Institut National de la Santé et de la Recherche Médicale Unité 1 499 and 2 449, Faculté RTH Laennec, 69008 Lyon, France; and 3 Centre de Recherche en Nutrition Humaine, Hôpital E. Herriot, 69003 Lyon, France
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ABSTRACT |
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To determine whether increased lipogenesis contributes to human obesity, we measured (postabsorptive state), in lean and obese subjects, lipid synthesis (deuterated water method) and the mRNA concentration (RT-competitive PCR) in subcutaneous adipose tissue of fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP)-1c. Before energy restriction, obese subjects had an increased contribution of hepatic lipogenesis to the circulating triglyceride pool (14.5 ± 1.3 vs. 7.5 ± 1.9%, P < 0.01) without enhancement of cholesterol synthesis. This increased hepatic lipogenesis represented an excess of 2-5 g/day of triglycerides, which would represent 0.7-1.8 kg on a yearly basis. The lipogenic capacity of adipose tissue appeared, on the contrary, decreased with lower FAS mRNA levels (P < 0.01) and a trend for decreased SREBP-1c mRNA (P = 0.06). Energy restriction in obese patients decreased plama insulin (P < 0.05) and leptin (P < 0.05) and normalized hepatic lipogenesis. FAS mRNA levels were unchanged, whereas SREBP-1c increased. In conclusion, subjects with established obesity have an increased hepatic lipogenesis that could contribute to their excessive fat mass but no evidence for an increased lipogenic capacity of adipose tissue.
fatty acid synthase; sterol regulatory element-binding protein-1c; stable isotope; messenger ribonucleic acid; lipids
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INTRODUCTION |
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ALTHOUGH IT IS CLEAR that both genetic (6) and environmental factors, such as decreased levels of physical activity and increased energy intake, play a role in the development of obesity, the mechanisms leading to the excessive depot of triglycerides (TG) in adipose tissue are still poorly defined. Both decreased lipolytic activity, through genetic variations or abnormal regulation of adrenoceptors (26) or hormone sensitive lipase (25, 27), and enhanced expression and activity of the TG synthesis and storage pathways can play a role. A decreased capacity of muscles for fatty acid oxidation could promote this storage by diverting fatty acid metabolism toward reesterification (22). Indeed, oxidation of an oral long-chain TG load was lower in obese than in lean subjects (4). Most of the TG appearing in the organism each day are provided by the diet. Endogenous synthesis of fatty acids (de novo lipogenesis), which takes place mainly in the liver and in adipose tissue, is considered to be a minor contributor (5). This was based, for adipose tissue, on in vitro studies examining the activity of lipogenic enzymes and incorporation of glucose carbons into fatty acids (summarized in Ref. 5) and on in vivo studies of the metabolic fate of orally ingested or intravenously infused (32, 33) glucose. These studies concluded that, contrary to what is observed in rats, the lipogenic capacity of adipose tissue is negligible in normal humans and, albeit increased, remains low in obesity (5). This view was recently challenged on the following grounds: 1) reexamination of the respective lipogenic capacity of rat and human adipose tissue suggested that human adipose tissue is an important site of fatty acid synthesis (41); 2) fatty acid synthase (FAS) gene transcription and FAS activity are increased by insulin in cultured human adipocytes (8, 38); and 3) the body weight gain of normal subjects overfed with carbohydrates could not be explained by the increase in liver lipogenesis, suggesting that significant de novo lipogenesis occurred in another place, probably adipose tissue (1). These observations supported the hypothesis that excessive expression and activity of the lipogenic pathway in adipocytes could play a role in the development of human obesity. In addition, the development of inhibitors of FAS activity (24) could provide a valuable approach to the treatment of obesity (30) if this hypothesis was demonstrated to be true. On the other hand, it has been shown recently that the levels of sterol regulatory element-binding protein (SREBP)-1c mRNA, the main transcription factor that controls the expression of the lipogenic pathway (16, 17), were decreased in the adipose tissue of obese mice (39). Therefore, to determine whether increased lipogenic capacity, not only of liver but also of adipose tissue, could play or not play a role in the pathogeny of obesity, we measured in the present report hepatic lipogenesis and the expression of FAS and SREBP-1c in adipose tissue of lean and obese subjects. These measurements were repeated in some obese subjects consuming a hypocaloric diet.
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METHODS |
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Subjects.
Written informed consent was obtained from 10 normal subjects and 8 obese patients after full explanation of the nature, purpose, and
possible risks of the study. The control group consisted of six women
and four men [age 20-51 yr, body mass index (BMI) 19-25]. No control subject had a personal or familial history of diabetes or
obesity or was taking any medication; all had normal physical examination and normal plasma glucose and lipid concentrations (Table
1). All had a stable body weight during
the year before the study. Subjects with unusual dietary habits were
excluded. The obese group consisted of six women and two men (age
22-50 yr, BMI 31-50) with normal physical examination, except
for the enlarged fat mass, and taking no medication. They had gained
between 2 and 4 kg of body weight during the previous year. Except for one subject who had slightly increased TG (2.17 mM) and cholesterol (6.80 mM) concentrations, all had plasma glucose and lipid levels within normal values (Table 1).
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Protocols. The protocol of the study was approved by the local ethical committee and by the Institut National de la Santé et de la Recherche Médicale, and the study was conducted according to the Hurriet law. All tests were performed in the Human Nutrition Research Center in Lyon. All subjects were studied while consuming their usual diet, and a detailed report of the diet consumed during the week before the study was obtained. Body weight was stable during this week for every control and obese subject. Four obese objects were studied again after 3-4 mo of a moderate hypocaloric diet and a 7- to 10-kg reduction in body weight. For women, the test was performed during the first 10 days of the menstrual cycle to take into account the known variations of lipogenesis during the menstrual cycle (there are no menstrual variations for cholesterol synthesis; see Ref. 13). All subjects abstained from alcohol and heavy physical activity the week before the study.
In the evening before the test, the subjects drank a loading dose of deuterated water (3 g/kg body water; one-half after the evening meal and one-half at 10:00 PM). Then until the end of the study, they drank only water enriched with 2H2O (4.5 g 2H2O/l drinking water). All tests were initiated in the postabsorptive state, after an overnight fast. At 07:30 AM, an indwelling catheter was placed in a forearm vein for blood sampling. Blood samples were drawn for the various concentrations and enrichment measurements. Thereafter, a sample of abdominal subcutaneous adipose tissue (150-250 mg) was obtained by needle biopsy under local anesthesia and immediately stored in liquid nitrogen until analysis.Analytical procedures. Metabolites were assayed with enzymatic methods on neutralized perchloric extracts of plasma (glucose) or on plasma (free fatty acid, TG; see Ref. 9). Plasma leptin, insulin, and glucagon concentrations were determined by RIA. Total cholesterol was measured by enzymatic assay. For the measurement of deuterium enrichment in plasma cholesterol and in the palmitate of plasma TG, plasma lipids were first extracted by the method of Folch et al. (15). Free cholesterol and TG were separated from other lipid fractions by TLC. Free cholesterol was scraped off the silica plates and eluted from silica with ether before its trimethylsilyl derivative was prepared (11). The transmethylated derivatives of the palmitate of TG were prepared according to Morrison and Smith (37). Deuterium enrichment determinations were performed on a gas chromatograph (HP5890; Hewlett-Packard, Palo Alto, CA) equipped with a 25-m fused silica capillary column (OV1701; Chrompack, Bridgewater, NJ) and interfaced with a mass spectrometer (HP5971A; Hewlett-Packard) operating in the electronic impact ionization mode (70 eV). Carrier gas was helium. Ions 368 to 370 (cholesterol) and 270 to 272 (palmitate) were monitored selectively. Special care was taken to obtain comparable ion peak areas between standard and biological samples, adjusting the volume injected or diluting the sample when necessary. Deuterium enrichment in plasma water was measured by the method of Yang et al. (44).
Total RNA was extracted from adipose tissue samples using the RNeasy total RNA kit (Qiagen, Coutaboeuf, France). Concentrations and purity were verified by measuring optimal density at 260 and 280 nm. Their integrity was checked by agarose gel electrophoresis. Total RNA was suspended in water and stored atCalculations. The fractional contributions of cholesterol synthesis and hepatic lipogenesis to plasma free cholesterol and to plasma TG pools, respectively, were calculated from the deuterium enrichments in free cholesterol, palmitate of TG, and in plasma water, as previously described (10, 11). In short, the deuterium enrichments that would have been obtained if endogenous synthesis were the only source of plasma cholesterol or palmitate of TG were calculated from plasma water enrichment. The comparison of the actual enrichments observed with these theoretical values gives the contributions, expressed as the fractional synthesis rate, of endogenous synthesis to the pools of rapidly exchangeable free cholesterol and of plasma TG during the time between the ingestion of the loading dose of deuterated water and blood sampling (12 h). An important assumption (21), and possible limitation, in these calculations of lipids synthesis is that the number of incorporation sites of deuterium in the molecules synthesized is not significantly modified by diet. Fat-free mass (FFM) was calculated from the volume of the loading dose (LD) of deuterated water ingested and the deuterium enrichment in plasma water (IEw) as FFM = (LD/IEw)/0.732 (42). All results are shown as means ± SE. Comparisons were performed with two-tailed Student's t-test for nonpaired values or paired values as appropriate.
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RESULTS |
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Lipid synthesis.
The concentrations of metabolites and hormones measured in the
postabsorptive state are shown in Table 1. Compared with control subjects, the obese group had higher concentrations of glucose, TG,
cholesterol, insulin, and leptin (P < 0.01 for all).
In the obese group studied after weight loss, plasma TG, cholesterol, insulin, and leptin were decreased (P < 0.05 for all)
compared with the values observed before restriction of energy intake. Table 2 shows the diet consumed by the
control and obese subjects. During the week before the study, obese and
control subjects had comparable total energy intake, expressed as
kilocalories per day or relative to FFM. Despite a tendency for higher
lipid intake, the proportions in the diet of carbohydrates, fat, and
proteins were similar. The daily intake of cholesterol and the
proportion of saturated (SFA), monunsaturated (MUFA), and
polyunsaturated (PUFA) fatty acids were also comparable. Energy
restriction in obese subjects was accompanied by a decrease in the
contribution of fat to energy intake; the proportions of SFA, MUFA, and
PUFA were unchanged.
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mRNA concentrations in adipose tissue.
Compared with control subjects, obese subjects had a large decrease in
FAS (P < 0.01) mRNA concentrations. The decrease of SREBP-1c mRNA levels in obese subjects was of borderline significance (P = 0.06). After caloric restriction, FAS mRNA
concentrations decreased slightly but not significantly in obese
subjects; SREBP-1c mRNA levels, on the contrary, were increased
(P < 0.05) to values identical to those of lean
subjects (Table 3).
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DISCUSSION |
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We searched in the present report for evidence that enhanced lipogenesis may contribute to the development and/or maintenance of the excessive fat mass of obese subjects. We found indeed an increase in postabsorptive hepatic lipogenesis that was normalized by a moderate restriction of energy intake. The lipogenic capacity of adipose tissue, as appreciated by the measurement of FAS mRNA concentrations, was, on the contrary, found to be decreased in obese subjects and was, if anything, further decreased during energy restriction. Moreover, SREBP-1c mRNA levels were also lower in the adipose tissue of obese subjects. Although we could not measure, because of the limited amount of adipose tissue sampled, FAS protein levels or the active, nuclear form of SREBP-1c protein, these findings strongly suggest that neither FAS expression nor the activity of the main transcription factor stimulating the expression of lipogenic genes was increased in obese patients. These modifications in obese subjects of hepatic lipogenesis and of expression in adipose tissue of lipogenic genes before energy restriction were observed in the absence of significant differences in the contribution of fat and carbohydrates to total energy intake or in the repartition of ingested SFA, MUFA, and PUFA.
The increase in hepatic lipogenesis agrees with previous reports
(13). In the absence of liver biopsies, not performed for obvious ethical reasons, we cannot determine the role of enhanced expression of lipogenic genes and of increased substrate availability for lipid synthesis in this stimulation of hepatic lipogenesis. However, the lack of a simultaneous increase in cholesterol synthesis would rather support a role for enhanced expression of lipogenic genes.
This would be consistent with the effects of high insulin levels on
liver lipogenic genes demonstrated in vitro (14, 18, 19).
Whatever the exact mechanism, this increase in hepatic lipogenesis
appears to be moderate at first glance. Assuming a basal postabsorptive
secretion rate of TG by the liver of ~0.15 µmol · kg1 · min
1
(20, 33), this lipogenesis would represent a net
production of 3.0 µmol/day instead of 1.0 in control subjects, i.e.,
a daily excess of ~1.5-2 g. This is a minimal estimate since it
is probable that this excess in lipogenesis is more marked in the
postprandial situation. If we assume an excess in liver TG secretion of
5 g/day, this still seems low compared with a daily oral intake of
~100 g/day. However, if we consider the possible contribution of
excess hepatic lipogenesis to body fat stores on a yearly basis, this would represent 0.7-1.8 kg. Thus a seemingly moderate metabolic disturbance could be not trivial on a long-term basis.
We found, on the other hand, no evidence for an increased lipogenic capacity of adipose tissue in obese subjects. However, we sampled only subcutaneous adipose tissue, and results could be different in visceral adipose tissue, as shown for other mRNA levels (29). It should be stressed also that we studied subjects with a large and long-lasting excess in body mass. Their picture is overall comparable to the one described recently in ob/ob mice with established obesity (39, 40). This picture could be different in recent-onset, dynamic obesity. Indeed Zucker rats have during their period of dynamic obesity with rapidly expanding fat stores a large increase in adipose tissue lipogenic capacity (20). Therefore, the possibility that the expression of lipogenic genes is also increased in adipose tissue of humans with dynamic obesity remains. The decreased expression of lipogenic genes that we observed in the present study could be a late and adaptive process aimed at limiting or preventing a further development of fat mass.
The decrease of FAS gene expression in adipose tissue contrasts anyway
with the enhanced hepatic lipogenesis, and the mechanisms behind this
discrepancy are unclear. Although there are some differences, as for
example in the way PUFA suppress the transcription of lipogenic genes
(34-36), the basic mechanisms responsible for the
regulation of the expression of the lipogenic pathway are considered to
be similar in hepatocytes and adipocytes (14, 19). Insulin
stimulates the transcription of lipogenic genes in rat hepatocytes and
adipocytes, and this action has been confirmed in human adipocytes
(8, 38). It is possible that the difference in insulin
concentration between portal and peripheral plasma plays a role in the
in vivo difference we observed between liver and adipose tissue
lipogenic capacity in obese patients. The raised leptin levels of obese subjects could also intervene. There are data supporting a suppressive action of leptin on the transcription of FAS (3) and
SREBP-1c (40) and on in vivo lipogenesis (7,
28). This action is present in both liver and adipose tissue,
but a direct, paracrine effect in adipose tissue could explain a more
marked action on adipocytes in vivo. The rise in SREBP-1c mRNA levels
in the presence of decreased leptin concentrations during energy
restriction in obese subjects would also support a role for leptin;
however, the trend for lower FAS mRNA concentrations after energy
restriction cannot be explained by these modifications of plasma leptin
and SREBP-1c mRNA levels. It remains possible that the active, nuclear form of SREBP-1c was decreased during energy restriction despite the
increase in mRNA levels. Tumor necrosis factor-, whose expression and secretion by adipocytes is increased in obesity (23),
could also explain the decrease in FAS mRNA levels, since it reduces the expression of several genes, including FAS, in adipocytes (12). Last, although it is clear that the transcription
factor SREBP-1c plays a major role in the regulation of lipogenic gene expression (16, 17), it should be kept in mind that
SREBP-1 alone is a weak activator of transcription and requires for its full action the presence of other transcription factors such as nuclear
factor-y and specificity protein-1 (31, 43).
Studies of the relative expression and interactions of SREBP-1 and its cofactors in liver and adipose tissue could help to better understand the decreased expression of lipogenic genes we observed in the adipose
tissue of obese patients and the discrepancy between the evolution of
SREBP-1c and FAS mRNA levels during energy restriction.
In conclusion, the present results are compatible with a role for enhanced hepatic lipogenesis in the development and/or maintenance of increased fat stores in obesity but do not support a role for increased lipogenic capacity of adipose tissue, at least for the maintenance of excess fat mass. This does not preclude the possible usefulness of inhibitors of FAS in the prevention or treatment of obesity, since such compounds have been shown in mice to act also through a decrease in appetite and food intake (30).
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ACKNOWLEDGEMENTS |
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We thank J. Peyrat for help in performing the tests and R. Cohen for the measurements of plasma leptin and insulin concentrations.
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FOOTNOTES |
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This work was supported by Fisheries and Agriculture Industrial Research Grant CT97-3011 from the European Economic Community.
Address for reprint requests and other correspondence: M. Beylot, INSERM U 499, Faculté RTH Laennec, Rue G Paradin, 69008, Lyon, France (E-mail: beylot{at}laennec.univ-lyon1.fr).
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. Section 1734 solely to indicate this fact.
Received 7 March 2001; accepted in final form 30 August 2001.
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1998[ISI][Medline].