously described (9Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google Scholar). All are as ± error of the mean. differences for the data were by of The area under the curve (AUC) was by a The were compared with an unpaired the data were not in which a test was V-A differences were for at and the values were differences are reported for TG so that the are were by product by the The of the two of study subjects are shown in Table 1. The obese subjects were the lean but the differences were not The BMI was by higher in the obese in the A of lipid as lipoprotein and glycerol were significantly higher in the obese group but mean values the normal ASP values were not significantly between the two groups, were higher in the lean M. S. Sniderman A.D. D. Cianflone K. Plasma acylation stimulating and in and obese J. Clin. Invest. 1999; Scholar). is for this but it to both the arterial and venous fasting insulin levels did not differ significantly between the two groups, although significantly higher values are in the obese P. The regulation of adipose tissue distribution in J. Obes. Scholar). The and differences across the subcutaneous adipose tissue for plasma TG for both are shown in 1. Plasma TG were significantly higher in the obese compared with the lean group The arterial TG AUC was also significantly greater in the obese compared with the lean ± ± P = and as be the gradient for that is, the in TG across the subcutaneous abdominal adipose tissue, in both over the postprandial period at except the last two the TG gradient was greater in the obese the although the differences were only at the overall AUC for TG gradient did not differ between the two ± ± the AUC from to 90 min was significantly greater in the obese compared with the lean ± ± P = are of when compared with ASP release by subcutaneous adipose tissue The lean subjects demonstrated increased release of ASP after the initial postprandial period, just as has been previously (9Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google Scholar). the was as to study (9Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google there was between ASP release in the and second of the postprandial period. There for the release of ASP to increase over in the obese at the Moreover, the AUC for ASP release as V-A was significantly greater in the 0- to 90-min period in the obese compared with the lean group ± ± the obese group both greater of ASP and greater plasma TG across the subcutaneous adipose tissue the lean in the early postprandial period. The V-A gradients for glycerol in both are shown in The AUC gradient was significantly greater in the obese compared with the lean group ± ± P = There were also differences in the insulin response between the during this period that fasting levels were plasma insulin increased substantially in the obese compared with the lean in the of the postprandial period = 0- to 90-min and these differences were so as to the total plasma insulin significantly by for the two = shown in 5, there was overall between the in of the V-A gradient for The V-A gradients for by 60 min into the postprandial period, and in the obese group this was in the of higher insulin levels in plasma and greater ASP release by shown in was significantly greater by in the obese in the lean to greater fatty acid trapping by adipose tissue in the obese in the was by the = is significantly greater in the obese in the lean as measured by = To examine the of obesity to the metabolism of subcutaneous adipose tissue correlations were BMI was significantly to a of the V-A gradient for fasting ASP = P 0- to 90-min AUC for ASP V-A gradient = P arterial fasting insulin = P gradient for fasting TG = P 0- to 90-min AUC for TG gradient = P postprandial in as area 0- to AUC = P 0- to 90-min AUC for glycerol V-A gradient = P 0- to 90-min AUC for = P The of this study were to examine whether fatty acid trapping was in subcutaneous adipose tissue in and if this was the whether there was also of increased activity of insulin and/or the ASP Our two of fatty acid trapping, the V-A TG gradient across the subcutaneous adipose tissue and fatty acid incorporation into were and greater in the obese in the lean In to fasting plasma insulin was not higher in the obese compared with the lean group P. The regulation of adipose tissue distribution in J. Obes. Scholar). it did higher in the early postprandial period in the obese subjects and this could certainly be in whole or in for the increased fatty acid trapping in the obese to ASP, in the lean ASP release by subcutaneous adipose tissue appeared to at the of the postprandial period. The differences were not of the but the is in with (9Saleh J. Summers L.K.M. Cianflone K. Fielding B.A. Sniderman A.D. Frayn K.N. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.J. Lipid Res. 1998; 39: 884-891Google Scholar). In contrast, in the obese ASP release did not over the postprandial period, to at the and during this period greater in the Moreover, there were positive and correlations between BMI and ASP increase in plasma insulin, and the of fatty acid trapping by adipose tissue. The of the data is that fatty acid trapping by adipose tissue, by insulin and/or ASP, is in this group of obese that the differences were in the early postprandial period, the that greater of TG from into adipocytes is involved be There are in the data that not be that fasting insulin levels are increased, and that was not in this study P. The regulation of adipose tissue distribution in J. Obes. Scholar). In plasma ASP levels were higher in the lean group previously and we have for this On the other ASP levels in the obese were to those previously and therefore the to any differences in ASP release between the two we is is even fatty acid trapping was increased, there was that the overall of postprandial TG clearance from plasma was in the obese group. the greater AUC for the arterial TG that it is, in delayed. is of In the it be that only a of TG is in adipose tissue during the postprandial period, the to muscle or the liver K.N. S. R. Humphreys S.M. Clark M.L. Fielding B.A. Coppack S.W. of fatty acid in human adipose tissue in the J. Scholar). There may not therefore, a between the overall of TG clearance from plasma and the effectiveness of fatty acid trapping by adipose tissue. obesity will increase the in adipose tissue over which can with lipoprotein lipase a that to increase the of dietary fatty acids adipose tissue. to is the of the clearance of from a chylomicron can be it to Our in studies have shown that on times the of lipoprotein for Cianflone K. D. Sniderman A.D. of to Lipid Res. 1999; 40: Scholar). On the other there are times chylomicron even at the of postprandial TG Therefore, even in as those in the will chylomicron clearance by increasing the for a chylomicron to to the effectiveness of fatty acid trapping by adipocytes is not determined by the of for a chylomicron to it is a of what the is and its and fatty acid uptake by adipocytes is The is mixed as to whether the obese are metabolically to be so, with for and this A metabolic has been reported in compared with those who were obese M. metabolic of versus lean metabolic and J. Clin. Nutr. 42: Scholar, J. B. J. A. metabolism in obese J. 1998; 274: Scholar, M. The metabolic of the and the J. Clin. Nutr. Scholar). It has also been reported that be reduced by from that in for the to at a normal J. in 1984; Scholar). Moreover, a to reduced of fat has also been reported A. and body fat in subjects with a to J. Obes. Relat. Metab. Disord. 1993; 17: Scholar, A. B. S. to increase lipid in response to increasing dietary fat in obese J. Scholar). On the other there is a substantial body of that to any metabolic between those who were obese and those who have not been A. J. A. for an postprandial response to a meal in to obesity.Am. J. Scholar, of Scholar, of obesity. of effect of and to of and Clin. Invest. 1995; Scholar, R. M. in obese before and after J. Obes. Relat. Metab. Disord. 1995; Scholar, R. M. Clark differences in of between and their lean J. Obes. Relat. Metab. Disord. 1992; Scholar). M. D. J. P. M. of human obesity on the metabolic of dietary and J. Clin. Nutr. 1998; a that a of dietary fatty acids was and a greater stored in obese compared with nonobese contrast, there was in the metabolic of which are not transported in plasma in that the differences with respect to the dietary fatty acids do to differences in the of by Our data, to those of also on these The plasma clearance of fatty acids in who as for obesity was compared with that of group of who been obese. of fatty acids was much in the previously obese. The that of fatty acids was not higher greater fatty acid trapping by In the present data demonstrate that subcutaneous adipose tissue in obese females in vivo TG and the fatty acids from adipose tissue in lean Moreover, the differences can be to greater postprandial in plasma insulin and to of the ASP in the obese was by to and by the of and to is a of the of apolipoprotein B acylation-stimulating protein area under the curve body mass index fatty acid incorporation into adipose tissue lipoprotein lipase nonesterified fatty acid triglyceride venoarterial

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