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TOXICOLOGY
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio (J.E.S., J.S.); Virginia College of Osteopathic Medicine and Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia (J.E.S., T.L.G.); and Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin, Texas (X.Y., E.M.M.)
Received May 12, 2006; accepted September 28, 2006.
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Abstract |
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-methylbenzylamine potentiated the hyperthermic effects of a 20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion according to levels of circulating plasma TH. Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression. Acute TH supplementation did not change the skeletal muscle UCP3 expression levels or temperature responses to MDMA. These findings suggest that, although MDMA-induced hyperthermia appears to result from increased NE and FFA levels, susceptibility is ultimately determined by TH regulation of UCP3-dependent thermogenesis.
). The lack of therapeutic options for the management of hyperthermia probably results from an inadequate understanding of the basic molecular mechanisms of thermogenesis.
The principal active thyroid hormone (TH) 3,5,3'-triiodo-L-thyronine is formed from the precursor 3,5,3',5'-tetraiodothyronine (T4, thyroxine) by deiodinases present in various tissues (Bianco and Larsen, 2005). Although TH has been established as the primary endocrinologic regulator of body temperature (Silva, 2005) and facultative thermogenesis (FT) (for review see Lowell and Spiegelman, 2000), the mechanisms involved are complex and incompletely characterized. One family of genes regulated by TH (Gong et al., 1997) and believed to play a significant role in FT encodes for the mitochondrial uncoupling proteins (UCPs).
UCPs "uncouple" free energy stored in the mitochondrial electrochemical proton gradient from ATP synthesis by regulating an inducible, thermogenic proton leak pathway (Krauss et al., 2005). The prototype UCP1 mediates FT in brown adipose tissue (BAT), an organ specialized for heat production in hibernating mammals and rodents (Lin and Klingenberg, 1980). However, because of the absence of BAT in humans, skeletal muscle (SKM) plays a much larger and more significant role in the thermogenic response to sympathetic nervous system (SNS) stimulation (Astrup et al., 1989; Ye et al., 1996; Rose et al., 1999). This FT is thought to be mediated by norepinephrine (NE)-induced activation of a TH-regulated homolog of UCP1 (UCP3), found primarily in SKM (Gong et al., 1997; Lombardi et al., 2002).
The sympathetic nervous system is the major regulator of fat mobilization in human skeletal muscle and white adipose tissue. In a mechanism similar to FT induction in BAT, SKM UCP3 activation is believed to be mediated by concerted activation of 1- and 
3-adrenergic receptors (1AR + 3AR) in SKM, leading to cAMP-dependent liberation of free fatty acids (FFAs), which are required for UCP activation (Zhao et al., 1997). In addition, 1AR, 3AR, and triglyceride lipase mediate white adipose tissue lipolysis and FFA liberation into the bloodstream (for review, see Raynor, 2001). Supported also by adrenoceptor expression studies in human tissues (Revelli et al., 1993; Chamberlain et al., 1999), these findings suggest a model in which the sympathetic nervous system may contribute to SKM UCP3 activation by increasing both circulating and i.m. generated fatty acids. Further support for the role of UCP3 in FT stems from the observation that UCP3-deficient (UCP3–/–) mice show almost complete protection from hyperthermia induced by the potent sympathomimetic agents 3,4-methylenedioxymethamphetamine (MDMA) (Mills et al., 2003) and methamphetamine (Sprague et al., 2004). The present study was designed to determine whether a TH-SNS-SKM-UCP3 axis may contribute to MDMA-induced hyperthermia in rats by examining the relationships between fluctuations in FFA, NE, and epinephrine (Epi) levels, acute and chronic changes in thyroid status, SKM UCP3 protein expression, and the extent of MDMA-induced changes in core body temperatures.
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Materials and Methods |
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Surgical procedures for thyroparathyroidectomy have been described previously (Sprague et al., 2003). Calcium needed to be maintained in these animals because of removal of the parathyroid gland, so TX animals were administered 2 to 4% calcium lactate solution as a drinking source for the duration of the experiment. Experiments were performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication 80-23, revised 1996) and were approved by the Virginia Tech and Ohio Northern Animal Care and Use Committees.
Drugs and Chemicals. MDMA was generously donated by Dr. David E. Nichols (Purdue University, West Lafayette, IN). Levothyroxine was purchased from Ameriasource-Bergen (Williamston, MI); ±2,3-dichloro--methylbenzylamine (DCMB) and all other chemicals and reagents were obtained from Sigma Chemical (St. Louis, MO).
Study Design. Male Sprague-Dawley rats were used to obtain blood samples via ventricular puncture for analysis of FFA levels. Rats were injected with either saline or MDMA (40 mg/kg s.c.) at time 0; the saline group (n = 6) was immediately sacrificed, and blood samples were obtained, whereas the two MDMA groups (n = 6) were sacrificed at 30 and 60 min post-treatment to procure blood samples in the same manner as the saline group. The dose of MDMA used in the present study is in accordance with previous reports (Mills et al., 2003; Sprague et al., 2003) and represents a severe human poisoning model where the degree change in temperature correlates with human mortality rates of 
45% (Gowing et al., 2002).
A crossover study design was used to investigate plasma NE and Epi levels, so each jugular vein-cannulated male Sprague-Dawley rat served as its own control. On the 1st treatment day, animals received a pretreatment of saline or DCMB (0.4 mmol/kg i.p.) 1 h prior to a main treatment of saline. DCMB is an inhibitor of phenylethanolamine N-methyltransferase (Fuller et al., 1973) and was administered to prevent elevations in plasma levels of Epi and increase levels of NE. The half-life of DCMB in the adrenal glands is 3.4 h (Fuller et al., 1973), so 24 h were given to allow full clearance before the groups (n = 6) were switched, and the second phase of the study was started, using MDMA (20 mg/kg s.c.) as the main treatment. Because combining DCMB with MDMA treatment was hypothesized to potentiate the hyperthermic response, dosing for these animals was reduced relative to that used in other portions of the study to prevent lethal complications.
For the chronic TH study, control euthyroid (EU) and TX male Sprague-Dawley rats with (HYPER) or without (HYPO) chronic thyroxine supplementation (levothyroxine 100 µg/kg i.p. daily for 7 days) were used to maintain a consistent thyroid status and avoid the confounding effects of autoregulation of plasma TH levels through an intact hypothalamic-pituitary-thyroid axis. To determine effects of acute changes in T4 status on MDMA-induced thermogenesis and UCP3 expression, HYPO and EU subjects were administered levothyroxine (100 µg/kg i.p.) 30 min before challenge with MDMA. TX and corresponding shams were treated with MDMA (40 mg/kg s.c.) or saline 1 week postsurgery. Animals were randomly allocated to the following treatment groups: sham (EU)-MDMA (n = 6), TX (HYPO)-MDMA (n = 9), sham (EU)-saline (n = 6), TX-chronic levothyroxine (HYPER; n = 5), HYPO-acute levothyroxine (n = 6), and sham (EU)-acute levothyroxine (n = 8).
Temperature Measurements. Temperatures of the animals used in the FFA study were taken just before and 30 and 60 min after the administration of saline or MDMA. Rectal temperatures for the plasma NE and Epi study were taken at 30-min intervals beginning just before the pretreatment and continuing until 1 h after the main treatment for a total of five measurements. Core temperatures for the TH study were determined in all animals before saline or MDMA administration and at 1, 2, and 3 h post-treatment as described. All rectal temperatures were measured using a Physiotemp Thermalert TH-8 thermocouple (Physitemp Instruments, Clifton, NJ) attached to a RET-2 rectal probe.
FFA Determination. Plasma nonesterified fatty acid levels were determined by the acyl-CoA synthetase-acyl-CoA oxidase method at the Diagnostic Laboratory of the College of Veterinary Medicine at Cornell University (Ithaca, NY). In brief, acyl-CoA was combined with the plasma to create CoA thiol esters. Acyl-CoA oxidase was then added, generating hydrogen peroxide, which along with included peroxidase oxidatively condensed 3-methyl-N-ethyl-N-(-hydroxy-ethyl)-aniline and 4-aminoantipyrine. This created a purple adduct that allowed for measurement of nonesterified fatty acids due to maximal absorption at 550 nm.
Plasma NE and Epi Analysis. Plasma was obtained via blood draws amounting to 500 µl each, obtained at three different time points: the time of the pretreatment and 30 and 60 min after the main treatment. After removal, blood was placed into Microtainer tubes with lithium heparin and centrifuged for extraction of plasma, which was subsequently stored at –80°C until analysis could be completed.
Plasma samples (70–100 µl) were prepared using the methods of Holmes et al. (1994) for analysis of NE and Epi levels. The only modifications were injection of samples and maintenance of the column at room temperature. Mobile phase consisted of 0.05 M sodium phosphate, 0.03 M citric acid buffer (with a pH range of 2.1–3.9), 0.1 mM EDTA, 0.42% sodium octyl sulfate, and 15% methanol. A high-performance liquid chromatography (480 series) with electrochemical detection (LC-44) and a C18 reverse-phase analytical column (3.0 mm i.d. x 10 cm o.d., 3 µm) was used (Bioanalytical Systems, Inc., West Lafayette, IN). ChromGraph 2.34 software (Bioanalytical Systems, Inc.) was used to integrate and analyze the raw data for the determination of Epi and NE levels, compared with internal standard curves.
Determination of T4 Levels. Immediately following temperature recordings in response to MDMA treatments in HYPO, EU, and HYPER groups, animals were euthanized, blood was drawn for plasma T4 measurements, and gastrocnemius biopsies were obtained for the determination of mitochondrial UCP3 expression by Western blots. Measurement of total plasma T4 levels was conducted using a SNAP T4 (Indexx Laboratories, Sacramento, CA) enzyme-linked immunosorbent assay along with a standard curve as described previously (Sprague et al., 2003). The lower limit of detection was 2.0 µg/dl.
Mitochondrial Isolation and Western Blot. Rat and mouse (UCP3–/– as a negative antibody control) skeletal muscle mitochondrial lysates were prepared as follows. Gastrocnemius biopsies were minced in isolation buffer (100 mM KCl, 50 mM Tris/HCl, and 2 mM EDTA, pH 7.4, 4°C) and homogenized followed by centrifugation at 500g for 10 min. Supernatants were centrifuged for 10 min at 10,500g to pellet mitochondria. Mitochondria were resuspended in lysis buffer (0.1% Triton X-100, phosphate-buffered saline, and protease inhibitor cocktail; Roche Diagnostics, Indianapolis, IN), and lysates were separated (30 µg of total mitochondrial protein/lane) by gel electrophoresis and transferred to nitrocellulose membranes, which were stained with the reversible water-soluble protein stain Ponceau S to verify equal loading and to identify a suitable control band for densitometric normalizations for determining relative UCP3 expression. Antibodies directed against UCP proteins notoriously recognize nonspecific proteins that migrate in the same range (32–37 kDa) as UCP. In the present study, we verified the specificity of UCP3 detection with several different antibodies by comparing immunoreactivities in mitochondrial lysates from rat gastrocnemius SKM and from wild-type and UCP3-deficient mouse SKM. Only the Abcam antibody specifically recognized both mouse and rat UCP3. Densitometric measurements of UCP3 band densities versus a control band (Ponceau S stain) were performed using UN-SCAN-IT 4.3 scientific digitization software (Orem, UT) and expressed as UCP3/control with the average of the UCP3 intensity obtained from EU animals set to 1.0.
Statistics and Linear Regression. Plasma FFA, NE, and Epi levels, TH data, and all respective rectal temperature data were analyzed by GraphPad InStat version 3.05 (InStat; GraphPad Software Inc., San Diego, CA) using an analysis of variance (ANOVA) with a Student-Newman-Keuls post hoc for between-group comparisons and a Dunnett's post hoc test for within-group comparisons. Statistical significance was set a priori at p < 0.05.
Linear regression and correlation coefficients were determined by plotting individual data points for each subject within HYPO, EU, and HYPER treatment groups (n = 4–6) for maximal change in temperature following MDMA administration, plasma T4 levels, and SKM UCP3 protein expression. The linearity of relationships between plasma T4 and UCP3 expression and UCP3 expression and maximal change in temperature were determined by linear regression analysis. Statistical significance was determined using a linear relationship ANOVA test (InStat).
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Chronic Changes in Thyroid Status Regulate Levels of Skeletal Muscle UCP3 Protein. Levels of plasma T4 (Fig. 4A) in the three groups were as follows: HYPO, undetectable; EU, 7.5 ± 0.36 µg/dl; and HYPER, 48.6 ± 7.6 µg/dl. Figure 4A is a representative Western blot showing UCP3 expression in isolated mitochondria (30 µg of mitochondrial protein/lane) in SKM biopsies from two of the six total animals per each of the HYPO, EU, and HYPER groups. UCP3 levels among all subjects within each group showed little variability. Based upon normalized band densities, UCP3 expression was decreased by approximately 70% in the HYPO (lanes 3 and 4) versus EU (lanes 5 and 6) animals. On the other hand, HYPER (lanes 7 and 8) animals showed an approximate 228% increase in UCP3 expression versus EU animals. Acute levothyroxine (30 min) and MDMA (180 min) treatments failed to change UCP3 SKM protein levels (data not shown).
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). Controversy exists regarding the involvement of the novel UCP isoforms (UCP2, UCP3) in thermoregulation because mice deficient in either homolog show only weak phenotypes; in particular, in each case, animals adapt appropriately to cold (Samec et al., 1998; Gong et al., 2000). Moreover, animals overexpressing SKM UCP3 exhibit normal basal body temperatures. However, these conclusions must be considered in light of substantial evidence showing that regardless of expression levels, proton leak mediated by UCP1–3 is not constitutive but rather requires activation by FFAs and/or ROS (Echtay et al., 2002). Unregulated uncoupling is generally held to occur when UCP is expressed at levels far exceeding the normal physiological range (Harper et al., 2002). Thus, it could be argued that the weak phenotypes observed in UCP3-deficient animals resulted from the lack of sufficient activation of UCP3 in wild-type subjects to resolve a thermoregulatory function and in UCP3-overexpressing animals resulted from a failure to adequately activate transgenic UCP3. The recent observation that UCP3-deficient mice show an almost complete blunting of the SKM thermogenic response to MDMA supports the argument that UCP3 requires activation in vivo (Mills et al., 2003) and that BAT UCP1 may not contribute significantly to FT in response to sympathomimetic agents.
The present data support the notion that UCP3 regulates TH-dependent FT in SKM. UCP3 activators FFAs and ROS accumulate in SKM during contraction or exercise (Watt et al., 2003; McArdle et al., 2004), and Curtin et al. (2002) found that SKM UCP3 overexpression enhances the thermogenic response to contraction ex vivo, but no differences in muscle temperatures were apparent at rest. Likewise, for any given amount of mechanical work, EU SKM generates more heat than HYPO (Leijendekker et al., 1987). This increased thermogenesis probably results from activation of an UCP because compared with EU; SKM mitochondria from HYPER rats exhibit increased proton conductance (Brand et al., 1992) along with increased levels of ROS (Gredilla et al., 2001), FFAs (Lombardi et al., 2002), and coenzyme Q, a putative cofactor for UCP activity (Venditti et al., 2003). Moreover, increased mitochondrial proton leak in HYPER SKM is abolished when FFAs are removed (Silvestri et al., 2005). Interestingly, fasting increases SKM UCP3 expression but does not increase SKM proton leak (Boss et al., 1998). However, fasting also decreases mitochondrial coenzyme Q (Moreno et al., 2003) levels in SKM, which probably leads to a decrease in UCP activity, regardless of increased expression. Although it is not clear whether ROS are generally required to activate UCP3, there is considerable agreement that UCP3-induced proton leak is FFA-dependent and that it represents the major ROS-induced target for respiratory uncoupling in SKM. In support of this contention, superoxide production induced by exogenous xanthine-xanthine oxidase activates FFA-dependent proton conductance in isolated wild-type mitochondria that is not observed in SKM mitochondria from UCP3 knockout mice (Talbot et al., 2004). In the present study, MDMA more than doubled plasma FFA levels, increasing the likelihood of uncoupling.
Insights gained from rodent models of thermoregulation probably underestimate the potential importance of SKM UCP3 to TH-dependent thermogenesis in humans. The most obvious reason is that adult humans lack BAT (and thus UCP1). Several other lines of evidence also support a significant role for SKM and UCP3. First, in the hyperthyroid state, UCP1-dependent thermogenesis is blunted as a result of suppression of adrenergic signaling in brown adipocytes (Golozoubova et al., 2004), but isolated SKM mitochondria from hyperthyroid rats show enhanced FFA-induced uncoupling (Brand et al., 1992). In addition, SKM is the primary contributor to thermogenesis and oxygen consumption induced by NE in animals (Rose et al., 1999), and humans (Astrup et al., 1985), and a 35-fold increase in plasma NE precedes MDMA-induced hyperthermia (Sprague et al., 2005). Interestingly, combined antagonism of 1- and 3-AR, which are expressed in SKM (Martin et al., 1990; Sillence et al., 1993), prevents and reverses hyperthermia induced by MDMA (Sprague et al., 2005). 3-ARs have an affinity 30 times greater for NE compared with Epi (Hoffmann et al., 2004), further suggesting that NE is the primary SNS neurotransmitter involved in MDMA-mediated hyperthermia. The role of NE was investigated in the present study by using DCMB to increase plasma NE levels and prevent elevations in circulating Epi. By combining DCMB and MDMA treatments, we were able to elicit an augmented response to the thermogenic effects of MDMA, providing additional support for the role of NE, and not Epi in mediating hyperthermia.
These observations reveal for the first time a direct, highly significant, linear relationship among plasma TH, SKM mitochondrial UCP3 expression, and extent of sympathomimetic-mediated hyperthermia and suggest that UCP3 may subserve an important function in FT regulated by TH, NE, and FFAs. This evidence also supports the notion that derangements in TH signaling may give rise to changes in UCP3 activity that may explain the idiosyncratic, nondose-responsive nature of sympathomimetic hyperthermia in humans. Important areas for future research will be to address the physiologic significance of UCP3 in thermoregulation in general and to elucidate the signal transduction mechanisms by which UCP3 is activated in SKM and the importance of SKM UCP3 in myolytic responses associated with hyperthermia.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: TH, thyroid hormone; T4, 3,5,3',5'-tetraiodothyronine, thyroxine; FT, facultative thermogenesis; UCP, uncoupling protein; BAT, brown adipose tissue; SKM, skeletal muscle; SNS, sympathetic nervous system; NE, norepinephrine; AR, adrenergic receptor; FFA, free fatty acid; MDMA, 3,4-methylenedioxymethamphetamine; Epi, epinephrine; TX, thyroparathyroidectomized; DCMB, ±2,3-dichloro--methylbenzylamine; EU, euthyroid; HYPER, with chronic thyroxine supplementation; HYPO, without chronic thyroxine supplementation; ANOVA, analysis of variance; ROS, reactive oxygen species.
Address correspondence to: Dr. Edward M. Mills, College of Pharmacy, 2409 University Avenue, PHR 5.218, 1 University Station A1915, Austin, TX 78712. E-mail: ted_mills{at}mail.utexas.edu
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, n = 6), HYPO (
, n = 9), and HYPER (
, n = 5) animals after measurement of baseline temperature (time 0), and temperatures were determined in all animals at 1-, 2-, and 3-h treatment time points. Sham-saline control (
, n = 6) were treated in the same manner. Hyperthyroidism was produced by daily administration of levothyroxine (100 µg/kg s.c.) for 7 days. B, lack of thermoregulatory effect of acute levothyroxine pretreatment (100 µg/kg s.c., 30 min) on MDMA thermogenesis. Thirty minutes following pretreatment, baseline temperature was determined in each animal. Saline (
, n = 8) and to HYPO (
, n = 6). Temperatures were determined in all animals at 1-, 2-, and 3-h post-treatment time points. Each value is the mean ± S.E.M. ***, significantly different from all other treatment groups, p < 0.001. EU animals treated acutely with levothyroxine exhibited the same characteristic hyperthermic response to MDMA as EU animals not receiving levothyroxine. Conversely, the hypothermic response to MDMA observed in HYPO animals was not significantly different from the response of HYPO animals treated acutely with levothyroxine.
