Endocrinology, doi:10.1210/en.2003-1401
Endocrinology Vol. 145, No. 8 3679-3685
Copyright © 2004 by The Endocrine Society
Retinoid X Receptor 
-Deficient Mice Have Increased Skeletal Muscle Lipoprotein Lipase Activity and Less Weight Gain when Fed a High-Fat Diet
Bryan R. Haugen,
Dalan R. Jensen,
Vibha Sharma,
Leslie K. Pulawa,
William R. Hays,
Wojciech Krezel,
Pierre Chambon and
Robert H. Eckel
Division of Endocrinology, Metabolism and Diabetes (B.R.H., D.R.J., V.S., L.K.P., W.R.H., R.H.E.), Department of Medicine, and Center for Human Nutrition (R.H.E.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Institut de Genetique et de Biologie Moleculaire et Cellulaire (W.K., P.C.), Clinique de la Souris and College de France, 67404 Illkirch Cedex, Communaute Urbaine de Strasbourg, France
Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., B151, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, Colorado 80262. E-mail: bryan.haugen{at}uchsc.edu.
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Abstract
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Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein by a lipoprotein lipase (LPL)-dependent pathway. The retinoid X receptor (RXR) 
isotype, which is highly expressed in skeletal muscle, may be important in mediating the effects of retinoids on skeletal muscle metabolism and triglyceride (TG) clearance. RXR-deficient (–/–) mice had lower fasting plasma TG levels compared with wild-type littermates (33.1 ± 2.0 vs. 51.7 ± 6.3 mg/dl, respectively; P < 0.05). Skeletal muscle LPL activity was higher in RXR mice (18.7 ± 2.2 vs. 13.3 ± 1.3 nmol free fatty acids/min·g; P = 0.03), but LPL activity was not different in adipose and cardiac tissue, suggesting a specific effect of RXR in skeletal muscle. In addition, when exposed to a 14-wk high-fat diet, RXR –/– mice had less weight gain, which was entirely due to lower fat mass (11.9 ± 1.8 vs. 14.4 ± 1.1 g; P = 0.01), and leptin levels were also lower in the RXR –/– mice (17.6 ± 5.0 vs. 30.9 ± 6.4 ng/ml; P = 0.03). These data suggest that RXR –/– mice are resistant to gain in fat mass in response to high-fat feeding. This occurs, at least in part, through up-regulation of LPL activity in skeletal muscle. An understanding of the mechanisms governing the role of RXR in TG disposal and metabolism may lead to the rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.
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Introduction
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RETINOIDS ARE NATURALLY occurring and synthetic derivatives of vitamin A that can influence development, differentiation, metabolism, and endocrine function through nuclear hormone receptors [retinoic acid receptor (RAR) and retinoid X receptor (RXR)]. Isotretinoin (13-cis retinoic acid), a retinoid used to treat acne, rosacea, and some patients with squamous cell carcinoma, causes hypertriglyceridemia in humans through decreased clearance of very low-density lipoprotein (VLDL) particles (1, 2). This action appears to occur, at least in part, through activation of RXR (2, 3). RXR can mediate the effects of retinoids as a homodimer or heterodimeric partner with other nuclear hormone receptors [RAR, thyroid hormone receptor, vitamin D receptor, peroxisome proliferator-activated receptor (PPAR), liver X receptor, and others]. Three different RXR isotypes (RXR
, ß, and ) have been described (4, 5). RXR has limited tissue expression including high levels in the brain, anterior pituitary, and skeletal muscle (5, 6, 7). We have previously shown that mice lacking the RXR isotype have a higher metabolic rate when compared with wild-type (WT) littermates (8). These mice also demonstrate a trend to less weight gain on a standard chow diet (P = 0.09). Based on the expression of RXR in skeletal muscle and the role of this receptor in basal metabolism, we predicted that RXR may play a role in skeletal muscle triglyceride (TG) disposal. Lipoprotein lipase (LPL) is the rate-limiting enzyme responsible for hydrolysis and uptake of TGs into tissues from chylomicrons and VLDL in the circulation. In this study, we examined the response of RXR-deficient (–/–) and WT mice to a high-fat (HF) diet and explored the effects of this gene deletion on plasma insulin, glucose, TG, and FFA levels as well as LPL activity in different tissues.
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Materials and Methods
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Experimental animals
WT and RXR-deficient (–/–) mice were housed in a pathogen-free transgenic facility at the University of Colorado Health Sciences Center. Mice were bred on the 129SvJ background and experiments were performed on littermate mice. All animal protocols were approved by the Animal Care and Use Committee.
Methods
Mice were studied at approximately 11 wk of age on a standard ad libitum chow diet. Measures of food and water intake as well as feces and urine output were measured over 3 d.
WT and RXR –/– mice at 6 wk of age were housed in standard caging with a 12-h light, 12-h dark cycle and fed a standard chow diet or a synthetic HF diet (Research Diets Inc., New Brunswick, NJ; D12344, 46.1% kcal from fat). HF diet was administered for 14 wk with bimonthly recordings of body weight and body composition measurements by dual energy x-ray absorptometry (DEXA) (see DEXA). After 2 wk of a HF diet, a subset of mice underwent indirect whole animal calorimetry and careful measures of food intake over 3 d as previously described (8). At 20 wk of age, mice were fasted for 4 h and anesthetized with an ip injection of Avertin (2,2,2 tribromoethanol, 32 mg; Aldrich, Milwaukee, WI). Blood was drawn via a cardiac stick of the right ventricle into EDTA tubes for collection of plasma. Plasma insulin and leptin was measured by RIA (Linco Research, St. Louis, MO) with a sensitivity of 0.1 ng/ml. Plasma free fatty acids (FFA) and glucose were measured enzymatically with a colorimetric endpoint and TGs by the method of Stravropoulos (9). Plasma was measured for T4 levels by standard RIA. White adipose tissue was collected from the abdominal fat pad, and skeletal muscle was collected from the quadriceps.
Quantitative RT-PCR
Quantitative mRNA analysis was carried out for RXR, RXRß, RXR, and LPL using the ABI 7700 system (PerkinElmer, Foster City, CA). Primers and probes (containing fluorochrome and quencher) were generated against each specific RNA using a Primer Express program (PerkinElmer). Primer and probe sequences are available upon request. Primer and probe concentrations were optimized against total RNA containing all RXR isotypes [TtT-97 RNA (10)]. TtT-97 total RNA was subsequently used to generate quantitative standard curves for sample analysis. Standard curves were linear between 0.1 and 200 ng of total RNA for RXR (r = 0.997), RXRß (r = 0.993), and RXR (r = 0.992). Mouse LPL cDNA was used to generate a standard curve for sample analysis. Total RNA was extracted from skeletal muscle using the RNeasy method (QIAGEN, Valencia, CA). Amplification reactions were performed in MicroAmp optical tubes (PerkinElmer) in a 50-µl volume containing 8% glycerol, 1x TaqMan buffer A [500 mM KCl, 100 M Tris-HCl (pH 8.3), 600 nM passive reference dye ROX], 300 µM each deoxy (d) ATP, dGTP, dCTP, 600 µM deoxyuridine triphosphate, 5.5 mM MgCl2, 12.5 U Moloney murine leukemia virus reverse transcriptase (Invitrogen, Carlsbad, CA), 1.25 U AmpliTaq Gold DNA polymerase (PerkinElmer), 20 U RNAsin ribonuclease inhibitor (Promega, Madison, WI), and input RNA. Samples were run in duplicate with a control lacking reverse transcriptase (no RT). The no RT signal was consistently less than 1% of the RT-PCR. Input total RNA was first determined against an 18S ribosomal RNA (rRNA) control (PerkinElmer, catalog no. 4308310), which correlated well with RNA amount determined by OD. Input total RNA was 300–700 ng for the RXR isotype measurements. Individual target RNA concentrations were corrected for input RNA based on rRNA measurements. RT was performed at 48 C for 30 min followed by activation of TaqGold at 95 C for 10 min. Subsequently 40 cycles of amplification were performed at 95 C for 15 sec and 60 C for 1 min. The detection threshold was set above the mean baseline fluorescence determined during the first 15 cycles. Threshold cycle was determined when fluorescence intensity first increased above detection threshold and sample values were generated from the standard curve.
LPL assay
Heparin releasable LPL from all tissues was assayed as previously described (11). Briefly, tissues were minced in cold Krebs-Ringer-Phosphate buffer to approximately 2–4 mm3 pieces and bundles of pieces weighing 40–50 mg were incubated in duplicate in a shaking 37 C water bath for 45 min in 0.4 ml Krebs-Ringer-Phosphate (pH 7.4) with 15 µg/ml heparin (Fisher Scientific, Fair Lawn, NJ; catalog no. H-19). A 100-µl aliquot was removed and incubated with 100 µl of a 14C-triolein phosphatidylcholine-stabilized substrate. After another 45 min incubation at 37 C, the reaction was solubilized and 14C-fatty acids partitioned according to the method of Belfrage and Vaughn (12). A 500-µl aliquot of the resulting aqueous supernatant was counted by ß-scintillation (Beckman Coulter, Inc., Fullerton, CA; LS6000TA). 14C-Oleic acid was used to control for extraction efficiency. LPL activity was expressed as nanomoles of FFA per min per gram of tissue. Aliquoted rat post-heparin plasma was used as a quality control for each assay.
DEXA
DEXA was used to determine the body composition (bone, lean, and fat mass) of mice at baseline and every 2 wk throughout the 14 wk of HF feeding (PixiMusII, GE-Lunar Corp., Madison, WI). Before measurements, calibration of the instrument was conducted with a quality control phantom provided by the manufacturer. Mice were lightly anesthetized with 2,2,2-tribromoethanol (Avertin, 400 mg/kg) and placed on the scanning surface in a prostrate position with front and back legs extended. As recommended by the manufacturer, the head was excluded from the analyses.
Statistical analysis
Data were analyzed using a two-way ANOVA (SigmaStat for Windows 2.03, SPSS, San Rafael, CA). For the chow experiments at 6 wk, Gender (M vs. F), Gene [WT vs. knockout (KO)] and the interaction (Gender x Gene) were in the model. For the HF feeding experiments, Gene, Weeks on diet and the interaction (Gene x Weeks) were included. t Tests were used to compare differences among groups. When data were not normally distributed, nonparametric tests were used. P < 0.05 was considered statistically significant. All data are presented as mean ± SEM.
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Results
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RXR isotype mRNA expression in skeletal muscle
RXR isotype RNA was measured in skeletal muscle from mice lacking the RXR isotype and WT littermates by quantitative RT-PCR (Fig. 1
). As expected, RXR mRNA was highly expressed in WT mice [both RXR1 and RXR2 isoforms (6)] and not detectable in RXR –/– mice. The RXR and RXRß isotypes were detectable in skeletal muscle and expressed at similar levels in WT and RXR –/– mice, suggesting that the lack of RXR does not alter expression of the other RXR isotypes in skeletal muscle.
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FIG. 1. mRNA levels of RXR isotypes in mouse skeletal muscle. RXR mRNA levels were measured by quantitative RT-PCR from skeletal muscle of WT and RXR –/– (KO) mice. Values are expressed as picograms of each isotype mRNA per nanogram of 18S RNA (rRNA). Values are averages (±SEM) from six separate mice for each group.
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Metabolic analysis of mice fed a chow diet
RXR –/– mice and WT littermates were studied at approximately 11 wk of age. Body weight was not significantly different between the two groups of mice (Table 1). Food intake and fecal output (measured over 3 d) were slightly, but not significantly higher in the RXR –/– mice, whereas carcass lipid content was not different in the two groups. Fasting TG levels were significantly lower in the RXR –/– mice (Table 1). Fasting insulin, glucose, and FFA levels were the same in both groups. As we have previously reported, T4 levels were slightly and significantly higher in the RXR –/– mice compared with WT littermates. Serum TSH and T3 were not measured [insufficient amount of plasma, previously studied (8)].
LPL activity and mRNA
LPL is a critical enzyme involved in TG disposal in muscle and fat. LPL activity was measured in adipose tissue, skeletal muscle, and cardiac muscle from RXR –/– and WT mice (Fig. 2). LPL activity in adipose tissue and cardiac muscle was not different in WT and RXR –/– mice, but LPL activity was significantly higher in skeletal muscle from RXR –/– mice (P = 0.03), suggesting a potential mechanism for lower TG levels in RXR –/– mice. These data would also suggest that the observed differences are unique to skeletal muscle and not a global effect of the slightly higher T4 levels on LPL activity. To explore potential mechanisms of LPL activity up-regulation in the skeletal muscle of RXR –/– mice, mRNA levels were measured in littermate mice using quantitative RT-PCR (Fig. 2C). LPL mRNA levels were no different in the WT and RXR –/– mice, suggesting that regulation is not at the transcriptional or RNA stability level.
Analysis of mice fed a HF diet
RXR –/– mice appear to have altered TG disposal (lower serum TG and higher skeletal muscle LPL) compared with WT littermates. We therefore challenged these mice with a 14-wk HF diet. Both the RXR –/– and WT mice gained weight on the HF diet, but the RXR –/– mice had significantly less weight gain than littermate controls (Fig. 3A, P = 0.015). Body composition was measured during the HF diet by DEXA analysis. Figure 3B shows that RXR –/– mice had significantly less gain in fat mass (18% lower at 14 wk) compared with WT controls (P = 0.011). Lean body mass was not significantly different between the two groups (Fig. 3C, P = 0.07), suggesting that the alteration in body weight was primarily through change in adipose mass.
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FIG. 3. Body composition changes in response to a HF diet. WT (n = 9) and RXR –/– (KO, n = 6) mice were fed a HF diet for 14 wk as described in Materials and Methods. Measurements were performed at 2-wk intervals. A, BW, Body weight (grams); B, fat, fat mass (grams) as measured by DEXA (Materials and Methods); C, lean mass (grams) as measured by DEXA (Materials and Methods).
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After 2 wk on the HF diet, a subset of mice underwent metabolic analysis over 3 d. Table 2 shows that energy intake was slightly lower and metabolic rate was slightly higher, but neither measurement reached statistical significance. This trend also held for metabolic rate when corrected for body weight and lean body mass, as well as overall energy balance (P = 0.10). Sample size calculations predicted that 26 mice would be required in each group to detect a significant difference of 1.3 kcal/d (SD = 1.0, power = 0.8, = 0.05), suggesting that these observed differences are quite subtle.
Fasting plasma was collected at the end of the 14-wk HF diet. Table 3 shows no significant differences in fasting insulin, glucose, cholesterol, TG, or FFA levels between the two groups of animals. Insulin levels were higher in each group of animals (WT and RXR–/–) after HF feeding when compared with the chow diet (Table 1
), suggesting increased insulin resistance with increased weight gain in all of the mice. Plasma leptin levels were significantly lower in the RXR –/– mice compared with WT mice after the HF diet, which correlates with the lower fat mass in individual animals irrespective of genotype, suggesting that leptin levels were another measure of fat mass in these animals and not directly influenced by absence of RXR (r = 0.76, P = 0.01).
LPL activity was measured in adipose, cardiac, and skeletal muscle tissues after the HF diet (Fig. 4). As was seen after chow diet (Fig. 2), LPL activity in adipose and cardiac tissues were no different between RXR –/– and WT animals, whereas LPL activity was significantly higher in the skeletal muscle of RXR –/– mice (P = 0.02).
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FIG. 4. LPL activity in mouse tissues after HF diet. LPL activity from tissue extracts was measured as described in Materials and Methods. A, AT, Adipose tissue; SM, skeletal muscle. B, HRT, Cardiac muscle. Values are averages (±SEM) from WT (n = 9) and RXR –/– (KO, n = 6) mice.
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Discussion
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Previous studies have demonstrated that RXR-selective ligands have significant metabolic effects in animals as well as isolated skeletal muscle and adipose cells. In this report, we have begun to analyze the role of RXR in this response. The RXR isotype has limited tissue expression and is highly expressed in skeletal muscle (5, 6, 7). We have previously demonstrated that mice lacking RXR have higher metabolic rates than littermate controls (8). In this report, we have further studied the role of RXR on body composition, plasma lipid levels, LPL activity, and response to a HF diet using an in vivo animal model.
Yamauchi et al. (13) examined the role of RXR in metabolism by treating mice with an RXR antagonist. This antagonist (HX531) appeared to be selective for RXR homodimers and RXR/PPAR heterodimers. Treatment of mice with HX531 blunted weight gain when these animals were fed a HF diet. The treated animals had increases in core body temperature and oxygen consumption, suggesting a higher metabolic rate. We have previously shown that mice lacking the RXR isotype, which is highly expressed in skeletal muscle, have a higher metabolic rate (8), and this isotype may play a role in metabolic responses to endogenous or exogenous retinoids. Yamauchi also showed that mice treated with HX531 had lower TG content in muscle as well as increases in molecules associated with fatty acid oxidation (uncoupling protein 2). In the current study, we have demonstrated that mice lacking the RXR isotype have lower plasma TG levels, higher skeletal muscle LPL activity (TG disposal), and resistance to weight gain after a HF diet. The RXR-deficient mice also have slightly higher T4 levels, and it is known that T4 can increase LPL activity. We feel that this is not a direct mechanism in our model because LPL activity was only increased in skeletal muscle and not in adipose or cardiac tissue. One may predict that LPL activity would be altered in all tissues by a general effect of T4. Taken together, these data would suggest that RXR alters uptake and oxidation of TGs in skeletal muscle through increased LPL activity and the RXR isotype plays a dominant role in this response. Indeed, Davies et al. (3) showed that the RXR agonist (LG268) increased serum TGs and decreased post-heparin plasma LPL activity in rats, supporting this hypothesis. They further demonstrated that LG 268 decreased LPL activity in C2C12 muscle cells, and this effect was not seen with agonists for thyroid hormone receptor, RAR, vitamin D receptor, liver X receptor, or PPAR, suggesting that the retinoid effect on LPL activity is through an RXR homodimer or a heterodimer with one of the orphan receptors. Standeven et al. (14) also showed that an RXR-agonist (AGN192849) increased serum TGs and decreased post-heparin plasma LPL activity. Jensen et al. (15) directly tested the effects of increased skeletal muscle LPL on TG disposal and response to a HF diet by generating transgenic mice overexpressing LPL in skeletal muscle. LPL transgenic mice had lower body weight (9%), carcass lipid content (40%), and plasma TG levels (18%) after a 13-wk HF diet when compared with littermate controls. In the present study, we observed that RXR –/– mice (higher LPL activity) had lower body weight (7%) and fat mass (18%) but not lower TG levels when compared with WT littermates. Although the two different transgenic models had similar phenotypes, the effects were more profound in the LPL transgenic model. One explanation may be the 10-fold increase in muscle LPL activity in the LPL transgenic compared with a 2-fold increase in LPL activity in our RXR –/– model. This difference may also explain why we didn’t see significantly lower TG levels after a HF diet. Higher chylomicron and VLDL levels after a HF diet may saturate LPL ability to hydrolyze TGs in the RXR –/– mouse and not the LPL transgenic mouse.
Lenhard et al. (16) found that LG 268 decreased serum TG levels in db/db diabetic mice, which is in contrast to data from Davies and our group in nondiabetic animals. The db/db mice had very high glucose levels (39.6 mmol/liter) that were significantly decreased by treatment with LG 268. The improved glucose control and insulin sensitivity after treatment with LG 268 was the apparent cause of lowered TG levels in this diabetic mouse model, and the most reasonable explanation for the differences observed in diabetic and nondiabetic mice.
The role of RXR in response to a HF diet has been studied in two different transgenic models. Imai et al. (17) selectively deleted the RXR isotype in adipose tissue using the tamoxifen-induced CreERT2 recombinase expressed in white and brown adipose under control of the aP2 promoter. Mice lacking RXR expression in adipocytes had normal adipocyte number and size when fed a standard chow diet. These mice demonstrated resistance to weight gain and increase in adipocyte size when challenged with a HF diet. Adipocyte LPL mRNA was lower in RXR-deficient mice on a standard chow and HF diet when compared with littermate controls. Mice lacking RXR in adipocytes appeared to have similar resistance to weight gain after a HF diet to the RXR-deficient mice in our current study. Interestingly, RXRß mRNA levels were not affected in the adipocytes of the RXR-deficient mice, but RXR mRNA levels were increased, suggesting a possible compensatory up-regulation of RXR in the adipocytes of these mice. We found no such compensatory changes in the levels of RXR or RXRß mRNA in the RXR-deficient mice. One may predict that mice lacking RXR and RXR in adipocytes would be even more resistant to weight/adipose gain, and that RXR and RXR have different but complementary roles in adipose and skeletal muscle tissue, respectively. Wan et al. (18) studied mice lacking RXR in hepatocytes. There were no observed changes in mRNA levels of RXRß or RXR in liver tissue from these transgenic mice. In contrast to the mice lacking RXR in adipoctyes and our RXR-deficient mice, mice lacking RXR in the liver demonstrated an increased weight gain compared with WT littermates when fed a HF diet. Liver fatty acid binding protein and cytochrome p450 4A1 mRNA levels were down-regulated in these transgenic mice, suggesting altered hepatocyte fatty acid metabolism leading to increased adipose storage and leptin levels. To our knowledge, no one has studied response to a HF diet in RXRß-deficient mice. Taken together, these data suggest that RXR plays an important role in TG uptake, storage, and fatty acid metabolism in many tissues. Our data further suggest that the relative resistance to weight gain and fat accumulation observed in the RXR-deficient mice may be a confluence of multiple mechanisms. The RXR mice, when fed a HF diet, displayed a trend toward a higher metabolic rate and reduced energy intake, as well as lower energy balance (intake – metabolic rate). These observations did not reach statistical significance, but the sample size may have been too small to observe significant differences in the 3 d of the study. The metabolic rate may be explained by the effect of RXR in skeletal muscle, whereas the explanation for reduced energy intake may lie in hypothalamic retinoid signaling as proposed by Ross et al. (19). This group observed that Siberian hamsters, which decrease food intake and lose significant amounts of weight when exposed to short light cycles, had significantly lower RXR expression in the dorsal tuberomamillary nucleus (DTM) of the hypothalamus. Syrian hamsters, which do not have weight loss associated with short light cycles, had no changes in RXR expression in the DTM, suggesting that RXR may play a role in regulation of appetite and energy balance. Our data, although only suggestive and not significant, would support this hypothesis. Indeed, signaling through RXR in different tissues may be altered with RXR-selective agonists and antagonists, leading to alterations in appetite as well as TG and fatty acid metabolism, which could ultimately lead to newer controls in TG storage/oxidation and weight management.
In conclusion, we have demonstrated that mice lacking RXR have increased metabolism, decreased plasma TGs, increased skeletal muscle LPL activity, and resistance to weight/fat mass gain when challenged with a HF diet. An understanding of the mechanism’s governing role of RXR in TG disposal and metabolism may lead to rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.
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Acknowledgments
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We acknowledge use of the Gene Expression Core Facility of the University of Colorado Cancer Center.
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Footnotes
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This work was supported by National Institutes of Health Grants DK 54383 (to B.R.H.) and DK26356 (to R.H.E.). This work was presented at the 83rd Annual Meeting of The Endocrine Society, Denver, Colorado, 2001.
Abbreviations: DEXA, Dual energy x-ray absorptometry; FFA, free fatty acids; HF, high-fat; KO, knockout; LPL, lipoprotein lipase; PPAR, peroxisome proliferator-activated receptor; RAR, retinoic acid receptor; rRNA, ribosomal RNA; RXR, retinoid X receptor; TG, triglyceride; WT, wild-type.
Received October 17, 2003.
Accepted for publication April 8, 2004.
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D. M. E. Harvell, J. K. Richer, D. C. Allred, C. A. Sartorius, and K. B. Horwitz
Estradiol Regulates Different Genes in Human Breast Tumor Xenografts Compared with the Identical Cells in Culture
Endocrinology,
February 1, 2006;
147(2):
700 - 713.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
