Regulation of leptin secretion from white adipocytes by free fatty acids
Philippe G. Cammisotto,
Yves Gélinas,
Yves Deshaies, and
Ludwik J. Bukowiecki
Department of Anatomy and Physiology, Faculty of Medicine, Laval
University, Quebec, Canada G1K 7P4
Submitted 6 February 2003
; accepted in final form 2 May 2003
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ABSTRACT
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Norepinephrine stimulates lipolysis and concurrently inhibits
insulin-stimulated leptin secretion from white adipocytes. To assess whether
there is a cause-effect relationship between these two metabolic events, the
effects of fatty acids were investigated in isolated rat adipocytes incubated
in buffer containing low (0.1%) and high (4%) albumin concentrations. Palmitic
acid (1 mM) mimicked the inhibitory effects of norepinephrine (1 µM) on
insulin (10 nM)-stimulated leptin secretion, but only at low albumin
concentrations. Studies investigating the effects of the chain length of
saturated fatty acids [from butyric (C4) to stearic (C18) acids] revealed that
only fatty acids with a chain length superior or equal to eight carbons
effectively inhibited insulin-stimulated leptin secretion. Long-chain mono-
and polyunsaturated fatty acids constitutively present in adipocyte
triglyceride stores (oleic, linoleic,
-linolenic, palmitoleic,
eicosapentanoic, and docosahexanoic acids) also completely suppressed leptin
secretion. Saturated and unsaturated fatty acids inhibited insulin-stimulated
leptin secretion with the same potency and without any significant effect on
basal secretion. On the other hand, inhibitors of mitochondrial fatty acid
oxidation (palmoxirate, 2-bromopalmitate, 2-bromocaproate) attenuated the
stimulatory effects of insulin on leptin release without reversing the effects
of fatty acids or norepinephrine, suggesting that fatty acids do not need to
be oxidized by the mitochondria to inhibit leptin release. These results
demonstrate that long-chain fatty acids mimic the effects of norepinephrine on
leptin secretion and suggest that they may play a regulatory role as
messengers between stimulation of lipolysis by norepinephrine and inhibition
of leptin secretion.
insulin; albumin; saturated and unsaturated fatty acids;
-oxidation
LEPTIN, THE PRODUCT OF THE ob gene, is a hormone mainly
secreted by white adipocytes
(1,
14,
15,
41). Binding of leptin to its
hypothalamic receptors alters various messengers that regulate energy
expenditure, food intake, and the activity of the sympathetic nervous system,
at least in rodents (25).
Plasma leptin levels are tightly correlated with the total amount of white fat
in the body. Leptin has therefore been considered as a "lipostatic
factor" contributing to the regulation of body weight via a negative
feedback loop (10).
Several hormones can modulate leptin transcription and secretion in vivo
and in vitro, the most important being insulin and norepinephrine
(11,
16,
26). In vivo, starvation or
food deprivation decreases plasma leptin concentrations and leptin
transcription in adipose tissue. These changes are closely associated with
decreased plasma insulin concentrations, activation of the sympathetic nervous
system, increased lipolysis, and elevated plasma free fatty acid levels.
Refeeding or injection of insulin reverses the decrease of plasma leptin
concentrations and leptin transcription in rodents and in humans (for a review
see Ref. 9). Cold exposure is
another physiological condition that dramatically decreases plasma leptin
levels and leptin transcription in white adipocytes
(26). Similarly to starvation,
cold exposure activates the sympathetic nervous system, increases the levels
of circulating norepinephrine and free fatty acids, and decreases plasma
insulin concentrations (30,
38). These effects of cold
exposure can be mimicked in vivo by administration of norepinephrine or by
treatment with
-agonists in mice
(21,
22) and humans
(29,
37).
In vitro studies using isolated adipocytes have shown that insulin acutely
stimulates leptin secretion and that
-agonists such as norepinephrine,
isoproterenol, or CL-316243 exert a strong inhibitory effect on
insulin-stimulated leptin secretion
(5,
33). A wide range of agents,
such as lipolytic hormones (ACTH and TSH), inhibitors of phosphodiesterases
(caffeine, theophylline, IBMX, imazodan, milrinone, and amrinone), adenylate
cyclase modulators (forskolin and pertussis toxin), and nonhydrolyzable cAMP
analogs, all suppressed insulin-stimulated leptin secretion and concomitantly
stimulated lipolysis and fatty acid release
(5). On the other hand, insulin
is known to be a strong antilipolytic hormone that increases the transcription
of lipogenic enzymes (6,
12). These observations
suggest, but do not demonstrate, that fatty acids play a messenger role by
mediating the inhibitory effects of lipolytic agents on insulin-stimulated
leptin secretion (2,
39).
To test this hypothesis, freshly isolated white adipocytes were incubated
in the presence of insulin, norepinephrine, and a wide range of saturated and
unsaturated fatty acids. In addition, inhibitors of mitochondrial fatty acid
oxidation were used to investigate the mechanisms by which fatty acids may act
on leptin secretion. We now report that medium- and long-chain fatty acids
(saturated or unsaturated) acutely suppress the stimulatory effects of insulin
on leptin secretion. This effect is independent of mitochondrial fatty acid
oxidation and of an increase in leptin transcription. Results from this study
indicate that fatty acids may mediate the inhibitory effects of norepinephrine
and other lipolytic agents on insulin-stimulated leptin secretion.
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METHODS
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Chemicals. Fatty acid-free BSA, norepinephrine, butyric, caproic,
caprylic, capric, lauric, myristic, palmitic, stearic, oleic, linoleic,
-linolenic, conjugated linoleic, palmitoleic, eicosapentaenoic, and
docosahexanoic acids, glycerol, acetoacetate, acetone,
-hydroxybutyrate
and collagenase (type II, lot 107H8649), bromocaproate, and bromopalmitate
were obtained from Sigma-Aldrich Canada (Oakville, Ontario, Canada).
Palmoxirate was a generous gift from R. W. Johnson Pharmaceutical Research
Institute (Spring House, PA). Insulin (Humulin R) was purchased from Eli Lilly
(Toronto, Ontario, Canada).
Animals. Male Wistar rats were obtained from Charles River (St.
Constant, Quebec, Canada) and were housed in individual cages at 24°C with
a 12:12-h light-dark cycle. The rats received standard Purina chow and water
ad libitum. The mean body mass of the rats used in the present experiments was
290 ± 15 g.
Adipocyte isolation. Adipocytes were isolated from epididymal fat
pads by a slight modification of Rodbell's
(32) method. Briefly, rats
were killed by decapitation, and their epididymal fat pads were removed and
placed in Krebs-Ringer bicarbonate (KRB) buffer of the following composition:
120 mM NaCl, 4.75 mM KCl, 2.5 mM CaCl2, 1.2 mM
KH2PO4, 1.2 mM MgSO4, 25 mM
NaHCO3, 5.5 mM glucose, 20 mM HEPES, and 1% fatty acid-free BSA, pH
7.4 (1% KRB). The minced tissue was incubated in 1% KRB containing 0.5 mg/ml
collagenase at 37°C for 15-20 min with a shaking frequency of 150
cycles/min. At the end of incubation, the cells were filtered through a
500-µm nylon filter (Nitex) and diluted with 5 ml of 1% KRB. The floating
cells were washed four times with 1% KRB, preincubated at 37°C for 15 min
in 1% KRB (shaking frequency of 40 cycles/min), and washed two times with warm
(37°C) KRB containing 4% fatty acid-free BSA (4% KRB). Finally, the cells
were incubated under the same conditions for 2 h (unless otherwise specified)
in the presence of hormones or drugs at a concentration of 3-5 x
105 cells/ml 4% KRB. The adipocytes were then allowed to float, and
the infranatants were frozen at -20°C for leptin and glycerol
measurements.
Leptin and glycerol assays. Leptin concentrations were determined
by RIA using a kit available from Linco Research (St. Charles, MO). Glycerol
was measured using an enzymatic method
(40).
Statistics. The data were analyzed using ANOVA. Values represent
the means ± SE of a number of individual experiments performed on
separate occasions (n), as indicated in the text. The half-effective
concentrations for the reversal of palmitate inhibition in the presence of
increasing albumin concentration (IC50) were determined by computer
analysis (Sigma Plot program) of concentration-response curves.
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RESULTS
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Effects of norepinephrine, palmitic acid, and albumin on
insulin-stimulated leptin secretion. In previous studies
(5), we reported that
norepinephrine inhibited insulin (10 nM)-stimulated leptin secretion between
0.1 and 1 µM and concurrently increased lipolysis in the same range of
concentrations. This provided a first indication that inhibition of leptin
secretion might be metabolically associated with the stimulation of lipolysis.
To test whether fatty acids play a messenger role between stimulation of
lipolysis by norepinephrine and inhibition of leptin secretion, adipocytes
were incubated with insulin (10 nM) in the presence of norepinephrine (1
µM) or palmitic acid (1 mM; Fig.
1). Because albumin strongly binds extracellular fatty acids
(4), experiments were carried
out at low (0.1%) and high (4%) albumin concentrations. Palmitic acid (1 mM)
mimicked the inhibitory effects of norepinephrine (1 µM) on leptin
secretion at low but not at high albumin concentrations
(Fig. 1). This indicates that
albumin, at high concentrations, effectively binds extracellular fatty acids
and consequently inhibits their effects on leptin secretion. Therefore,
subsequent experiments were carried out at low albumin concentrations.
Concentration-response curves carried out in the presence of 0.1% albumin
revealed that palmitic acid inhibited insulin (10 nM)-stimulated leptin
secretion between 0.1 and 1 mM without significantly affecting basal values
(Fig. 2). In fact, the palmitic
acid effect critically depended on the ratio of the molar concentrations of
palmitic acid over albumin with an IC50 of 4.5
(Fig. 3). This is consistent
with the observation that one molecule of albumin has several low- and
high-affinity binding sites for long-chain fatty acids
(8).

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Fig. 1. Effects of norepinephrine (NE), palmitic acid (palm), and BSA on leptin
release. Adipocytes were incubated in the presence of insulin (10 nM) and
fixed concentrations of norepinephrine (1 µM) or palmitic acid (1 mM) in
the presence of low (0.1%) or high (4%) albumin concentrations. Bars and
vertical lines indicate means ± SE (n = 5).
**Significant differences compared with basal values at the level
of P < 0.01.
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Fig. 2. Concentration-response curve of the effect of palmitic acid on basal and
insulin-stimulated leptin secretion. Adipocytes were incubated in a medium
containing albumin (0.1%), insulin (10 nM), and various concentrations of
palmitic acid. The incubation conditions were as described under
METHODS (n = 5 experiments).
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Fig. 3. Effect of the molar ratio palmitic acid/albumin on insulin-stimulated
leptin secretion. Adipocytes were incubated in medium containing insulin (10
nM), palmitic acid (1 mM), and increasing concentrations of BSA (0.1-4%). The
molar ratio palmitic acid/albumin was calculated using 55,000 as the albumin
molecular weight. The incubation conditions were as described under
METHODS (n = 6).
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Effect of fatty acid chain length on insulin-stimulated leptin
secretion. Adipocytes were incubated in a medium containing albumin
(0.1%), insulin (10 nM), and various saturated fatty acids with a chain length
varying from 4 (butyric acid) to 18 carbons (stearic acid).
Concentration-response curves similar to those described for palmitic acid
(Fig. 3) were generated for all
fatty acids. Results for a fatty acid concentration of 1 mM are given in
Fig. 4 (as well as in Figs.
5 and
6), since the maximal effect
for all fatty acids occurred at this concentration. Results were expressed as
percentages of basal values observed in the absence of insulin. It can be seen
that fatty acids with a chain length equal or superior to eight carbons
markedly inhibited insulin-stimulated leptin secretion. These observations
indicate that the fatty acid effect is specific for medium- and long-chain
fatty acids.

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Fig. 4. Inhibition of insulin-stimulated leptin secretion by saturated FFAs of
various chain lengths. Adipocytes were incubated in the presence of insulin
(10 nM) and 1 mM of one of the following saturated fatty acids: butyric (C4),
caproic (C6), caprylic (C8), capric (C10), lauric (C12), myristic (C14),
palmitic (C16), and stearic (C18) acids. Albumin concentration in the medium
was 0.1%. Results were expressed by taking each respective fatty acid basal as
100% inhibitory values. The incubation conditions were as described under
METHODS (n = 5).
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Fig. 5. Inhibition of insulin-stimulated leptin secretion by unsaturated fatty
acids. Adipocytes were incubated in the presence of 10 nM insulin, 1 µM
norepinephrine (NE), or 1 mM of one of the following fatty acids: oleic
(C18:1), linoleic (C18:2), -linolenic (C18:2), conjugated linoleic
(CLA), palmitoleic (C16:1), eicosapentaenoic (C20:5), and docosahexaenoic
(C22:6) acids. Albumin concentration in the medium was 0.1%. Inhibition of
fatty acids and norepinephrine was compared with basal.
**P < 0.01.
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Fig. 6. Effect of inhibitors of mitochondrial fatty acid transport and oxidation on
the inhibitory effect of palmitate and norepinephrine on insulin-stimulated
leptin secretion. Adipocytes were incubated in the presence of insulin (10
nM), palmitic acid (1 mM), or norepinephrine (1 µM) and one of the
following agents: palmoxirate (X; 100 µM), 2-bromopalmitate (BrP; 10
µM), or 2-bromocaproate (BrC; 10 µM). Albumin concentration in the
medium was 0.1%. Effects of palmoxirate, 2-bromopalmitate, or 2-bromocaproate
were compared with their respective controls (bars without these inhibitors).
*P < 0.05 and **P < 0.01.
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Effects of various mono- and polyunsaturated fatty acids on
insulin-stimulated leptin secretion. To determine the importance of chain
unsaturation, adipocytes were incubated in medium containing albumin (0.1%),
with various unsaturated fatty acids (C18:1 oleic, C18:2 linoleic, C18:3
-linolenic, C16:1 palmitoleic, C20:5 eicosapentaenoic, C22:6
docosahexanoic, conjugated linoleic acids) in the presence of insulin (10 nM;
Fig. 5). Concentration-response
curves (data not shown) revealed that unsaturated fatty acids exerted their
inhibitory effects with IC50 values similar to that observed with
palmitic acid (Fig. 3). Thus
saturated and nonsaturated fatty acids inhibited insulin-stimulated leptin
secretion with the same potency and without any significant effect on basal
secretion.
Effects of inhibitors of fatty acid oxidation on insulin-stimulated
leptin secretion. To determine whether fatty acids need to be oxidized by
adipose tissue mitochondria to exert their inhibitory action, we used several
inhibitors of mitochondrial palmitate carnitine transferase
(Fig. 6). Palmoxirate (100
µM), 2-bromopalmitate (10 µM), or 2-bromocaproate (10 µM) was added
at optimal inhibitory concentrations
(19,
23), in the presence or
absence of insulin (10 nM), palmitate (1 mM), or norepinephrine (1 µM) in a
0.1% albumin medium. All carnitine transferase inhibitors slightly obtunded
the stimulatory effects of insulin on leptin release without reversing the
effects of palmitic acid or norepinephrine. On the contrary, their inhibitory
effect on insulin-stimulated leptin secretion was additive to the inhibitory
effect of palmitic acid or norepinephrine. Similar results were obtained with
several fatty acids such as lauric, oleic, linoleic, and docosahexanoic acids
(data not shown). These observations suggest that long-chain fatty acids,
saturated or not, do not need to be oxidized by adipose tissue mitochondria to
exert their inhibitory action on leptin secretion.
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DISCUSSION
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The present results demonstrate that long-chain fatty acids, the principal
products of activated lipolysis, acutely inhibit insulin-stimulated leptin
secretion from isolated adipocytes (Figs.
1,
2,
3,
4,
5,
6). We have previously shown
that insulin-stimulated leptin secretion can be inhibited by a wide variety of
agents known to increase intracellular cAMP concentrations either by
stimulating its production at the adenylate cyclase level (catecholamines,
lipolytic hormones, pertussis toxin, or forskolin), by inhibiting its
degradation by phosphodiesterases (methylxanthines, imazodan, milrinone, or
amrinone), or by mimicking its action (nonmetabolizable cAMP analogs; see Ref.
5). Without exception, all
these agents stimulated lipolysis in the range of concentrations at which they
inhibited insulin-stimulated leptin secretion. These observations, combined
with the present results, strongly indicate that fatty acids mediate the
inhibitory effects of lipolytic agents on insulin-stimulated leptin
secretion.
The fact that concentrations of albumin similar to those found in plasma
(4%) inhibit the effects of palmitic acid (1 mM) indicates that circulating
fatty acids (the concentration of which varies at the millimolar level) have
little influence on leptin secretion, at least directly (Figs.
1 and
3). This is supported by
several in vivo studies in humans, which failed to demonstrate any inhibitory
effects of fatty acids on plasma leptin concentrations
(35,
37). It is more likely that an
intracellular increase in fatty acids, generated in consequence of activated
lipolysis, causes the inhibition of leptin secretion. In the present studies,
the intracellular increase was mimicked by adding fatty acids in the presence
of low albumin concentrations. In fact, we previously demonstrated that it is
possible to dynamically titrate the effects of fatty acids on brown adipose
tissue thermogenesis with albumin
(4). The effects of fatty acids
were not directly proportional to the extracellular fatty acid concentration
but to the molar ratio of fatty acid concentration to albumin concentration.
In agreement with these observations, we found that palmitic acid inhibits
insulin-stimulated leptin secretion with an IC50 value of the molar
ratio of palmitic acid concentration to albumin concentration equal to 4.5
(Fig. 3). This value is also
compatible with the fact that a single molecule of albumin possesses several
binding sites for fatty acids with different affinities
(18). In addition, fatty
acid-binding proteins other than albumin are also present inside the cells.
Therefore, it is likely that the final fatty acid effect depends on the
concentration and the localization of intra- and extracellular binding
proteins (aP2 and others) as well as on the properties of membrane-associated
fatty acid transport proteins such as CD36
(8,
36).
There are several possible mechanisms by which fatty acids may regulate
leptin secretion. These mechanisms must include the facts that the fatty acid
effect is specific for medium- and long-chain fatty acids and that it does not
depend on their degree of saturation (Figs.
4 and
5). In addition, we have
attempted to determine whether fatty acids need to be oxidized to exert their
effects using three different inhibitors of palmitoyl carnitine transferase
(palmoxirate, 2-bromopalmitate, and 2-bromocaproate) that strongly inhibit the
oxidation of long-chain fatty acids
(19,
23). None of these agents
reversed the inhibitory effects of norepinephrine, palmitic acid
(Fig. 6), or other saturated or
unsaturated fatty acids (results not shown). On the contrary, all three
inhibitors slightly inhibited basal and insulin-stimulated leptin secretion
(Fig. 6), indicating that
leptin exocytosis, similarly to insulin exocytosis
(19), depends on some degree
of oxidation of long-chain fatty acids. However, although it is likely that
some fatty acids serve as an energy source for leptin secretion, mitochondrial
fatty acid oxidation does not appear to represent a metabolic step that is
absolutely required for observing the inhibitory effects of fatty acids.
Consistent with these observations, concentration-response experiments (data
not shown) revealed that ketone bodies (acetoacetate,
-hydroxybutyrate,
and acetone) and glycerol, added at concentrations varying between 5 and 10
mM, did not significantly affect insulin (10 nM)-stimulated leptin
secretion.
There are several other mechanisms by which fatty acids may inhibit
insulin-stimulated leptin secretion. First, fatty acids may specifically bind
mitochondrial uncoupling proteins (UCP) present in white adipocytes
(3). In brown adipocytes, it is
well established that fatty acids bind UCP-1, increase the permeability of the
inner mitochondrial membrane to protons, and consequently stimulate
thermogenesis. Although UCP-1 is not detectable in white adipocytes, a
regulatory effect of fatty acids on other UCPs (UCP-2, -3, or others) remains
to be tested.
Another possibility is that fatty acids directly affect either
transcription or translation of leptin mRNA. It has been reported that, in the
pancreas, palmitate inhibits the transcription of the insulin gene
(31). Likewise, the inhibitory
role of polyunsaturated fatty acids on numerous tissue gene transcription
factors is very well documented
(7,
28). Using Northern blots, we
have found that, under the present conditions, insulin, norepinephrine, or
fatty acids do not affect leptin mRNA levels (data not shown). This suggests
that the short-term regulation of leptin secretion principally occurs at the
posttranscriptional level. This finding was not unexpected because of the
short period of time (2 h) within which leptin secretion was influenced by
hormones and fatty acids. It should be emphasized that the mechanisms by which
fatty acids affect leptin secretion might be different in the short and long
term. Indeed, in cell culture experiments, it has been reported that some
fatty acids inhibit basal leptin transcription in the absence of insulin or
other stimulating agents (17,
27,
34). Our work is the first to
provide extensive data on the acute effects of fatty acids on leptin secretion
using a wide range of fatty acids naturally present in adipose tissue
triglycerides (24).
In summary, the present results demonstrate that fatty acids mimic the
effects of norepinephrine on leptin secretion. This effect is specific for
medium- and long-chain fatty acids and does not depend on their degree of
saturation. The fatty acid action does not directly require their oxidation.
Consequently, long-chain fatty acids may play an important metabolic role as
messengers between the hormonal activation of lipolysis and the final
inhibition of leptin secretion from white adipocytes.
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DISCLOSURES
|
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This work was supported by a grant from the Canadian Institutes of Health
Research.
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FOOTNOTES
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Address for reprint requests and other correspondence: L. J. Bukowiecki,
Faculty of Medicine, Dept. of Anatomy and Physiology, Laval Univ., Quebec,
Canada G1K 7P4 (E-mail:
ludwik.bukowiecki{at}phs.ulaval.ca).
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.
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