Fat oxidation and plasma removal capacity of an intravenous fat emulsion in elderly and young men

Nutrition 22 (2006) 738 –743 www.elsevier.com/locate/nut

Applied nutritional investigation

Fat oxidation and plasma removal capacity of an intravenous fat emulsion in elderly and young men Wiveca Åberg, R.N.a,b, Anders Thörne, M.D., Ph.D.c, Thomas Olivecrona, M.D., Ph.D.d, and Jorgen Nordenström, M.D., Ph.D.a,b,* b

a Department of Surgery, Karolinska University Hospital-Solna, Stockholm, Sweden Department of Molecular Medicine and Surgery, Karolinska University Hospital-Huddinge, Clintec, Karolinska Institutet, Stockholm, Sweden c Department of Surgery, Karolinska University Hospital-Huddinge, Clintec, Karolinska Institutet, Stockholm, Sweden d Department of Medical Biosciences, Physiological Chemistry, Umeå University, Umeå, Sweden

Manuscript received November 1, 2005; accepted April 23, 2006.

Abstract

Objective: We explored metabolic and thermogenic responses to exogenous fat in relation to age as a basis for a rational design of parenteral nutrition in elderly patients. Methods: Ten healthy elderly men (70 –78 y of age, body mass index 21–27 kg/m2) and 10 healthy young men (19 – 45 y of age, body mass index 19 –26 kg/m2) were studied with a hypertriglyceridemic clamp (primed infusion of a long-chain triacylglycerol emulsion to reach and stabilize at a triacylglycerol concentration of 4 mmol/L for 180 min). Continuous indirect calorimetry was carried out in the basal state and throughout the study period. Results: The infusion rates required to maintain plasma triacylglycerol levels at 4 mmol/L were similar in elderly and young individuals (mean ⫾ SEM 0.201 ⫾ 0.027 versus 0.203 ⫾ 0.014 mmol/min, not significant). Plasma concentrations of free fatty acids and ␤-OH-butyrate were higher in the elderly before the infusion and increased in a similar manner in both groups during infusion. Energy expenditure at baseline was higher in the young than in the elderly (79 ⫾ 2 versus 64 ⫾ 3 kcal/h; P ⬍ 0.001), although the respiratory quotient was similar in the two groups (0.80 ⫾ 0.01 versus 0.78 ⫾ 0.01, not significant). During lipid administration there was a similar increase in energy expenditure in the old and young individuals (⫹9.0 ⫾ 1.3% versus ⫹6.0 ⫾ 1.8%, not significant). Lipid infusion resulted in similar increments in fat oxidation in the young and elderly (23.9 ⫾ 7.0% versus 15.1 ⫾ 4.9%, respectively, not significant). Plasma lipoprotein lipase activity was almost three times higher in the young than in the elderly subjects (0.23 ⫾ 0.02 versus 0.65 ⫾ 0.09 mU/mL, respectively, P ⬍ 0.001). During lipid infusion, a similar increment (four- to five-fold) in plasma lipoprotein lipase activity was noted in the two groups. Conclusions: Elderly healthy men have a similar capacity as young healthy men to clear and oxidize a high triacylglycerol load administered as a hypertriglyceridemic clamp. © 2006 Elsevier Inc. All rights reserved.

Keywords:

Age; Elimination rate; Fatty acids; Indirect calorimetry; Long-chain fatty acid triacylglycerol; Lipoprotein lipase; Randomized, controlled trial

Introduction Advancing age is accompanied by several metabolic alterations such as a decrease in energy expenditure (due

This work was supported by grants from the Karolinska Institute, the Swedish Society of Medicine, and the Swedish Research Council (grant 03X-727). * Corresponding author. Tel.: ⫹46-8-51773355; fax: ⫹46-8-331587. E-mail address: (J. Nordenström)[email protected] 0899-9007/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2006.04.010

to a lower basal metabolic rate and a lower activityrelated energy expenditure) [1,2], a reduction of lean body mass [3], and an increased proportion of body fat [4]. Knowledge of the metabolic and thermogenic responses to nutrients in relation to age is of clinical importance, e.g., for our understanding of nutritional requirements in old age and for the administration of adequate nutrition in elderly patients. The elderly comprise a large proportion of hospitalized patients in need of artificial nutritional support. Pre-

W. Åberg et al. / Nutrition 22 (2006) 738 –743

scriptions are often based on weight, height (or derivatives of these), and requirements related to the patient’s specific disease. Further, clinical and experimental studies underlying current nutritional recommendations are largely based on observations in heterogeneous groups of patients or, for experimental studies, in young (usually male) healthy volunteers. Considerations related to age-specific changes seem to be taken into account less often when prescribing nutritional regimes. Decreased capacity to use fat as fuel may theoretically be an important factor in older individuals because they have a smaller skeletal muscle mass, which is the primary site for fat oxidation [5,6]. Toth and Tchernof [7] recently reviewed the effect of age on lipid metabolism. Previous studies have documented several changes in the metabolism of lipids in the elderly population, which include a lesser lipolytic capacity of endogenous fat stores and a lesser capacity to oxidize fat [5,7]. Further, lesser wholebody fat oxidation capacity has been documented by several investigators [8,9]. However, the possible consequences of these observed changes on the metabolic handling of fat emulsions in the elderly are unknown. This study determined the intravenous lipid elimination capacity as measured by a hypertriglyceridemic (HTG) clamp technique, with simultaneous determination of the potentially rate-limiting enzyme lipoprotein lipase (LPL) and measurement of substrate oxidation by indirect calorimetry.

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arterialized blood sampling, by placing the hand in a heated box with the temperature automatically held at 60 – 65°C. No heparin was used to maintain catheter permeability. During the investigations, subjects rested in a recumbent position and at an ambient temperature of 22°C. After placing the subject’s head in a ventilated plastic hood, respiratory gas exchange was continuously measured for 1 h in the basal resting state and then during administration of a fat emulsion as a HTG clamp. The HTG clamp procedure was carried out as previously described [10]. In brief, a long-chain triacylglycerol (TG) emulsion (20% Intralipid, Fresenius Kabi, Sweden) was administered by using a volumetric pump (IVAC, IVAC Scandinavia AB, Täby, Sweden) at a rate of 13 mg of TGs per kilogram of body weight per minute to reach a TG concentration of 4 mmol/L. The infusion rate was thereafter adjusted to maintain a high and stable TG level of 4 mmol/L during a period of 180 min and the TG concentration was determined enzymatically every 10 min with Reflotron (Boehringer Mannheim AG, Mannheim, Germany) equipment. Blood samples were drawn from the arterialized hand vein in the basal state and at timed intervals throughout the study for analysis of substrates and hormones. Analytical procedures

Ten elderly and 10 young men participated in this study. The elderly men had an average age of 73 y (range, 70 –78 y), average weight of 74 kg (range, 65– 84 kg), and average body mass index of 24 kg/m2 (range, 21–27 kg/m2); the young men had an average age of 30 y (19 – 45 y), average weight of 79 kg (range, 65–93 kg), and average body mass index of 23 kg/m2 (range, 19 –26 kg/m2). All subjects were healthy, did not smoke, and had stable weight; none had diabetes mellitus, lung or thyroid dysfunction, or any other metabolic disorder; and none took any medication. The nature, purpose, and possible risks of the study were explained to all individuals before they consented to participate. The study protocol was reviewed and approved by the institutional ethics committee.

A commercial apparatus (Deltatrac, Datex Instrumentarium Corp., Helsinki, Finland) was used for indirect calorimetry. This device measures oxygen and carbon dioxide concentrations in the gas from the ventilated hood by a paramagnetic analyzer and by an infrared analyser, respectively. The analyzers were calibrated before each study with air and precisely known gas concentrations (95.0% oxygen and 5.0% carbon dioxide). Plasma concentrations of glucose were analyzed by the hexokinase method. Serum concentrations of TG were determined enzymatically (Reflotron), which provides a value within 190 s. The TG concentration in serum was also measured at timed intervals by a routine method at the hospital by using an L-␣-glycerol-phosphate oxidase (GPO) method [11]. Free fatty acids (FFAs) and ␤-OH-butyrate concentrations were measured enzymatically in plasma [12]. Plasma LPL was analyzed as previously described by using antibodies to suppress hepatic lipase during assay of LPL [13]. In vitro release of FFAs in nanomoles per minute reflects LPL activity expressed in milliunits. LPL mass was determined by an enzyme-linked immunosorbent assay technique, using a semipurified preparation of human LPL as the standard [13].

Experimental protocol

Calculations

All studies were performed after an overnight (12-h) fast and subjects arrived to the laboratory at 0800 h. Before each study, all volunteers ingested their habitual diet containing at least 150 g/d of carbohydrates. Indwelling catheters were inserted percutaneously into an antecubital vein, one for administration and the other for

The amount of administered exogenous fat during the 180-min steady-state clamp period was considered to reflect clearance of TG from the plasma compartment. Plasma volumes were calculated before each HTG clamp as previously described by using a regression equation based on height, weight, and hematocrit values [14]. Respiratory gas

Materials and methods Subjects

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W. Åberg et al. / Nutrition 22 (2006) 738 –743 TG

uals (0.201 ⫾ 0.027 versus 0.203 ⫾ 0.014 mmol/min; Fig. 1b). The calculated plasma volume was similar in the elderly men (3.0 ⫾ 0.1 L) and the young men (3.1 ⫾ 0.1 L). In consequence, the fractional elimination rate per liter of plasma was not influenced by age (0.067 ⫾ 0.009 and 0.064 ⫾ 0.006 mmol · min⫺1 · L⫺1 in old and young men, respectively, not significant). The priming volume to reach steadystate TG levels did not differ between groups. During this period, 128 ⫾ 4 mL (47 ⫾ 4% of total amount) was administered to the elderly men and 109 ⫾ 6 mL (41 ⫾ 3%) to the young individuals (not significant). The TG concentrations determined with the Reflotron equipment and the GPO method were almost identical and showed no differences between groups in the basal state or during infusion of lipids. The average TG level (GPO method) during the clamp period was similar in elderly and young individuals (4.18 ⫾ 0.09 versus 4.30 ⫾ 0.06 mmol/L, not significant). Baseline glucose concentrations were identical (5.3 ⫾ 0.1 mmol/L) in the two groups and were not influenced by administration of fat (data not shown). In the basal state, concentrations of FFA and ␤-OH-butyrate were higher in the elderly than in the young subjects (0.63 ⫾ 0.07 versus 0.42 ⫾ 0.05, mmol/L, P ⬍ 0.05; 0.12 ⫾ 0.02 versus 0.06 ⫾ 0.01 mmol/L, P ⬍ 0.05, respectively). During lipid infusion, similar

a.

5

mmol/l

4

3

2

1

0 Infusion rate 0,4

b.

mmol/min

0,3

0,2 Elderly Young

0,1

0,0 0

60

120

180

Minutes in clamp

FFA

## **

# ***

## ***

mmol/l

1,0 # ***

***

***

0,5

0,0 b.

ß-OH butyrate 1,0

*** ***

0,8 ***

mmol/l

exchange data were continuously measured and average values were calculated over each 1-min period for oxygen consumption, carbon dioxide production, respiratory quotient (RQ), and energy expenditure according to previously presented formulas [15]. Baseline energy expenditure calculations were based on gas exchange data from the final 30 min of the basal fasting period. Results in text, tables, and figures are presented as means ⫾ standard errors of the mean (SEMs). Between-within analyses of variance were used for repeated measurements to assess the effect of age on substrate oxidation and plasma removal capacity of intravenous fat emulsion with post hoc least significant difference tests, when appropriate (Statview 5.0; SAS Institute Inc., Cary, NC, USA). Statistical significance was accepted at P ⬍ 0.05.

a.

1,5

Fig. 1. (a) TG concentrations and (b) infusion rate, i.e., plasma elimination rate, of exogenous fat during hypertriglyceridemic clamp in 10 elderly (solid circles) and 10 young (open circles) healthy individuals. Values are means ⫾ SEMs. TG, triacylglycerol.

0,6 ***

0,4

*** ***

0,2

Elderly Young

#

0,0 Basal

Results

0

60

120

180

Minutes in clamp

During the clamp, similar TG levels were obtained in the elderly and young individuals (Fig. 1a). The average infusion rate of fat emulsion during the steady-state clamp period, i.e., plasma elimination rate of exogenous fat, was also similar (not significant) in elderly and young individ-

Fig. 2. elderly Values values. acids.

Serum concentrations of (a) FFA and (b) ␤-OH-butyrate in 10 (solid circles) and 10 young (open circles) healthy individuals. are means ⫾ SEMs. **P ⬍ 0.01, ***P ⬍ 0.001 versus baseline # P ⬍ 0.05, ##P ⬍ 0.01, elderly versus young men. FFA, free fatty

W. Åberg et al. / Nutrition 22 (2006) 738 –743

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Table 1 Plasma LPL activity and mass in 10 elderly and 10 young men before and during hypertriglyceridaemic clamp* Baseline

LPL activity (mU/mL) Elderly Young LPL mass (ng/mL) Elderly Young

Minutes in clamp 60

120

180

0.23 ⫾ 0.02‡ 0.65 ⫾ 0.09

0.94 ⫾ 0.13†‡ 2.66 ⫾ 0.36†

0.99 ⫾ 0.16†‡ 2.93 ⫾ 0.36†

1.08 ⫾ 0.17†‡ 3.12 ⫾ 0.31†

208 ⫾ 18 180 ⫾ 18

197 ⫾ 21 184 ⫾ 14

202 ⫾ 24 176 ⫾ 17

203 ⫾ 23 164 ⫾ 15

LPL, lipoprotein lipase * Values are mean ⫾ SEMs. † P ⬍ 0.001, significantly different from baseline. ‡ P ⬍ 0.001, elderly versus young men.

increments in FFA and ␤-OH-butyrate levels were obtained in the elderly and young individuals (Fig. 2). In the basal state, LPL activity in plasma was lower in the elderly individuals (P ⬍ 0.001), whereas LPL mass was similar in the two groups (Table 1). Using the value of 0.35 ⫾ 0.08 mU/ng for the specific activity of LPL in human postheparin plasma reported by Tornvall et al. [13], it can be calculated that the proportions of active LPL were 0.31 ⫾ 0.03% and 1.13 ⫾ 0.15% (P ⬍ 0.0001) after overnight fasting elderly and young men, respectively. During lipid infusion, LPL activity increased fourto five-fold in the young and elderly men, whereas there was no statistically significant change of LPL mass (Table 1). At the end of the study period, the proportion of active LPL in elderly men was approximately one-third

of that in young individuals (1.68 ⫾ 0.30% versus 5.77 ⫾ 0.64%, P ⬍ 0.001). Energy expenditure in the basal state was lower (P ⬍ 0.001) in the elderly group, whereas the RQ was similar (not significant) in the two groups (Table 2). The increase in energy expenditure during fat infusion was similar in the elderly and young individuals (9.0 ⫾ 1.3% versus 6.0 ⫾ 1.8%, not significant). During the clamp there was a statistically significant decrease in the RQ at 120 min (P ⬍ 0.01) in the young but not in the elderly subjects. During the HTG clamp, fat oxidation increased in both groups and this difference reached statistical significance at the end of the clamp (P ⬍ 0.01; Table 2). At baseline carbohydrate oxidation was significantly higher in the young than in the elderly individuals (P ⬍ 0.05). During

Table 2 Energy expenditure, respiratory quotient, and fat and carbohydrate oxidations in 10 elderly and 10 young men before and during a hypertriglyceridaemic clamp Baseline

Minutes in clamp 60

Energy expenditure (kcal/h) Elderly Young Respiratory quotient Elderly Young Fat oxidation (kcal/h) Elderly Young Carbohydrate oxidation (kcal/h) Elderly Young

120

180

64 ⫾ 3###储 79 ⫾ 2

68 ⫾ 2###储 84 ⫾ 2

69 ⫾ 3###储 83 ⫾ 2

72 ⫾ 3##§ 85 ⫾ 2

0.78 ⫾ 0.01 0.80 ⫾ 0.01

0.77 ⫾ 0.01 0.78 ⫾ 0.01

0.77 ⫾ 0.01 0.76 ⫾ 0.01†

0.76 ⫾ 0.01 0.77 ⫾ 0.01

49 ⫾ 2 55 ⫾ 4

54 ⫾ 2#‡ 63 ⫾ 3

55 ⫾ 2##§ 66 ⫾ 2

58 ⫾ 2*##†‡ 67 ⫾ 3**†

15 ⫾ 2#‡ 25 ⫾ 3

15 ⫾ 2 20 ⫾ 3

14 ⫾ 1 17 ⫾ 2

14 ⫾ 1 18 ⫾ 2

Significant differences from baseline values are denoted by asterisks; * Values are means ⫾ SEMs. ** p ⬍ 0.01, and differences between elderly and young men are denoted by the # p ⬍ 0.05. ## p ⬍ 0.01. ### p ⬍ 0.001. † P ⬍ 0.01, significantly different from baseline. ‡ P ⬍ 0.05, elderly versus young men. § P ⬍ 0.01, elderly versus young men. 储 P ⬍ 0.001, elderly versus young men.

#

symbol.

742

W. Åberg et al. / Nutrition 22 (2006) 738 –743

the HTG clamp there was an approximately 14.8% decrease in carbohydrate oxidation in the young versus 3.2% in the elderly individuals. This difference did not reach statistical significance.

Discussion This study examined age-related effects on plasma elimination of fat and substrate oxidation during a HTG clamp by comparing elderly with young men. Adiposity increases with age and fat-free mass decreases with age [4,6]. In the present study, the plasma TG elimination rate was similar in the elderly and young subjects. The capacity to hydrolyze the load of exogenous TGs supplied during the HTG clamp was thus unaffected by age. This was evident also from similar increments in plasma FFA in the two groups. In agreement with previous reports [16], our study demonstrated that elderly subjects had lower energy expenditure in the basal state than did young individuals. During the clamp, energy expenditure and fat oxidation increased in the elderly and young individuals (Table 2). However, the increase in energy expenditure was not statistically significantly greater in the elderly than in the young individuals (9.0 ⫾ 1.3% versus 6.0 ⫾ 1.8%, not significant) The increase in fat oxidation was also similar in the elderly and younger subjects (15.1 ⫾ 4.9% versus 23.9 ⫾ 7.0%, not significant). This indicates that elderly subjects are capable of oxidizing fat as readily as young individuals. Studies by others have reported that the capacity to release FFAs from endogenous fat stores is similar in elderly and young individuals [17,18]. However, as mentioned in the INTRODUCTION, there are also reports indicating that elderly may have a lesser capacity to mobilize and oxidize fat [5,7]. The reasons for these opposing findings are not clear. The basal measurement of energy expenditure and RQ was performed after a 12-h fast. RQ values of 0.78 to 0.80 indicated that subjects at baseline had a metabolic situation in which fat was the prominent oxidative fuel. Administration of large amounts of fat during the clamp therefore could not be expected to change this situation, and fat continued to be the dominant supplier of energy. Under physiologic conditions, the amount of LPL in plasma is low [13]. This enzyme is associated with lipoproteins [19] and generally is in a catalytically inactive form [20]. Animal and tissue perfusion studies have indicated that plasma LPL reflects a slow transport of the enzyme from peripheral tissues to the liver, where the enzyme is degraded [21–23]. In humans, Coppack et al. [24] found a release of active LPL from forearm muscle but found no release of LPL activity from adipose tissue in the fasting state and only a small release after feeding [24]. Karpe et al. [25], who also studied arterio-venous differences, found substantial release of LPL activity from forearm muscle in the fed and fasted states [25]. In contrast, there was no release of LPL activity over the adipose tissue, and in the fasted state there was actually

a net uptake. These studies show that, in humans, skeletal muscle is probably the main contributor to plasma LPL activity. In our study, plasma LPL activity was about three times higher in the young than in the elderly individuals. This presumably reflects the larger and more active muscle mass in the young. Plasma LPL activity increases after a mixed meal [24 –26] and during infusion of fat emulsions [27,28]. The likely mechanism is that binding to the large lipid/ lipoprotein particles increases extraction of the lipase from the endothelial binding sites. In the present study, LPL activity increased during infusion. The increase was larger in the young than in the elderly individuals, but the increase was the same, i.e., three-fold to four-fold. This indicates that the difference in the amounts released was due to a larger amount of extractable LPL in the young individuals, and not because of differences in the mechanisms by which the emulsion increased the release of lipase into plasma. In conclusion, the present study has shown that elderly men have a capacity to hydrolyze intravenously a high TG load administered as a HTG clamp, which is not quantitatively different from the capacity of young men. Further, the elderly have a capacity similar to that of young individuals to oxidize administered fat.

Acknowledgments The authors thank Ann-Sofie Jacobsson for technical assistance with lipase assays and Elisabeth Dungner for technical assistance in performing the FFA and ␤-OHbutyrate assays.

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