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Endocrinology Vol. 144, No. 2 605-611
Copyright © 2003 by The Endocrine Society

ARTICLE

Hepatocyte Retinoid X Receptor-{alpha}-Deficient Mice Have Reduced Food Intake, Increased Body Weight, and Improved Glucose Tolerance

Yu-Jui Yvonne Wan, Guang Han, Yan Cai, Tiane Dai, Tamiko Konishi and AI-She Leng

Department of Pathology, Harbor-University of California, Los Angeles Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Yu-Jui Yvonne Wan, Ph.D., Department of Pathology, Harbor-University of California, Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509. E-mail: agarose{at}ucla.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Hepatocyte retinoid X receptor (RXR){alpha}-deficient mice and wild-type mice were fed either a regular or a high-saturated-fat diet for 12 wk to study the functional role of hepatocyte RXR{alpha} in fatty acid and carbohydrate metabolism. Food intake was significantly reduced in hepatocyte RXR{alpha}-deficient mice when either diet was used. The amount of food intake was negatively associated with serum leptin level. Although mutant mice ate less, body weight and fat content were significantly higher in mutant than wild-type mice. Examination of the expression of peroxisome proliferator-activated receptor-{alpha} target genes indicated that the peroxisome proliferator-activated receptor-{alpha}-mediated pathway was compromised in the mutant mice, which, in turn, might affect fatty-acid metabolism and result in increased body weight and fat content. Although mutant mice were obese, they demonstrated the same degree of insulin sensitivity and the same level of serum insulin as the wild-type mice. However, these mutant mice have improved glucose tolerance. To explore a mechanism that may be responsible for the improved glucose tolerance, serum IGF-I level was examined. Serum IGF-1 level was significantly increased in mutant mice compared with wild-type mice. Taken together, hepatocyte RXR{alpha} deficiency increases leptin level and reduces food intake. Those mice also develop obesity, with an unexpected improvement of glucose tolerance. The result also suggests that an increase in serum IGF-I level might be one of the mechanisms leading to improved glucose tolerance in hepatocyte RXR{alpha}-deficient mice.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TYPE 2 NON-INSULIN-DEPENDENT diabetes mellitus is caused by a combination of genetic and environmental factors such as diet. Among environmental factors, the high-fat content of the Western diet is considered a major cause of non-insulin-dependent diabetes mellitus. A high-fat diet can promote progression from normal to impaired glucose tolerance and induce insulin resistance (1).

Retinoid X receptor (RXR){alpha} serves as an active partner of peroxisome proliferator-activated receptors (PPARs) and is involved in the control of various aspects of fatty-acid metabolism. Three PPAR isoforms have been identified, and they can be activated by fatty acids (for review, see Ref. 2). In addition, PPAR{alpha} can be activated by hypolipidemic drugs (3, 4), and PPAR{gamma} can be activated by the thiazolidinedione drugs used for type 2 diabetes therapy (5). PPAR{alpha} deficiency leads to elevated serum cholesterol levels in young adult mice and increased serum triglyceride levels and steatosis in aging mice. PPAR{alpha} deficiency also prevents the induction of fatty-acid-synthesizing enzymes and oxidizing enzymes by the hypolipidemic fibrate Wy14,643 (6, 7, 8). Disruption of the PPARß gene results in decreased gonadal adipose tissue in female mice (9). Targeted disruption of the PPAR{gamma} gene is embryonically lethal, in part because of placental dysfunction (10). A tetraploid-rescued mutant and PPAR{gamma} +/- chimeric mice demonstrate that PPAR{gamma} is required for adipose tissue development (10, 11). Heterozygous PPAR{gamma}-deficient mice have improved insulin sensitivity (12, 13). Under a high-fat diet, heterozygous PPAR{gamma}-deficient mice are protected from the development of insulin resistance (12). These data have established the role of PPARs in fatty acid and glucose homeostasis.

Similar to the PPAR{alpha}-deficient mice, hepatocyte RXR{alpha}-deficient mice have elevated serum cholesterol levels (14). Distinct from young PPAR{alpha}-deficient male mice, which have normal serum triglyceride and apolipoprotein CIII (apoCIII) mRNA levels, 2-month-old hepatocyte RXR{alpha}-deficient male mice demonstrate elevated serum triglyceride levels and increased apoCIII mRNA levels (14). These data define the unique role of hepatocyte RXR{alpha} in lipid metabolism. To further investigate the functional role of RXR{alpha} in fatty-acid and carbohydrate homeostasis in the liver, we performed metabolic studies in the hepatocyte RXR{alpha}-deficient mice fed either a regular or a high-saturated-fat diet. We report that using either diet, hepatocyte RXR{alpha} deficiency causes an increase in leptin level, reduction of food intake, and obesity. However, these obese mice have normal insulin levels and insulin sensitivity. In addition, hepatocyte RXR{alpha}-deficient mice have improved glucose tolerance, which may be attributable to an increased IGF-I level.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental procedures
Mouse.
Mice carrying the RXR{alpha} mutation in hepatocytes have been described elsewhere (15). Hepatocyte RXR{alpha}-deficient mice have a mixed genetic background of C57/Bl/6, 129/SvEvTac, and DBA-2 (15 and references therein). Animals used in the experiments were age-matched (13-wk-old) male mice housed in groups of two or three in plastic microisolator cages at 22 C with a 12-h light, 12-h dark cycle and had free access to food and water. Under normal conditions, mice were fed a standard lab chow containing about 12 energy percent (en%) fat. In the high-fat diet experiment, a high-saturated-fat diet (coconut oil based, 39 en% fat) (ICN Research Diets, Costa Mesa, CA) was used to feed mice for 12 wk.

Serum leptin level.
Serum leptin level was determined using a mouse Leptin RIA kit (Linco Research, Inc., St. Charles, MO).

Insulin tolerance tests.
Mice were injected ip (0.75 mU/g body weight) with human insulin (Sigma, St. Louis, MO). Blood samples were also collected at 0, 20, 40, 60, 80, and 100 min after the insulin injection. Glucose levels were measured by the One Touch Fast Take Compact Blood Glucose Monitoring System (LifeScan, Inc., Milpitas, CA).

Serum insulin concentration and ip glucose tolerance test.
Mice were fasted overnight. Blood samples were collected before (time = 0) and after 30 and 60 min of glucose administration (1.5 mg glucose/g body weight, ip). Then, insulin levels were measured using an Insulin RIA kit (Linco Research, Inc.). Additional blood samples were collected at 0, 30, 60, and 150 min for the glucose tolerance test.

Northern blot hybridization.
Liver total RNA was extracted by the guanidinium isothiocyanate method (16). Twenty micrograms of total RNA per lane were resolved by electrophoresis on 1.2% agarose gels containing 2.2 M formaldehyde and then transferred to nylon membranes by capillary blotting. The genes probes used were cytochrome P450 4A1 (CYP4A1) (provided by Dr. F. Gonzalez), liver fatty-acid-binding protein (LFABP; provided by Dr. J. Gordon), and apoA1 and apoCIII (provided by Dr. J. Auwerx). cDNA fragments were labeled by random priming and hybridized to membranes in 7% (wt/vol) sodium dodecyl sulfate, 0.5 M sodium phosphate (pH 6.5), 1 mM EDTA, and 1 mg/ml BSA at 68 C overnight. The membranes were washed twice in 1% sodium dodecyl sulfate, 50 mM NaCl, and 1 mM EDTA at 68 C for 15 min each and autoradiographed using intensifying screens. At least three animals from each group were studied for each gene. The amount of mRNA expressed was quantitated by densitometry and then normalized with the level of ß-actin to obtain means and SEMS.

IGF-1 level.
Serum IFG-1 was assayed using an IGF-1 RIA kit (Diagnostic Systems Laboratories, Inc., Webster, TX).

Statistical analysis.
Values shown represent the mean ± SEM. Values were compared by ANOVA and corrected by Student-Newman-Keul’s test for differences between groups. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Hepatocyte RXR{alpha}-deficient mice have increased body weight, decreased food intake, and higher leptin level compared with wild-type mice
To analyze the role of hepatocyte RXR{alpha} in fatty-acid homeostasis, regular and high-fat diet were used to feed wild-type and hepatocyte RXR{alpha}-deficient mice for 12 wk. The high-fat diet used in the experiment was based on coconut oil, a saturated-fat diet containing about 40 en% fat, which was more than 3-fold higher than the regular diet. Food intake was monitored throughout the 12-wk period. Mutant mice ate less than wild-type mice did, regardless of the type of diet provided (Fig. 1Go). Even though mutant mice ate less than wild-type mice, the body weight of mutant mice was significantly higher than that of wild-type mice. The difference in body weight became evident when the mice were 15–16 wk old (Fig. 1Go). Furthermore, the fat depot amount (inguinal, reproductive, and retroperitoneal fat pads) was also higher in mutant than wild-type mice, using either diet (Fig. 2Go). Leptin level was significantly higher in high-fat-fed than in regular-diet-fed mice. Mutant mice had a higher leptin level than wild-type mice before and after the high-fat diet treatment (Fig. 3AGo; before the high-fat diet treatment, the serum leptin level for wild-type and mutant mice was 1.8 ± 0.1 and 2.6 ± 0.2 ng/ml, respectively.). The scatter plot, with leptin on the y-axis and percentage of fat on the x-axis, indicates that the wild-type and hepatocyte RXR{alpha}-deficient mice fall on the same line, suggesting that the leptin levels are at the level expected for the degree of adiposity (Fig. 3BGo).



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  		Figure 1. Body weight (A) and food intake (B) of wild-type (WT) and hepatocyte RXR{alpha}-deficient mice [knockout (KO)] fed a regular and high-fat diet. Values are expressed as means ± SEM (n = 7–10). *, P < 0.05; **, P < 0.01.

 


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  		Figure 2. Fat pads (inguinal, reproductive, and retroperitoneal fat) and body weight ratios of wild-type (wt) and knockout (ko) mice. Values are expressed as means ± SEM (n = 7–10). *, P < 0.05; **, P < 0.01.

 


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  		Figure 3. A, Serum leptin levels in wild-type (WT) and knockout (KO) mice after 12 wk of regular and high-fat diet treatment. Values are expressed as means ± SEM (n = 7–10). A significant difference is detected between WT and KO (*, P < 0.05). B, A scatter plot, with leptin level on the y-axis and percentage of fat on the x-axis, to show that the leptin levels are at the level expected for the degree of adiposity.

 
These data suggested that the increased body weight in the mutant mice might be attributable to accumulation of adipose tissue and that fatty-acid metabolism was altered because of interference of hepatocyte RXR{alpha}/PPAR{alpha}-mediated pathways. To further investigate the underlying mechanism, the expression of PPAR{alpha} target genes was studied. Figure 4Go demonstrated that high-fat diet induced the expression of the LFABP and apoAI genes (P < 0.05). In addition, in regular as well as high-fat-diet-fed mice, the expression of LFABP and CYP4A1 mRNA was down-regulated, whereas the levels of apoAI and apoCIII mRNA in the liver were up-regulated in the mutant mice (P < 0.05). These data strongly indicated that fatty-acid metabolism was compromised in hepatocyte RXR{alpha}-deficient mice, which, in turn, might lead to obesity of the mutant mice.



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  		Figure 4. Representative Northern blots demonstrate the expression of PPAR{alpha} target genes in the livers of wild-type (RXR{alpha} +/+) and hepatocyte RXR{alpha}-deficient (RXR{alpha} -/-) mice fed with either a regular or a high-fat diet. Total RNA (20 µg) from mouse livers were electrophoresed and hybridized with the indicated cDNA probes. Two represent RNA samples from two independent livers are shown for each probe. The data (mean ± SEM, n = 4–5) shown below the blots are normalized by the levels of ß-actin mRNA. A significant difference was found between wild-type and mutant mice for all the probes used (P < 0.05).

 
Hepatocyte RXR{alpha}-deficient mice have improved glucose tolerance
Compared with the regular-diet group, high-fat-diet induced insulin resistance in wild-type and mutant mice (Fig. 5AGo). However, the glucose-lowering effect of insulin was the same in wild-type and mutant mice, as determined by an insulin tolerance test (Fig. 5AGo). Thus, unlike the PPAR{gamma} +/- mice, which have increased insulin sensitivity, hepatocyte RXR{alpha} deficiency did not alter insulin sensitivity. Furthermore, there was no significant difference in insulin levels, both at baseline and after glucose injection (Fig. 5BGo). Insulin levels were measured during the glucose tolerance test. The high-fat diet increased blood glucose levels in mice with either genotype (Fig. 5CGo). During ip glucose tolerance tests, blood glucose levels were lower in hepatocyte RXR{alpha}-deficient mice than in wild-type mice using regular diet, and the difference became even greater when a high-fat diet was provided (Fig. 5CGo). Taken together, these data indicate that hepatocyte RXR{alpha} deficiency results in an improved glucose tolerance without altering insulin level or insulin sensitivity.



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  		Figure 5. A, Glucose levels in an insulin tolerance test. Mice on a regular (left) and a high-fat (right) diet were fasted for 16 h and then injected ip (0.75 mU/g body weight) with human insulin. Glucose levels were measured at the indicated time points. Values are expressed as means ± SEM (n = 7–10). No difference is detected between the two genotypes. B, Serum insulin levels in a glucose tolerance test. Mice on a regular (left) and a high-fat (right) diet were fasted for 16 h and then given 1.5 mg glucose/g body weight, via ip injection. Insulin levels were measured at the indicated time points. No difference is detected between the two genotypes. C, Glucose levels in a glucose tolerance test. While measuring insulin levels, additional blood samples were collected at indicated time points for measuring glucose levels. Significant differences were noted between the wild-type (WT) and knockout (KO) mice. Values are expressed as means ± SEM (n = 7–10). *, P < 0.05; **, P < 0.01.

 
IFG-I is induced in hepatocyte RXR{alpha}-deficient mice
To investigate the possible cause for improved glucose tolerance in hepatocyte RXR{alpha}-deficient mice, serum IGF-I was determined in wild-type and mutant mice, using RIA. As shown in Fig. 6Go, serum IGF-I level was significantly increased in hepatocyte RXR{alpha}-deficient mice. Thus, improved glucose tolerance in hepatocyte RXR{alpha}-deficient mice is associated with increased serum IGF-I concentration.



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  		Figure 6. Serum IGF-I level in wild-type (wt) and knockout (ko) mice. Values are expressed as means ± SEM (n = 7–10). *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Because RXR{alpha} dimerizes with all three PPAR isoforms and many other nuclear receptor superfamily members, the hepatocyte RXR{alpha} knockout mouse provides a unique opportunity for analyzing the functional roles of RXR{alpha} as well as PPARs and other receptors in the liver. By comparing their phenotypes with other conventional knockout mice, such as PPAR{alpha} and {gamma}, the tissue-specific role of the receptor can be analyzed. PPAR{alpha}-null mice are obese and have elevated serum cholesterol and leptin level and increased apoAI mRNA expression (6, 17). The PPAR{gamma} +/- mice have very little body weight gain, compared with the wild-type mice, when they are fed a high-fat diet. The fat mass in PPAR{gamma} +/- mice is also less than that of the wild-type mice. The heterozygous PPAR{gamma} mutants have less food intake and increased serum leptin levels (12). Therefore, hepatocyte RXR{alpha}-deficient mice possessed both PPAR{alpha} and PPAR{gamma} knockout-mice phenotypes. Like the PPAR{alpha}-null mice, hepatocyte RXR{alpha}-deficient mice are obese, have a larger fat mass, and higher serum leptin level, compared with wild-type mice. In addition, serum cholesterol and liver apoAI mRNA levels are elevated in both PPAR{alpha}-null and hepatocyte RXR{alpha}-deficient mice (13, 18). Similar to PPAR{gamma} +/- mice, hepatocyte-RXR{alpha}-deficient mice also have reduced food intake and increased serum leptin levels. These data indicate that hepatocyte RXR{alpha}-deficient mice and other nuclear-receptor knockout mice have overlapping phenotypes. Because the PPAR{alpha}-null and PPAR{gamma} +/- mice are not hepatocyte-specific knockout mice, it would be important to further analyze which of the RXR{alpha} partners in the liver contributes to those hepatocyte RXR{alpha}-deficient phenotypes. Only male mice are included in the present study. Compared with male mutant mice, female hepatocyte RXR{alpha}-deficient mice have a different phenotype. Female mice are partially protected from RXR{alpha} deficiency (unpublished data). It would be interesting to further determine whether there is a sexual dimorphic difference in RXR{alpha}-mediated fatty-acid and carbohydrate metabolism.

It is well known that activation of PPAR{gamma} leads to amelioration of insulin resistance, because in vivo administration of thiazolidinedione has been shown to increase the insulin sensitivity in obese insulin-resistant humans and animals (19, 20). Therefore, it is very surprising that, with a high-fat diet, heterozygous deficiency of the PPAR{gamma} gene results in an increased insulin-sensitive phenotype, compared with wild-type mice (12). This unexpected finding was explained by the induction of leptin in the PPAR{gamma} +/- mice, which alters energy balance and results in increased insulin sensitivity. It is also surprising that the obese hepatocyte RXR{alpha}-deficient mice are protected from high-fat diet-induced glucose intolerance. In fact, hepatocyte RXR{alpha}-deficient mice have improved glucose tolerance, even when the mice are on a regular diet. Obviously, the improved glucose tolerance in hepatocyte RXR{alpha}-deficient mice is neither caused by elevated insulin level nor caused by increased insulin sensitivity. What remains to be explained is why elevated serum leptin level in hepatocyte RXR{alpha}-deficient mice does not increase insulin sensitivity, similar to what occurred in the PPAR{gamma} +/- mice. One possible explanation is that the effect of leptin is compromised because of the obesity of hepatocyte RXR{alpha}-deficient mice.

Similar to hepatocyte RXR{alpha}-deficient mice, high-fat-fed PPAR{alpha}-null mice also demonstrate increased adiposity and elevated blood leptin level (18). However, the increase in adiposity is noncorrelated with insulin resistance induced by a high-fat diet. PPAR{alpha}-null mice do not exhibit high-fat-diet-induced insulin resistance. In addition, similar to hepatocyte RXR{alpha}-deficient mice, PPAR{alpha}-null mice also have increased glucose tolerance, compared with wild-type mice, when they are fed a high-fat diet (18). It would be worthwhile to examine whether PPAR{alpha}-null mice have elevated IFG-I. Therefore, in terms of glucose metabolism, PPAR{gamma} +/-, PPAR{alpha}-null, and hepatocyte RXR{alpha}-deficient mice have overlapping and unique phenotypes.

IGF-I has an insulin-like activity. Although it has only about 5–10% of the hypoglycemic action of insulin on a molar basis (21), IGF-I circulates at about 1,000 times the concentration of insulin in plasma (22). The liver produces the majority of circulating IGF-I. The bioactivity of IGF-I is determined by its binding proteins (23). Our data showed that serum IGF-I level was significantly increased in the mutant mice. IGF-I has been demonstrated to be effective in improving glucose uptake both in human subjects and laboratory animals (24, 25, 26). IGF-I is a useful adjunct for the treatment of diabetes and may even be the drug of choice in some patients with extreme insulin resistance and metabolic emergencies (24). IGF-I can increase insulin-stimulated glucose uptake (25). Abrogating the normal function of IGF-I receptor would lead to insulin resistance (26). Therefore, increased IGF-I level might account for improved glucose tolerance in hepatocyte RXR{alpha}-deficient mice. It would be important to further characterize the molecular mechanisms underlying retinoid-mediated regulation of IGF-I.


   Acknowledgments
 
We thank Drs. Robert Morin and Thomas Magee for critical reading of this manuscript.


   Footnotes
 
This work was supported by NIH Grant CA-53596.

Abbreviations: apoCIII, Apolipoprotein CIII; CYP4A1, cytochrome P450 4A1; en%, energy percent; LFABP, liver fatty-acid-binding protein; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor.

Received September 25, 2002.

Accepted for publication October 11, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Retinoid X Receptor {gamma}-Deficient Mice Have Increased Skeletal Muscle Lipoprotein Lipase Activity and Less Weight Gain when Fed a High-Fat Diet
Endocrinology, August 1, 2004; 145(8): 3679 - 3685.
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Y. Wu, X. Zhang, F. Bardag-Gorce, R. C. V. Robel, J. Aguilo, L. Chen, Y. Zeng, K. Hwang, S. W. French, S. C. Lu, et al.
Retinoid X Receptor {alpha} Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver
Mol. Pharmacol., March 1, 2004; 65(3): 550 - 557.
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Y. Cai, T. Dai, Y. Ao, T. Konishi, K.-H. Chuang, Y. Lue, C. Chang, and Y.-J. Y. Wan
Cytochrome P450 Genes Are Differentially Expressed in Female and Male Hepatocyte Retinoid X Receptor {alpha}-Deficient Mice
Endocrinology, June 1, 2003; 144(6): 2311 - 2318.
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