Effect of hypothyroidism on pathways for iodothyronine and
tryptophan uptake into rat adipocytes
James W. A.
Ritchie,
Charmian J. F.
Collingwood, and
Peter M.
Taylor
School of Life Sciences, University of Dundee, Dundee DD1 5EH,
Scotland, United Kingdom
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ABSTRACT |
Adipocytes are an important
target tissue for thyroid hormone action, but little is known of the
mechanisms of thyroid hormone entry into the cells. The present results
show a strong interaction between transport of iodothyronines
[L-thyroxine (T4),
L-triiodothyronine (T3), reverse
T3 (rT3)], aromatic amino acids,
and the System L amino acid transport inhibitor
2-amino[2,2,1]heptane-2-carboxylic acid (BCH) in white adipocytes.
System L appears to be a major pathway of iodothyronine and large
neutral amino acid entry into these cells in the euthyroid state. We
also demonstrate expression of the CD98hc peptide subunit of the System
L transporter in adipocyte cell membranes. Experimental hypothyroidism
(28-day propylthiouracil treatment) has no significant effect on System
L-like transport of the amino acid tryptophan in
adipocytes. In contrast, uptake of T3 and especially
T4 is substantially reduced in adipocytes from hypothyroid
rats, partly due to reduction of the BCH-sensitive transport component.
Transport of iodothyronines and amino acids in adipocytes therefore
becomes decoupled in the hypothyroid state, as occurs similarly in
liver cells. This may be due to downregulation or dissociation of
iodothyronine receptors from the System L transporter complex.
Regulation of iodothyronine turnover in fat cells by this type of
mechanism could contribute significantly to modulation of
T4-T3/rT3 metabolism in the
hypothyroid state.
adipose tissue; amino acid; thyroid hormone; membrane transport
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INTRODUCTION |
THE THYROID
HORMONES L-thyroxine (T4) and
L-triiodothyronine (T3) exert their major
physiological effects by regulating gene expression in target cells.
The hormones must therefore cross the plasma membrane to reach their
intracellular destination within the nucleus (12, 13).
White adipose tissue is an important target tissue for thyroid hormone
action, where effects include modulation of fatty acid synthesis via
regulation of expression of lipogenic enzymes (3) as well
as modulation of hormone sensitivity via regulation of expression of
receptor number (29). There is a surprising lack of
knowledge of the mechanisms of thyroid hormone entry into adipocytes,
although there is growing evidence that iodothyronines enter other cell
types using a variety of mechanisms (1, 4, 7, 15, 32)
including transporters for large zwitterionic amino acids (4, 25,
28).
The major transporter of large zwitterionic amino acids in mammalian
cells is termed System L (16, 30) and is composed of a
heterodimer of two peptides, CD98hc and an isoform of the LAT permeases (5). We have recently established that this
transporter also accepts iodothyronines as substrates
(25). Major System L substrates also include the
branched-chain amino acids (BCAA) and aromatic amino acids (16,
24). Rat adipose tissue is a site of significant BCAA
degradation and utilization for fatty acid synthesis (8,
27). BCAA (notably leucine) also appear to be involved in
modulation of the p70S6 kinase signaling pathway in
adipocytes (6). Nevertheless, the mechanisms effecting and
modulating transport of BCAA and aromatic amino acids in adipose tissue
are as poorly characterized as those of iodothyronines. In the present
study, we have therefore investigated routes of entry of iodothyronines
into fat cells, focusing on pathways that interact with transport of
large zwitterionic amino acids, as well as on effects of hypothyroidism
on the uptake processes.
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EXPERIMENTAL PROCEDURES |
Materials and animals.
All chemicals were obtained from Sigma (Poole, UK) unless stated
otherwise. Radioactive tracers were obtained from NEN Research Products
(Stevenage, UK). Male Wistar rats of 250 g initial weight were
purchased from Bantin and Kingman (Hull, UK) and maintained on a
standard laboratory diet. Rats were made hypothyroid by addition of
0.05% propylthiouracil (PTU) to drinking water for 28 days (15,
21). Development of a hypothyroid state was confirmed from
measurement of markedly elevated plasma thyroid-stimulating hormone
(TSH) concentration (35.5 ± 6.0 mU/l; n = 8 rats)
relative to control rats (3.3 ± 0.7 mU TSH/l; n = 8).
Isolation of adipocytes.
Hypothyroid and control (euthyroid) rats were killed by cervical
dislocation, and their epididymal fat pads were removed immediately. Adipocytes were harvested at 37°C from the fat pads by use of collagenase (type II) in Krebs-Ringer phosphate buffer, pH 7.4, containing 20 mg/ml bovine serum albumin (26).
Transport studies.
Tryptophan (Trp) and iodothyronine uptakes were measured at 37°C in
450 µl of the cell suspension, to which were added 50 µl of
reaction buffer to start measurement. For Trp studies, the reaction
buffer consisted of Krebs-Ringer containing
L-[3H]Trp (0.05 mM final concentration unless
stated otherwise) and [14C]inulin as an extracellular
marker with a 3H-to-14C ratio of 10:1. For
iodothyronine studies, the reaction buffer consisted of Krebs-Ringer
containing [125I]T4 (4 nM) or
[125I]T3 (4.5 nM unless stated
otherwise), and extracellular ([14C]inulin) space was
measured in separate experiments performed in parallel. The cell
suspension was continuously agitated during the incubation period.
Uptake was terminated after a timed period by transferring 300 µl of
the reaction mixture to a 400-µl Eppendorf microtest tube (BDH,
Poole, UK) containing 100 µl of diisononylphthalate (Riedel-de Haen,
Aberdeen, UK) and by centrifuging for 20 s in a microcentrifuge.
The adipocytes remained on top of the oil while the reaction buffer
passed through the oil layer to lie below it. The test tube was then
cut in two just above and below the cell layer, and the section of tube
containing the cells was transferred to a scintillation vial for liquid
spectrometric assay of radioactivity. Tracer uptake into adipocytes was
corrected for adhering extracellular radioactivity (estimated as
[14C]inulin space). Adipocyte cell number was estimated
by counting live (trypan blue-excluding) cells under a microscope with
the use of a hemocytometer.
In certain experiments, adipocytes were preincubated with either the
endocytosis inhibitor monodansylcadaverine [0.1 mM;
(14)] or the organic anion hippurate (0.1-10 mM) for
30 min before uptake assay.
Membrane isolation and Western blotting.
Adipocyte membranes were prepared by subcellular fractionation as
described elsewhere (11). Membrane proteins were resolved by SDS-PAGE and electroblotted onto nitrocellulose membranes. CD98hc
(4F2hc) protein (5, 30) was detected immunologically using
enhanced chemiluminescence (Amersham) with anti-rat CD98hc (goat)
obtained from Santa Cruz Biotechnology (Santa Cruz, CA). The primary
antibody was used at 1:250 and horseradish peroxidase-labeled secondary
antibody (donkey anti-goat; Scottish Antibody Production Unit, Carluke,
UK) was used for visualization.
Data analysis.
The data are expressed as means ± SE for n adipocyte
preparations, where each experimental measurement in an individual
preparation was performed in triplicate. Statistical significance was
assessed using Student's t-test; differences were
considered significant where P < 0.05.
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RESULTS |
Iodothyronine uptake into euthyroid rat adipocytes.
In preliminary experiments, we established that uptake of
[125I]T4 and
[125I]T3 was linear with time for
15 min
(Fig. 1A). In experiments described below, the initial rate of tracer iodothyronine uptake was
measured over 10 min. Extrapolation of uptake to zero time for the two
tracers revealed instantaneous binding components equivalent to 11 and
37% of total uptake over this time period for T4 and
T3, respectively (Fig. 1A). Total uptake of
T4 and T3 (at 4 and 4.5 nM, respectively) into
adipocytes included substantial saturable components (Fig.
2) that were sensitive to inhibition by
iodothyronines including reverse T3 (rT3; Fig.
2) and also by the amino acids Trp, phenylalanine, and
2-amino[2,2,1]heptane-2-carboxylic acid (BCH; Fig. 2 and data not
shown). The iodothyronine concentration used in inhibitor experiments
(10 µM) is close to the water solubility limit of these compounds,
and concentrations of amino acid inhibitors used were found to produce
maximal effects in preliminary experiments. The synthetic amino acid
analog BCH is used throughout this study as a specific inhibitor of
System L-mediated solute transport (16, 24).

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Fig. 1.
Time courses of uptake of thyroxine (T4;
A), triiodothyronine, and tryptophan (T3;
A Trp; B) into euthyroid rat adipocytes.
A: uptake of [125I]-labeled T4 (4 nM) or [125I]-labeled T3 (4.5 nM) was
measured over the denoted time periods at 37°C in isolated rat
adipocytes. Results are presented as total iodothyronine uptake,
expressed as means ± SE for 3 (T4) or 6 preparations
(T3). B: uptake of [3H]Trp (1 µM) was measured over the denoted time periods at 37°C in isolated
rat adipocytes. Results are presented as total Trp uptake, expressed as
means ± SE for 4 preparations.
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Fig. 2.
Effect of amino acids and iodothyronines on uptake of
T4 and T3 into isolated euthyroid rat
adipocytes. Uptake of [125I]T4 (4 nM) or
[125I]T3 (4.5 nM) was measured in the
presence and absence of potential inhibitors for 10 min at 37°C in
isolated rat adipocytes. Results are presented as means ± SE for
4-8 preparations. All inhibitions were significantly different
from zero (P < 0.05). Inhibitor concentrations used
were: Trp, 10 mM; 2-amino[2,2,1]heptane-2-carboxylic acid (BCH), 1 mM; T4, reverse T3, and T3 10 µM.
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System L transport in euthyroid rat adipocytes.
In view of the inhibitory effect of BCH on tracer T4 and
T3 uptake, we subsequently focused on System L transport as
a major pathway for iodothyronine transport in adipocytes. Western
blotting confirmed the presence of the System L transporter heavy chain (CD98hc) in adipocyte membranes (Fig. 3).
The CD98hc glycoprotein is seen as a broad band centered at 86 kDa
under reducing conditions and as a 130-kDa protein complex [presumably
with transporter light chains such as LAT1 (5, 30)] under
nonreducing PAGE conditions. This is consistent with previous
observations of the behavior of CD98hc protein in other cell types
(5, 30). We next investigated interactions between
iodothyronines and amino acid substrates of System L. We used Trp as
our amino acid of study because it is a System L substrate and has
well-characterized interactions with iodothyronine transport in several
cell types (4, 15, 28). Uptake of
L-[3H]Trp tracer into adipocytes reached an
equilibrium value within 1 min (Fig. 1B), and the initial
rate of tracer tryptophan uptake was measured over 10 s.
Extrapolation of Trp uptake to zero time revealed an instantaneous
binding component equivalent to 52% of total uptake over this time
period (Fig. 1B). Trp uptake into adipocytes was unaffected
by replacement of Na+ in the transport buffer with choline
ions and therefore appears to be Na+ independent (data not
shown). Uptake of 1 µM [3H]Trp into adipocytes included
a substantial saturable component (Table
1) that was sensitive to inhibition by
excess of large zwitterionic amino acids (unlabeled L- and
D-Trp, phenylalanine, BCH; Table 1 and data not shown), as
well as by iodothyronines, including T4, rT3,
and, to a lesser extent, T3 (Table 1). Inhibition of Trp
uptake by T4 and BCH was not additive (therefore it may occur possibly by a common System L-mediated pathway; see Table 1).
Saturable Trp uptake at Trp concentration ([Trp]) between 1 µM and 5 mM (Fig. 4) appeared to
consist of a single transport component with estimated values for the
Michaelis-Menten constant of 0.23 mM and maximal velocity of 40 pmol
Trp · 100,000 cells
1 · 10 s
1.

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Fig. 3.
Expression of CD98hc in rat adipocyte membranes. Western
blot of euthyroid adipocyte membrane proteins (40 µg) probed with
anti-rat CD98hc. Samples prepared under reducing and nonreducing
conditions [with and without -mercaptoethanol (B-MeOH),
respectively] are shown in adjacent lanes. Rat kidney microsomes are
shown as a positive control where indicated.
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Fig. 4.
Saturable Trp uptake into euthyroid rat adipocytes. Hanes
plot relating [3H]Trp uptake in euthyroid rat adipocytes
(corrected for nonsaturable component) against external Trp
concentration. Inset: raw transport data (n = 3 measurements at each [Trp]). The saturable transport component
has an estimated Michaelis-Menten constant of 0.23 mM and maximum
velocity of 40 pmol Trp · 100,000 cells 1 · 10 s 1.
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The instantaneous (zero-time) binding components of T4,
T3, and Trp tracers were not displaced by excess unlabeled
BCH (1 mM); thus a BCH-sensitive transport component represents the
major part (61, 67, and 52%, respectively) of the "time-dependent"
tracer influx (i.e., total uptake
instantaneous uptake) for all
three tracers. The balance of total tracer uptake is likely to include components from specific high-affinity binding sites, partitioning of
tracer into the adipocyte membrane, passive diffusion, and endocytosis.
Some involvement of the latter process in total Trp uptake is indicated
by the fact that it is partly inhibited by the endocytosis inhibitor
monodansylcadaverine (Table 1), although monodansylcadaverine had no
statistically significant effect on uptake of iodothyronines by
adipocytes (data not shown). The organic anion hippurate had no
significant effect on Trp or T3 uptake, although it had a
slight (35 ± 4%) stimulatory effect on T4 uptake.
Effects of hypothyroidism and desipramine on iodothyronine uptake
into rat adipocytes.
Experimental hypothyroidism resulted in substantial decreases in both
saturable and total uptake of T4 and (to a lesser extent) T3 by adipocytes (Fig. 5).
The decrease occurred largely in an uptake component sensitive to
inhibition by BCH, indicative of reduced iodothyronine transport
through System L (Table 2). In contrast,
BCH-sensitive Trp transport in adipocytes (an index of overall System L
transport activity) was not significantly affected by altered thyroid
status from the euthyroid value (Table 2). Overall, these data are
consistent with an uncoupling of iodothyronine uptake from System
L-mediated amino acid transport in hypothyroid adipocytes. A
substantial component of uptake of both iodothyronines and Trp in
euthyroid adipocytes was also sensitive to inhibition by the tricyclic
antidepressant desipramine (Table 3).
Desipramine is reported to interact with iodothyronine uptake into rat
brain in a manner dependent on thyroid status (9) and also
to inhibit Trp transport by System L [CD98-IU12 heterodimers (25)] expressed in Xenopus oocytes
(unpublished observations of J. W. A. Ritchie, G. R. Christie and P. M. Taylor). Desipramine-sensitive transport of
T4, but not of Trp, is significantly reduced in adipocytes from hypothyroid rats (Table 3), an effect similar to that seen with
BCH-sensitive transport of these substances (Table 2).

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Fig. 5.
Uptake of T4 (A) and
T3 (B) in euthyroid and hypothyroid rat
adipocytes. Uptake of [125I]T4 (4 nM) or
[125I]T3 (4.5 nM) tracers was measured in the
presence and absence of unlabeled iodothyronine competitors
(T4 and T3, both at 10 µM) for 10 min at
37°C in isolated rat adipocytes. Results are expressed as means ± SE for 4-6 preparations. Tracer uptake in the absence of
inhibitor was significantly (P < 0.05) lower in
hypothyroid than in euthyroid state for both T4 and
T3. Inhibition of tracer uptake by unlabeled iodothyronines
was statistically significant (P < 0.05), except where
denoted not significant (NS).
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Table 2.
Effect of experimental hypothyroidism on iodothyronine and tryptophan
uptake by System L in rat adipocytes
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Table 3.
Desipramine-sensitive uptake of iodothyronines and tryptophan in
euthyroid and hypothyroid rat adipocytes
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DISCUSSION |
The present studies have revealed strong interactions between
transport processes for iodothyronines and large zwitterionic amino
acids in white adipocytes from the rat. These interactions (plus common inhibition of uptake by BCH) indicate that the
Na+-independent System L transporter contributes
substantially to iodothyronine and large neutral amino acid transport
in adipocytes, at least in the euthyroid state. This view is supported
by our previous discovery that iodothyronines (including
T4, T3 and rT3) are substrates for
the System L transporter overexpressed in oocytes (25) and
is strengthened by the observations that rT3 is an effective inhibitor of the uptake of Trp, T4, and
T3 into rat adipocytes. We have further observed that both
L- and D-Trp inhibit tracer L-Trp
and L-T3 transport in adipocytes, and this lack
of stereoselectivity for L-isomers as substrates is also
consistent with known functional characteristics of System L (16,
30). Functional measurements of System L transport activity in
adipocytes are supported by immunological detection of the CD98hc
subunit of the heteromeric System L transporter in adipocyte cell
membranes. Self and reciprocal inhibition between uptake of
T4 and T3 into adipocytes is not significantly
greater than inhibition by BCH. System L may therefore be the major
carrier for iodothyronines in the adipocyte plasma membrane and thus
for delivery of thyroid hormones from the plasma to the cytosol, where,
ultimately, they reach the cell nucleus. Certain organic anion
transporters are also known to accept iodothyronines as substrates
(1, 7). The organic anion hippurate does not inhibit
either iodothyronine or Trp transport here (indeed, it has a minor
stimulatory effect on T4 uptake), but we cannot exclude the
possibility that some iodothyronines cross adipocyte membranes by
hippurate-insensitive organic anion transporters. A small but
significant proportion of Trp uptake may be by an endocytotic pathway
inhibitable by monodansylcadaverine (14), but we find no
evidence that this pathway is an important route for iodothyronine
entry into adipocytes.
The antidepressant desipramine inhibits both iodothyronine and Trp
uptake in euthyroid adipocytes and is also reported to affect uptake
and turnover of thyroid hormones and Trp in other rat tissues (2,
9). We now have evidence that desipramine inhibits Trp uptake by
System L overexpressed in Xenopus oocytes and here show that
desipramine- and BCH-sensitive T4 uptakes are reduced to a
similar extent in hypothyroid rat adipocytes. These observations are
consistent with our suggestion that System L mediates the greater part
of saturable iodothyronine transport in adipocytes. Nevertheless, the
diverse effects of desipramine also include potent inhibition of
transporters for biogenic amines (e.g., norepinephrine, serotonin).
Therefore, given that there is a high activity of norepinephrine
transport in white adipocytes (23), we cannot exclude the
possibility of additional interactions between amine and amino acid
receptor-transporter mechanisms in the process of iodothyronine uptake
by adipocytes.
T4 and rT3 are more effective inhibitors than
T3 of Trp uptake under our experimental conditions. We did
not find them to be preferred over T3 as substrates of
System L overexpressed in oocytes (25), but it is
conceivable that they are preferentially targeted for transport by
specific receptors in the adipocyte membrane. There is evidence that
iodothyronine transport in other cell types (e.g., hepatocytes,
erythrocytes) may be facilitated by co-operative interactions between
transporters and iodothyronine receptors on the plasma membrane
(15, 28, 32). High-affinity receptors for both
T4 and T3 have been identified associated with the plasma membrane of adipocytes (17, 22), and these may be involved in iodothyronine uptake.
The System L transporter is likely to be the major saturable route of
entry for large neutral amino acid transport into adipocytes. In
contrast, small neutral amino acids are reported to be taken up into
adipocytes by the Na+-dependent amino acid transport
systems A (10) and ASC (19). Experimental
hypothyroidism has no significant effect on BCH-sensitive uptake of Trp
in adipocytes, indicating that there is no overall change in System L
transporter activity in this condition. In contrast, there are
substantial reductions in saturable uptake of T3 (by 48%)
and in particular T4 (by 79%) in adipocytes from hypothyroid rats, due at least partly to reduction in activity of a
BCH-sensitive transport component. These results are consistent with an
uncoupling between transport of iodothyronines and amino acids in the
hypothyroid state, as we have observed previously in liver cells
(15). Thus BCH-sensitive amino acid transport is retained,
but that of thyroid hormones is reduced, arguing against a generalized
effect of hypothyroidism, such as change in cell size
(20), on adipose tissue transport properties. We have
hypothesized elsewhere that thyroid-dependent interactions between
transport of iodothyronines and amino acids include downregulation or
decoupling of iodothyronine receptors from an amino acid transporter complex in the hypothyroid state (15). The System L
transporter heavy chain CD98hc is known to exhibit functional
interactions with other membrane proteins (e.g., integrins) in addition
to its covalent associations with a transporter light chain such as
LAT1 (5); therefore, a direct interaction between CD98hc and iodothyronine receptors is conceivable.
White adipose tissue has the capacity to deiodinate T4 and
(especially) rT3 by action of 5'-deiodinase
(31). Given that white adipose tissue represents ~18%
of body mass on average, regulation of iodothyronine turnover in fat
cells through this pathway could contribute significantly to modulation
of whole body T4-rT3 metabolism. It is
therefore relevant to note that the system L transporter operates an
exchange mode (16, 30) that may enable amino
acid-T4 or T4-T3/rT3
exchanges (15, 32) across the adipocyte plasma membrane.
Further work is required to reveal whether this mechanism also
contributes to the metabolically important processes of iodothyronine
turnover in brown adipose tissue (29). Rat adipose tissue
in vivo releases tyrosine (18), a System L substrate that
may exchange at least partly for uptake of iodothyronines. In the
hypothyroid state, downregulation of transport at the cell
membrane would tend to reduce T4 and rT3 catabolism and help conserve hormone and iodine availability to other
tissues. Adipose tissue sensitivity to hormonal activation is generally
repressed in hypothyroidism, but the relative retention of
T3 uptake capacity should enable this more active hormone
to maintain some metabolic effect in adipocytes. System L transport activity for amino acids in adipocytes is not downregulated by hypothyroidism, and indeed, there is evidence that BCAA metabolism in
fat tissue is increased in hypothyroidism (8), driven by upregulation of BCAA catabolic enzymes in adipocytes.
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ACKNOWLEDGEMENTS |
We are indebted to Ian Hannings (Ninewells Hospital and Medical
School, Dundee) for measurement of plasma TSH concentrations, Dr. Gary
Litherland for preparation of rat adipocyte membranes, and Tatiana
Panova for technical assistance.
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FOOTNOTES |
This work was supported by the UK Biotechnology and Biological Sciences
Research Council and the University of Dundee.
Address for reprint requests and other correspondence: Dr.
Peter M. Taylor, School of Life Sciences, MSI/WTB Complex, Univ. of
Dundee, Dundee DD1 5EH, Scotland, UK (E-mail:
p.m.taylor{at}dundee.ac.uk).
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 2000; accepted in final form 20 October 2000.
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