Department of Human Nutrition and Metabolism, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel
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ABSTRACT |
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Adipose tissue lipolysis
and fatty acid reesterification by liver and adipose tissue were
investigated in rats fasted for 15 h under basal and calorigenic
conditions. The fatty acid flux initiated by adipose fat lipolysis in
the fasted rat is mostly futile and is characterized by
reesterification of 57% of lipolyzed free fatty acid (FFA) back into
adipose triglycerides (TG). About two-thirds of FFA reesterification
are carried out before FFA release into plasma, whereas the rest
consists of plasma FFA extracted by adipose tissue. Thirty-six percent
of the fasting lipolytic flux is accounted for by oxidation of plasma
FFA, whereas only a minor fraction is channeled into hepatic very low
density lipoprotein-triglycerides (VLDL-TG). Total body calorigenesis
induced by thyroid hormone treatment and liver-specific calorigenesis
induced by treatment with ,
'-tetramethylhexadecanedioic acid
(Medica 16) are characterized by a 1.7- and 1.3-fold increase in FFA
oxidation, respectively, maintained by a 1.5-fold increase in adipose
fat lipolysis. Hepatic reesterification of plasma FFA into VLDL-TG is
negligible under both calorigenic conditions. Hence, total body fatty
acid metabolism is regulated by adipose tissue as both source and sink.
The futile nature of fatty acid cycling allows for its fine tuning in
response to metabolic demands.
adipose tissue; lipoproteins; stable isotopes; thyroid hormone; Medica 16
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INTRODUCTION |
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THE TRANSITION to the fasting state, in which free fatty acids (FFA) derived by adipose tissue lipolysis become a major source of oxidizable metabolic fuel for heart, skeletal muscle, and liver, is accompanied by major changes in overall lipid and fatty acid metabolism. The FFA cycle is initiated by lipolysis of adipose triglycerides (TG) catalyzed by hormone-sensitive lipase (HSL). Fat lipolysis may either yield plasma FFA or result in intracellular reesterification of lipolyzed FFA back into adipose fat before their release (primary reesterification). Plasma FFA that escape direct oxidation are thought to be secondarily reesterified in liver into very low density lipoprotein-triglycerides (VLDL-TG) (17, 41). These are hydrolyzed by intravascular lipoprotein lipase, followed by reuptake of the released FFA into adipose tissue, muscle, or liver. However, secondary reesterification of FFA into VLDL-TG has recently been shown in humans to account for only a minor fraction of total FFA released from adipose tissue, thus leaving unsolved the fate of plasma FFA that escape oxidation or secondary reesterification into VLDL-TG (12).
Long-chain fatty acid metabolism is closely associated with calorigenesis induced by hormones and drugs and is therefore of particular interest under conditions of treatment with thyroid hormones (TH). However, despite studies concerned with the effects exerted by TH on discrete steps of fatty acid metabolism, a quantitative and integrative in vivo view of long-chain fatty acid metabolism in TH-treated animals is still lacking. Thus TH was reported to induce lipolysis in isolated adipose tissues (1) or adipocytes (18, 26) as a result of sensitization of adipocytes to the lipolytic effect of catecholamines (5, 18). Increased lipolysis was corroborated by increased total body lipid oxidation as well as a decrease in adipose tissue weight (31). However, an integrative view consisting of quantitative evaluation of the in vivo production rates of FFA and glycerol as well as the FFA fraction that is either oxidized or secondarily reesterified in rats treated with TH is still lacking. Similarly, despite in vitro evidence suggesting that hepatic VLDL release (11, 39) and lipoprotein lipase activity (10, 34) are affected by TH treatment, the in vivo production rate of hepatic VLDL-TG as a fraction of the overall fatty acid flux still remains to be investigated.
Calorigenesis induced by ,
'-tetramethylhexadecanedioic acid
(Medica 16) (2) is apparently similar to that induced by TH. Thus, similarly to TH, Medica 16 treatment results in sensitization of adipose tissue to catecholamines, leading to lipolysis, ketogenesis, and weight reduction (38). Furthermore, similarly to TH,
Medica 16 treatment induces a pronounced decrease in liver phosphate and redox potentials (24, 25) with a
concomitant decrease in mitochondrial membrane potential observed in
both isolated mitochondria and liver cells (19). The
thyromimetic activity of Medica 16 is further reflected by its capacity
to induce liver genes classically considered to be TH dependent,
e.g., malic enzyme, mitochondrial glycerol-3-phosphate
dehydrogenase, S14, and others (20, 21).
However, in contrast to TH, the calorigenic activity of Medica 16 is
liver specific. Thus, whereas TH induces a decrease in phosphate
potential in both liver and heart, the decrease in phosphate potential
induced by Medica 16 is observed in liver only (24,
25). Similarly, transcriptional activation by TH of
TH-dependent genes is observed in both liver and heart, whereas the
respective nuclear activity of Medica 16 is, again, liver specific.
Also, the thyromimetic activity of Medica 16 has been shown to be
independent of TH levels and is not transduced by the TH nuclear
receptor (20, 21). The apparent liver
specificity of Medica 16 has been shown elsewhere to be accounted for
by its failure to enter cardiac or skeletal muscle (H. Bdeir,
unpublished observations).
Long-chain fatty acid metabolism was evaluated here in the fasting rat in terms of the in vivo fluxes of adipose tissue lipolysis, fatty acid oxidation, and the recycling of fatty acids in liver and adipose tissue as a function of whole body calorigenesis induced by TH or hepatic calorigenesis induced by Medica 16.
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METHODS |
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Animals.
Male Albino rats of the Hebrew University strain weighing 300-400
g were fed a standard laboratory chow diet containing 4.5% fat. Rats
were treated for 4-6 wk with 390 mg · kg1 · day
1 Medica 16 by mixing the
drug in the powdered diet. Hyperthyroidism was induced by six daily
intraperitoneal injections of 10 µg T3 · 100 g
body wt
1 · day
1 in 0.01 M NaOH in
saline. Control rats were injected with the vehicle only. All animals
had free access to food and drinking water. Animal care and
experimental procedures were in accordance with guidelines of the
Animal Care Committee of Hebrew University.
Cannulation procedures. Rats fasted for 15 h were restrained in restriction cages (Harvard Apparatus) and cannulated under local anesthesia with lignocaine through the tail artery and vein for blood sampling and isotope infusion, respectively (28). After catheter placement, animals were released to their cages, where they could move freely, and allowed to recover for 90 min. Biting off of tail catheters was prevented by wrapping the tail with a plastic sheath coated with castor oil repellent. Catheter patency was maintained with saline to avoid heparin during measurement of lipolytic rates.
Indirect calorimetry. Whole body O2 consumption and CO2 production rates were measured several times before and during the infusion study by open-circuit indirect calorimetry using a NAGA O2/CO2 analyzer (Franztec, Haifa, Israel). The time of urination and urine volumes during the infusion period were recorded using an intracage moisture-sensitive alarm. Urinary nitrogen was determined by Kjeldahl analysis in urine acidified with 1 N H2SO4.
FFA, glycerol, and VLDL-TG production rates.
Cannulated recovered animals were infused constantly for 150 min
(20-30 µl/min) through the tail vein with 98%-enriched
[2,2-2H2]palmitate (Cambridge Isotope
Laboratories, Andover, MA) (bound to albumin at a ratio of 6:1) at a
rate of 0.16 µmol · min1 · kg body
wt
1 and with 98%-enriched
[2H5]glycerol (ISOTEC, Miamisburg, OH) in
saline at a rate of 0.6 µmol · min
1 · kg
body wt
1 using a Harvard Apparatus syringe pump. For
measurement of FFA and glycerol production rates, blood samples were
withdrawn at intervals of 20-30 min during the last 50- to 150-min
period of constant infusion for measurements of steady-state enrichment of plasma palmitate and glycerol. For measurement of VLDL-TG production rate, the infusion of label was stopped, allowing for a decay in the
enrichment of palmitate in plasma VLDL-TG. The enrichment of plasma
TG-palmitate was followed for 60-80 min in blood samples collected
at intervals of 5-15 min. Sampled blood amounted to 1.5-3.0 ml.
Secondary reesterification in adipose tissue.
Cannulated recovered animals were primed with 12 µCi
[3H]palmitate in saline, followed by constant infusion
for 100-280 min with 0.6 µCi [3H]palmitate
· min1 · kg body wt
1 accompanied
by 0.03 µmol · min
1 · kg
1
fatty acid free albumin. An isotopic steady state of plasma
[3H]palmitate was reached within the first few minutes of
infusion. Three blood samples of 0.5 ml each were then taken for
measurement of specific activity of plasma free palmitate. Animals were
then killed by decapitation, and samples of the epididymal,
subcutaneous, and perirenal adipose tissues were quickly removed and
stored in liquid air.
Analytic procedures. Tissue triacylglycerols were determined in samples extracted with 20 vols of chloroform-methanol at a ratio of 2:1. The dried lipid extract was solubilized in warm 0.4% SDS. Plasma and tissue triacylglycerols were measured using a commercial kit (Boehringer Mannheim). FFA composition of plasma was determined by GC analysis of methyl ester derivatives. Plasma glucose was measured by glucose test strips using an Elite glucometer (Bayer) based on glucose oxidase. Plasma insulin was measured by a rat insulin RIA kit (Linco).
Calculations. Total body lipid oxidation was calculated, as described previously (13), on the basis of O2 consumption and CO2 production rates derived from indirect calorimetry and was corrected for protein oxidation (0.13 mg/min) as deduced from urinary nitrogen.
Rates of appearance of palmitate (Ra palmitate) and glycerol (Ra glycerol) (in µmol · min
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Statistics. All values are presented as means ± SE. Statistical analysis was performed by one-way analysis of variance (ANOVA). When significant values were obtained, differences between individual means were analyzed by pairwise multiple comparison analysis (Student-Newman-Keuls method).
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RESULTS |
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Basal characteristics.
The effect of TH and Medica 16 treatment on plasma concentrations of
FFA, triacylglycerols, glucose, and insulin in rats in the fasting
state are presented in Table 1. Plasma
FFA were not significantly affected by either treatment. Plasma
triglycerides were decreased 2.4-fold in Medica 16-treated rats and
were only slightly but not significantly decreased in hyperthyroid
rats. Plasma glucose and insulin concentrations were slightly increased in both Medica 16- and TH-treated rats.
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Adipose tissue lipolysis and primary reesterification.
FFA production and release into plasma were determined by measuring the
enrichment of labeled palmitate and glycerol in plasma under conditions
of isotopic steady state (Table 2).
Glycerol production rates (Ra glycerol), which reflect
adipose tissue lipolysis, were increased 1.5- and 1.4-fold by TH and
Medica 16, respectively. These increases in lipolytic flux were
accompanied by a 1.9-fold increase in primary (intra-adipose)
reesterification of FFA. Consequently, the increased lipolytic flux
resulted in compromised FFA release into plasma (Ra FFA)
with a concomitant decrease in the ratio of Ra FFA to
Ra glycerol. Primary reesterification accounted for 39, 47, and 52% of total lipolytic flux in the fasting state in nontreated and
TH- and Medica 16-treated rats, respectively.
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Fatty acid oxidation.
Total body O2 consumption increased by 55% in TH-treated
animals compared with age-matched controls (34.2 ± 0.9 vs.
22.1 ± 0.5 ml O2 · min1 · kg
1, P < 0.05). Because total body
O2 consumption decreased with age (when normalized to body
weight), and in light of the relatively long period of treatment with
Medica 16 compared with the short treatment period with TH,
O2 consumption of Medica 16-treated animals was measured
twice, following 1 and 6 wk of treatment. O2 consumption
was significantly increased by 15% in Medica 16-treated rats following
1 wk of treatment (25.4 ± 0.6 vs. 22.1 ± 0.5 ml O2 · min
1 · kg
1,
P < 0.05) and persisted through the 6 wk of the
treatment period (19.7 ± 0.3 vs. 17.2 ± 0.2 ml
O2 · min
1 · kg
1,
P < 0.05).
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Secondary reesterification. Secondary reesterification rates were evaluated by subtracting total body FFA oxidation rates from Ra FFA. As shown in Table 3, secondary reesterification was significantly decreased in hyperthyroid rats in light of the substantial increase in lipid oxidation.
Hepatic VLDL-TG production was evaluated by analyzing the decay curve of plasma TG-palmitate enrichment when labeled palmitate infusion was interrupted. As shown in Fig. 1, plasma TG-palmitate enrichment reached isotopic steady state after 120-140 min of labeled palmitate infusion compared with 50-60 min for plasma free palmitate. A slow turnover rate for plasma TG-palmitate compared with that for free palmitate was also reflected by the slow decay of plasma TG-palmitate compared with that of free palmitate (Fig. 1). Also, plasma TG-palmitate enrichment in nontreated animals during isotopic steady state amounted to 70 ± 5.5% of plasma free palmitate (Fig. 1), indicating that only ~70% of liver fatty acids incorporated into VLDL-TG were derived in nontreated animals from plasma FFA, whereas 30% were derived from an unlabeled hepatic pool of fatty acids. This nonplasmatic liver pool was significantly decreased in animals treated with TH or Medica 16 and in which plasma TG-palmitate enrichment during isotopic steady state amounted to 82 ± 2.9 and 83 ± 1.8% of plasma free palmitate enrichment, respectively. Hepatic VLDL-TG production rates as calculated from the respective decay of the enrichment curves of the three groups are shown in Table 3. VLDL-TG production accounted for 13% of total body secondary reesterification in nontreated animals, and because only 70% of VLDL-TG were synthesized from plasma FFA, hepatic reesterification accounted for only 9% of secondary reesterification or only 3% of total body lipolytic flux. Moreover, Medica 16 and TH treatments resulted in a 3- and 1.5-fold decrease in VLDL-TG production rate, respectively, indicating that hepatic reesterification of FFA under calorigenic conditions accounted for an even lower fraction of total body secondary reesterification. The calorigenesis-induced decrease in hepatic VLDL-TG production was not compromised by changes in liver TG content (data not shown).
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DISCUSSION |
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Fatty acid metabolism in fasted rats: an integrative view. Long-chain fatty acid metabolism in the fasting state is initiated by HSL-catalyzed lipolysis of adipose fat, resulting in plasma FFA as a source of metabolic fuel for the heart, skeletal muscle, and liver. Total body FFA oxidation in the nontreated fasted rat amounts to only 36% of total body lipolytic flux, indicating that adipose tissue lipolysis is activated much beyond the requirement for total body fat oxidation. Moreover, plasma FFA channeled into VLDL-TG production is only 5% of Ra FFA, indicating that the oxidizable fatty acid pool in the postabsorptive state consists mainly of plasma FFA released from adipose fat and directly oxidized by respective tissues, rather than fatty acids derived from intravascular lipolysis of VLDL-TG. The higher production rates of VLDL-TG previously reported by Wolfe and Durkot (40) could perhaps result from the use of labeled dog VLDL instead of rat VLDL or from plasma VLDL enrichments lower than isotopic steady-state levels.
Most FFA resulting from fat lipolysis in adipose tissue in the postabsorptive state are reesterified back into TG. Because hepatic reesterification of FFA into VLDL-TG accounts for only a minor fraction of total body FFA flux, most of the reesterified FFA would have to be accounted for by extrahepatic tissues. Indeed, 39% of total body lipolytic FFA was found here to be primarily reesterified into adipose fat even before its release into plasma, in line with a previous report (40) pointing to a ratio of 1:1 for Ra FFA/Ra glycerol in the postabsorptive rat. Another 18% of total body lipolytic FFA was found here to be secondarily reesterified in adipose tissue, making this tissue the most important site of reesterification of recycled FFA in general and of secondary reesterification in particular. Hence, primary and secondary reesterification of lipolytic FFA in adipose tissue accounts for almost all FFA produced by HSL and that escape oxidation in oxidizing tissues. Total body fatty acid metabolism and steady-state levels of plasma FFA appear, therefore, to be controlled by adipose tissue, as both a source and sink. Similarities and differences between the FFA cycle reported here in fasted rats and previously in fasted humans are worth noting. The overall FFA flux in rats (49.2 ± 3.0 µmol · minThe fatty acid cycle in TH-treated fasted rats.
TH was found here to activate lipolysis of adipose fat 1.5-fold, in
line with 3-fold activation previously reported in humans (3). This increase in lipolytic rate may be ascribed to
adipose tissue sensitization to catecholamines as a result of the
increased expression of -adrenoreceptors (5,
18). The increase in lipolytic rate by TH was, however,
compromised by a dramatic increase in primary reesterification. The
increase in lipolytic flux induced by TH was accompanied by a 55%
increase in total body O2 consumption and a 1.7-fold
increase in lipid oxidation, in line with a similar increase previously
reported by Oppenheimer et al. (31). The increase in
oxidation may be ascribed to mitochondrial uncoupling due to transition
from a low to a high mitochondrial conductance (23).
TH-induced oxidation of FFA limits the extent of secondary reesterification of plasma FFA. The decrease in hepatic VLDL-TG production could perhaps reflect the lower availability of hepatic fatty acids for reesterification under conditions of TH-induced calorigenesis and may account for the somewhat lower plasma TG observed
in postabsorptive TH-treated rats. Secondary reesterification in
adipose tissue completes the FFA cycle and again accounts for most
recycled plasma FFA. In summary, the calorigenic effect of TH is
dominated by high turnover of the FFA cycle with a concomitant absolute
and relative increase in primary reesterification and FFA oxidation.
The thyromimetic-calorigenic effect of Medica 16. Similarly to TH, Medica 16 was found here to increase adipose fat lipolysis by 41%, in line with activation of lipolysis by Medica 16 in obese, insulin-resistant fa/fa rats (28). Activation of the lipolytic flux under conditions of sensitization to insulin (28) may imply that Medica 16-induced lipolysis of adipose fat is transduced by an insulin-independent pathway. Activation of adipose lipolysis by Medica 16 is indeed accompanied by increased sensitization of adipocytes to variable lipolytic activators (e.g., catecholamines, forskolin, ACTH) (38). The 41% increase in lipolytic flux induced by Medica 16 is only partially compromised by the 27% increase in lipid oxidation, leaving a substantial fraction to primary and secondary reesterification. Similarly to TH, Medica 16 indeed increased primary reesterification of FFA in adipose tissue, in line with that recently reported in obese fa/fa rats, under either basal or hyperinsulinemic-euglycemic clamp conditions (28). Secondary reesterification in liver was, however, significantly inhibited by Medica 16 treatment, leaving most secondary reesterification to adipose tissue. Hence, under conditions of increased total body FFA turnover induced by Medica 16 treatment, FFA reesterification (primary + secondary) in adipose tissue again accounted for 61% of lipolytic flux in the fasting state.
Medica 16 treatment resulted in a 15% increase in total body O2 consumption with a concomitant 1.3-fold increase in lipid oxidation. Calorigenesis induced by Medica 16 was in line with that in a previous study from this laboratory reporting uncoupling of mitochondrial oxidative phosphorylation by Medica 16 (19). The lower increase in total body O2 consumption induced by Medica 16 compared with that induced by TH reflects the liver-specific thyromimetic activity of Medica 16 compared with the nonselective calorigenic activity of TH (25). The pronounced inhibition of hepatic VLDL-TG production by Medica 16 may account for the hypolipidemic effect of Medica 16 in the fasting state. This hypolipidemic effect complements the previously reported hypolipidemic activity of Medica 16 in the absorptive state due to activated clearance of plasma VLDL and chylomicrons as a result of transcriptional suppression of the hepatocyte nuclear factor-4 (HNF-4)-controlled apolipoprotein CIII (14, 15, 22). The postabsorptive hypolipidemic effect of Medica 16 could perhaps reflect transcriptional suppression of other HNF-4-controlled genes involved in liver VLDL assembly and, in particular, of apolipoprotein B and microsomal triglyceride transfer protein. Liver VLDL-TG production could perhaps be further limited by the limited availability of liver FFA for reesterification under conditions of pronounced hepatic calorigenesis induced by Medica 16 treatment, in line with recent reports (27, 36) pointing to the reciprocal interplay between fatty acid oxidation and its hepatic reesterification into VLDL-TG. In summary, adipose tissue serves as a main source as well as a sink for fatty acid metabolism in the fasted rat. The fatty acid flux initiated in rat adipose tissue is mostly futile and results in reesterification of 57% of lipolyzed FFA back into adipose TG. Two-thirds of FFA reesterification into adipose fat are carried out before FFA release into plasma, whereas the rest results from extraction of plasma FFA. Thirty-six percent of total lipolytic FFA flux is accounted for by net FFA oxidation, whereas only a minor fraction of FFA flux is channeled into hepatic VLDL-TG. Fatty acid cycling in excess of oxidative demands allows for rapid response to sudden changes in energy requirements (41). Moreover, the futile nature of the cycle allows for its fine tuning in response to even mild changes in metabolic demands (30). This high responsiveness of the fatty acid cycle is preserved under conditions of calorigenesis induced by thyroid hormones or Medica 16 due to an increase in lipolytic flux, maintaining essentially constant the oxidative flux-to-cycling flux ratio. ![]() |
ACKNOWLEDGEMENTS |
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This work was supported by the Israeli Ministry of Science and Technology.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. Bar-Tana, Dept. of Human Nutrition and Metabolism, Faculty of Medicine, The Hebrew Univ., PO Box 12272, Jerusalem 91120, Israel (E-mail: bartanaj{at}cc.huji.ac.il).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 1 November 1999; accepted in final form 5 January 2000.
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