Postabsorptive Free Fatty Acid Research Articles

Storage of Circulating Free Fatty Acid in Adipose Tissue of Postabsorptive Humans

OBJECTIVEPreferential upper-body fat gain, a typical male pattern, is associated with a greater cardiometabolic risk. Regional differences in lipolysis and meal fat storage cannot explain sex differences in body fat distribution. We examined the potential role of the novel free fatty acid (FFA) storage pathway in determining body fat distribution in postabsorptive humans and whether adipocyte lipogenic proteins (CD36, acyl-CoA synthetases, and diacylglycerol acyltransferase) predict differences in FFA storage.RESEARCH DESIGN AND METHODSRates of postabsorptive FFA (palmitate) storage into upper-body subcutaneous (UBSQ) and lower-body subcutaneous (LBSQ) fat were measured in 28 men and 53 premenopausal women. Stable and radiolabeled palmitate tracers were intravenously infused followed by subcutaneous fat biopsies. Body composition was assessed with a combination of dual-energy X-ray absorptiometry and computed tomography.RESULTSWomen had greater FFA (palmitate) storage than men in both UBSQ (0.37 ± 0.15 vs. 0.27 ± 0.18 μmol · kg−1 · min−1, P = 0.0001) and LBSQ (0.42 ± 0.19 vs. 0.22 ± 0.11 μmol · kg−1 · min−1, P < 0.0001) fat. Palmitate storage rates were significantly greater in LBSQ than UBSQ fat in women, whereas the opposite was true in men. Plasma palmitate concentration positively predicted palmitate storage in both depots and sexes. Adipocyte CD36 content predicted UBSQ palmitate storage and sex-predicted storage in LBSQ fat. Palmitate storage rates per kilogram fat did not decrease as a function of fat mass, whereas lipolysis did.CONCLUSIONSThe FFA storage pathway, which had remained undetected in postabsorptive humans until recently, can have considerable, long-term, and sex-specific effects on body fat distribution. It can also offer a way of protecting the body from excessive circulating FFA in obesity.

Free fatty acid kinetics in the late phase of postexercise recovery: importance of resting fatty acid metabolism and exercise-induced energy deficit

Free fatty acid (FFA) availability increases several-fold during exercise and remains significantly elevated for at least 3 to 6 hours after exercise cessation. Little, however, is known regarding the duration of the postexercise rise in FFA flux. In the present study, we used stable isotope–labeled palmitate infusion to examine fatty acid metabolism in 27 healthy untrained men and women (age, 29 ± 7 years; body mass index, 25 ± 4 kg/m2) between 13 to 16 hours and 21 to 24 hours after a single bout of moderate-intensity endurance exercise (1-2 hours at 60% of peak oxygen consumption), performed in the evening, and after a time-matched resting trial. Postabsorptive FFA rate of appearance (Ra) and FFA concentration in plasma were significantly greater after exercise than rest throughout the recovery period (P < .015), but the exercise-induced increases declined from approximately 40% at 13 to 16 hours to approximately 10% at 21 to 24 hours postexercise (P = .001). The magnitude of the exercise-induced increase in plasma FFA concentration was proportional to the increase in FFA Ra. Correlation analysis demonstrated that exercise-induced changes in plasma FFA Ra at 13 to 16 hours are (1) negatively associated with resting plasma FFA Ra and (2) positively associated with the net energy expenditure of exercise and the exercise-induced changes in whole-body fat oxidation rate (all P values < .05). In multivariate stepwise linear regression analysis, baseline plasma FFA Ra (P ≤ .008) and net energy expenditure of exercise (P ≤ .005) independently predicted the exercise-induced change in plasma FFA Ra at 13 to 16 hours. We conclude that the exercise-induced increase in FFA mobilization is (1) long-lived, persisting for 12 to 24 hours after exercise, with a progressive decline with time; (2) greater in subjects with low than high resting plasma FFA availability; and (3) greater after exercise with high than low energy demand.

The effect of carbohydrate and fat variation in euenergetic diets on postabsorptive free fatty acid release.

Diet composition and energy content modulate free fatty acid (FFA) release. The aim of this study was to evaluate the dose-response effects of euenergetic variations in dietary carbohydrate and fat content on postabsorptive FFA release. The rate of appearance (Ra) of palmitate was measured by infusion of [2,2-2H2]palmitate after an overnight fast in six healthy men on three separate occasions, i.e. after 7 d on euenergetic control, high-carbohydrate and high-fat diets. The protein content and composition was identical for each diet. Postabsorptive plasma fatty acid concentrations were not different between the high-carbohydrate and control diets (0.36 (se 0.07) v. 0.43 (se 0.04) mmol/l), but were increased after the high-fat diet (0.75 (se 0.09) mmol/l, (P<0.01 compared with the other diets). Ra palmitate was not different between the high-carbohydrate and control diets (1.36 (se 0.20) v. 1.47 (se 0.15) micromol/kg per min). However, Ra palmitate was increased to 2.36 (se 0.26) micromol/kg per min after the high-fat diet (P<0.01 compared with the other diets). The fatty acid flux and whole-body fat oxidation were not affected by the high-carbohydrate diet compared with the control diet, but were increased by 67 and 47 % respectively, on the high-fat diet (P<0.01 compared with the other diets). A euenergetic high-fat diet results in increased postabsorptive FFA release and fat oxidation, whereas a euenergetic high-carbohydrate diet does not affect these variables of fat metabolism.

The effect of carbohydrate and fat variation in euenergetic diets on postabsorptive free fatty acid release

Diet composition and energy content modulate free fatty acid (FFA) release. The aim of this study was to evaluate the dose–response effects of euenergetic variations in dietary carbohydrate and fat content on postabsorptive FFA release. The rate of appearance (Ra) of palmitate was measured by infusion of [2,2-2H2]palmitate after an overnight fast in six healthy men on three separate occasions, i.e. after 7 d on euenergetic control, high-carbohydrate and high-fat diets. The protein content and composition was identical for each diet. Postabsorptive plasma fatty acid concentrations were not different between the high-carbohydrate and control diets (0·36 (SE 0·07) V. 0·43 (se 0·04) mmol/l), but were increased after the high-fat diet (0·75 (se 0·09) mmol/l, (P&lt;0·01 compared with the other diets). Ra palmitate was not different between the high-carbohydrate and control diets (1·36 (se 0·20) v. 1·47 (se 0·15) μmol/kg per min). However, Ra palmitate was increased to 2·36 (se 0·26) μmol/kg per min after the high-fat diet (P&lt;0·01 compared with the other diets). The fatty acid flux and whole-body fat oxidation were not affected by the high-carbohydrate diet compared with the control diet, but were increased by 67 and 47 % respectively, on the high-fat diet (P&lt;0·01 compared with the other diets). A euenergetic high-fat diet results in increased postabsorptive FFA release and fat oxidation, whereas a euenergetic high-carbohydrate diet does not affect these variables of fat metabolism.

In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia

Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL). As enhanced free fatty acid (FFA) flux to the liver may be one of the determinants of VLDL overproduction, we studied FFA changes and products of hepatic FFA metabolism in response to a 24-h oral fat loading test (50 g/m2) in 7 FCHL subjects and 7 matched control subjects. The response to the meal was subdivided into a postprandial (up to 8 h after ingestion of the meal) and postabsorptive period (from 8 to 24 h). Although postheparin plasma lipolytic activities were not different between both groups, the postprandial FFA area under the curve (FFA-AUC) and FFA incremental area under the curve (FFA-dAUC) were higher in FCHL subjects than in control subjects (6.05 ± 0.45 vs. 3.43 ± 0.46 and 2.60 ± 0.49 vs. 0.96 ± 0.31 mmol·h/L, respectively; P < 0.01 for each). The postprandial increase in ketone bodies was almost four times higher in FCHL patients. As ketogenesis occurs predominantly in hepatocytes, these findings suggest that during the postprandial period in FCHL an increased flux of FFA to the liver occurs, possibly because of inadequate incorporation of FFA into triglycerides (TGs) in adipocytes. In the postabsorptive period, FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased. These results may represent a diminished release of FFA from adipocytes by hormone-sensitive lipase (HSL) in FCHL patients. The decrease in postabsorptive FFA and ketone bodies in FCHL patients could not be explained by insulin-mediated inhibition of HSL, as both FCHL subjects and control subjects had similar postabsorptive insulin concentrations, which were below fasting concentrations.This study provides in vivo evidence of impaired metabolism of postprandial FFA in FCHL, which may explain in part the hepatic VLDL overproduction characteristic of FCHL subjects.

Regional postprandial fatty acid metabolism in different obesity phenotypes.

To examine if postprandial splanchnic/hepatic free fatty acid (FFA) delivery is increased in upper-body (UB) obesity, and to determine the adipose tissue depots responsible for the greater postprandial FFA availability, we measured systemic and regional uptake and release of FFAs ([1-(14)C]palmitate) before and during a 5-h frequent-feeding mixed meal in eight UB and eight lower-body (LB) obese women. Postabsorptive FFA flux and splanchnic FFA delivery were not different in UB and LB obese women; however, postprandial FFA concentrations (257 +/- 45 vs. 81 +/- 12 micromol/l, P < 0.0001), FFA flux (8.5 +/- 1.2 vs. 3.9 +/- 0.8 micromol x kg(-1) fat-free mass x min(-1), P < 0.0001), splanchnic FFA delivery (275 +/- 45 vs. 88 +/- 24 micromol/min, respectively, P < 0.005), and estimated hepatic FFA delivery were greater in UB than LB obese women. Nonsplanchnic UB adipose tissue FFA release was greater in UB than in LB obese women (276 +/- 71 vs. 97 +/- 37 micromol/min, respectively, P < 0.05) and accounted for the greater postprandial FFA availability in UB obesity. Postprandial leg glucose uptake was less in UB than in LB obese women (8.4 +/- 5.1 vs. 22.9 +/- 2.6 micromol x kg(-1) leg fat-free mass x min(-1), P < 0.05). We conclude that the elevated postprandial FFA release observed in UB obese women originates from the nonsplanchnic UB fat, not visceral fat. These results suggest that visceral fat may be a marker for, but not the source of, excess postprandial FFAs in obesity.

Contribution of leg and splanchnic free fatty acid (FFA) kinetics to postabsorptive FFA flux in men and women

We have previously shown that upper-body adipose tissue is more lipolytically active than lower-body adipose tissue in lean and obese women. The present studies were conducted to determine whether these regional differences are also present in men. Twenty-five lean, healthy men and 24 lean, healthy women underwent measures of body composition, postabsorptive systemic free fatty acid (FFA) flux, and leg and splanchnic FFA uptake and release. Upper-body adipose tissue was more lipolytically active than lower-body adipose tissue in both men (53.4 ± 32.2 ν 26.6 ± 12.9 μmol · kg fat −1 · min −1, P < .001, respectively) and women (41.2 ± 22.3 ν 18.4 ± 8.2 μmol · kg fat -1 P < .001, respectively). The correlations between leg FFA release and systemic FFA flux were modest in women and men ( r = .38, P = .07 and r = .56, P = .003, respectively) as were the correlations between splanchnic FFA release and systemic FFA flux ( r = .41, P = .06 and r = .40, P = .07, respectively). No effect of gender on the relationship between leg or splanchnic FFA release and systemic FFA flux was detected. In summary, upper-body FFA release is greater than lower-body FFA release in both men and women, and the relationship between leg or splanchnic FFA release and systemic FFA release is weak and similar in men and women. These findings suggest that regional differences in postabsorptive FFA kinetics are unlikely to be responsible for differences in regional fat distribution.

Hepatic insulin action in adolescents with insulin-dependent diabetes mellitus: Relationship with long-term glycemic control

The relationship between hepatic insulin action and long-term glycemic control was assessed in 20 adolescents with insulin-dependent diabetes mellitus (IDDM) and five healthy matched controls using a two-step (0.8 and 1.6 mU/kg/min) hyperinsulinemic-euglycemic clamp and [6,6- 2H 2]glucose. The night before the study, diabetic patients received variable-rate intravenous insulin in an attempt to normalize fasting plasma glucose concentrations. In the postabsorptive state, hepatic glucose production (HGP) was similar in IDDM patients and controls (593 ± 40 v 518 ± 27 μmol/m 2/min); however, plasma glucose and free insulin concentrations were higher in IDDM patients than in controls (6.5 ± 0.4 v 5.4 ± 0.1 mmol/L [ P = .01], and 207 ± 21 v 104 ± 10 pmol/L [ P < .001], respectively). There was a positive correlation ( r = .62 P = .002) between basal HGP and glucohemoglobin level (HbA 1). Separation of the patients at the median HbA 1 (group no. 1 < and group no. 2. > 11.4% HbA 1) revealed two distinct patient populations with regard to hepatic and peripheral insulin action and plasma free fatty acid (FFA) suppression. During hyperinsulinemia, the percent suppression of HGP was lower in group no. 2 compared with group no. 1 (65.7% ± 9.8% v 94.4% ± 3.8%; P = .018). Rates of glucose disposal were lower in group no. 2 compared with controls and with group no. 1. Postabsorptive FFA levels were similar between group no. 2 and group no. 1 (0.45 ± 0.03 and 0.43 ± 0.04 mmol/L) despite higher free-insulin concentrations in group no. 2 (260 ± 30 v 171 ± 25 pmol/L; P = .04). Hyperinsulinemia in group no. 2 did not produce a significant decrease in FFA levels, unlike group no. 1 and controls. Group no. 2 patients compared with group no. 1 patients had higher basal growth hormone (GH) levels (8.5 ± 1.6 v 3.0 ± 0.9 μg/L; P = .008). We conclude that (1) poorly controlled adolescents with IDDM have significant degrees of hepatic insulin resistance, (2) insulin action in suppressing FFA levels in impaired in these adolescents, and (3) long-term glycemic/metabolic control adversely affects hepatic insulin action, possibly through elevated GH levels.