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Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Health Science Center, Denver, CO 80262
2To whom correspondence should be addressed. E-mail: Michael.Bizeau{at}uchsc.edu.
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ABSTRACT |
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 TOP ABSTRACT METHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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60% lower in the soleus and gastrocnemius and 75% lower in the white quadriceps after 24 h. Additional refeeding experiments were conducted using a high fat diet in place of a high cornstarch diet. This diet diminished the increase in SREBP-1c RNA at all time points and in all muscles. This effect could not be explained by plasma glucose or insulin concentration. In conclusion, SREBP-1c RNA and SREBP-1 protein levels respond to nutritional status in skeletal muscle.
KEY WORDS: • skeletal muscle • transcription factor • insulin • glucose • rats
Although extensively studied in liver, the role of the sterol response element binding protein family of transcription factors in skeletal muscle is only beginning to receive attention. Sterol regulatory element binding proteins (SREBP) are unique forms of basic helix-loop-helix leucine zipper transcription factors first identified as important regulators of cholesterol metabolism (1–4) and adipocyte differentiation (5). SREBP are synthesized and inserted into the endoplasmic reticulum and nuclear envelope as immature membrane-bound 125-kDa precursor proteins. In liver, cholesterol depletion (1,2) and insulin stimulation (6–10) result in cleavage of the immature SREBP to produce a 68-kDa "mature" transcription factor that migrates to the nucleus and activates gene transcription. There are three SREBP isoforms, 1a, 1c and 2. SREBP-1a and -1c are produced from the SREBP-1 gene, which contains two distinct promoters (1). SREBP-1a has a longer amino terminal domain, which contains more acidic amino acids than SREBP-1c, making SREBP-1a a stronger transcriptional activator than SREBP-1c (11). SREBP-1c is the prevalent SREBP-1 isoform expressed in most mammalian organs (12). The third isoform, SREBP-2, is produced as a single gene product from the SREBP-2 gene (1).
In liver, SREBP-1c regulates genes associated with glucose and fatty acid metabolism, including glucokinase, fatty acid synthase, acetyl-CoA carboxylase and glycerol-3-phosphate acyltransferase (9,13–16). SREBP-2 regulates genes involved in cholesterol metabolism (2–4). In mice, deletion of SREBP-1c in the liver results in a dramatically diminished ability to induce genes involved in fatty acid synthesis upon refeeding food-deprived rats a high carbohydrate meal (17). Data such as these have been used to suggest that SREBP-1c functions as a sensor of nutritional status in vivo. Numerous studies have shown that insulin and glucose increase and polyunsaturated fatty acids decrease SREBP-1c mRNA and protein levels (6–8,10,13,18,19). Thus, it is thought that SREBP-1c responds to both nutrients and hormones to control the integration of fuel metabolism at the level of gene regulation (20).
It has recently been reported that SREBP-1c is the predominant SREBP-1 isoform expressed in rat skeletal muscle (21). SREBP-1c RNA is decreased in streptozotocin-induced diabetes and increased by insulin in primary muscle cell culture (21), indicating that insulin may regulate SREBP-1c in skeletal muscle much as it does in the liver. Evidence is also emerging that the regulation of SREBP-1c is altered in human diseases such as type 2 diabetes and obesity. In healthy control subjects, SREBP-1c RNA is increased in human skeletal muscle in response to a euglycemic-hyperinsulinemic clamp (22,23), whereas this increase is blunted in individuals with type 2 diabetes (22). Thus, it appears that insulin regulates SREBP-1c in skeletal muscle as it does in other tissues. It is not known whether skeletal muscle SREBP-1c expression responds to nutritional status (i.e., food deprivation and feeding). Thus, the primary goal of the present study was to examine nutrient regulation of SREBP-1c RNA and SREBP-1 protein in skeletal muscle in response to food deprivation and refeeding both a high carbohydrate and a high fat meal. Additionally, we examined SREBP-1c expression in multiple skeletal muscle fiber types representative of different insulin sensitivities and fuel oxidation capacities.
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METHODS AND MATERIALS |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats, weighing 180 g, were obtained from Charles River (Madison, WI). Rats were housed individually in a temperature-controlled room with a 12-h light:dark cycle and free access to food and water. All procedures for animal use were approved by the Institutional Animal Care and Use committee at the University of Colorado Health Sciences Center. Rats had free access to a semipurified starch diet (Research Diets, New Brunswick, NJ; Table 1) and were allowed to acclimate for 1 wk before use in any experiments. After 1 wk of consuming the starch diet, food was withdrawn for 48 h. After 48 h, rats were provided either a high cornstarch or a high fat diet (Table 1). Rats were killed after 48 of food deprivation or 6, 12, or 24 h after access to food. Rats were anesthetized with sodium pentobarbitol (60 mg/kg), blood was drawn from the portal vein and the soleus, gastrocnemius and white portion of the quadriceps muscles were removed and immediately freeze-clamped in liquid nitrogen. To study the effect of food deprivation, a separate group of rats was fed the high cornstarch diet on their normal diurnal cycle. Food was withdrawn at the beginning of the light cycle and blood and tissue collected exactly as described above at 0, 6, 12 or 24 h after food was removed.
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Total RNA was isolated from 100 mg of tissue using TRIzol (Invitrogen, Carlsbad, CA) reagent according to the manufacture’s instructions. The RNA was purified using centrifugation (10,000 x g for 15 min at 4°C) and ethanol precipitation. Total RNA was then DNase-treated (RQ1, Promega, Madison WI). Reverse transcription was performed on 0.5 µg of the DNAse-treated RNA using Superscript II RnaseH- and random hexamers (Invitrogen). The transcribed cDNA (2 µL) was subjected to duplex PCR amplification using 25 pmol of oligonucleotide primers specific for the genes listed in Table 2 and a competimer/primer mix specific for 18S ribosomal RNA (Ambion, Austin, TX). All PCR reactions were also run with DNAse-treated RNA samples that had not been subjected to reverse transcription. These samples did not yield any products. The PCR products were separated by electrophoresis through 2% agarose gels and visualized with ethidium bromide staining. A digital image of the gel was obtained with an Alphalmager2000 (Alpha Innotech, San Leandro, CA) and band intensities quantified using SigmaGel (SPSS, Chicago, IL) gel analysis software. The ratio between the target RNA and 18S ribosomal RNA was calculated. Data are presented based on the fold change in the target/18S ratio compared with the value obtained for the food-deprived rats. Each PCR reaction was performed in duplicate on two individual preparations of reverse-transcribed cDNA.
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Frozen skeletal muscle (50- to 100-mg portions) was powdered in liquid nitrogen and homogenized in 10 volumes of a lysis buffer containing 50 mmol/L Tris, 150 mmol/L NaCl, 20 mmol/L NaF, 10 mmol/L EDTA, 1 mmol/L Na3VO4, 0.3 mmol/L phenylmethylsulfonyl fluoride, 2 µmol/L leupeptin, 2 µmol/L pepstatin, 10 mg/L aprotinin, and Triton 1% (v/v), pH 7.4. The homogenate was rotated for 30 min at 4°C and then centrifuged at 20,300 x g for 30 min at 4°C. The supernatant was removed and analyzed for protein concentration and stored at -70°C for use in Western blotting.
Western blotting.
Equal amounts of total protein were subjected to SDS-PAGE and electrotransferred to nitrocellulose membranes. Nitrocellulose blots were incubated overnight at 4°C with an antibody for SREBP-1 (2A4, Santa Cruz Biotechnology, Santa Cruz, CA). Detection was performed using enhanced chemiluminescence reagents (Amersham Pharmacia Biotech, Bucks, UK) and the band intensity was quantified using optical densitometry as described above.
Analytical methods.
Plasma insulin was measured using a rat-specific RIA kit according to the manufacture’s directions (Linco Research, St. Charles, MO). Plasma glucose was measured enzymatically using the GAHK-20 kit (Sigma, St Louis MO).
Statistical methods.
Data were analyzed using a two-way ANOVA. If the overall F was significant, comparisons between mean values were made to either the food-deprived group or the group fed overnight, depending on the experiment, using a Student-Newman-Keuls test. Significance was set at P < 0.05 for all comparisons. All data are presented as means ± SEM.
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RESULTS |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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Portal vein plasma insulin and glucose concentrations were increased (P < 0.05) by refeeding in rats fed both the high fat and the high starch (cornstarch) diets at 6 h and remained elevated at 12 and 24 h (Table 3). There were no differences in portal vein insulin or glucose concentrations between the two groups of rats at any of the time points. Feeding the starch diet significantly (P < 0.05) increased SREBP-1c RNA in all muscles compared with the food-deprived group (Fig. 1A–C). In all muscles, the peak increase in SREBP-1c RNA occurred with 12 h of refeeding. A high fat meal attenuated the increase in SREBP-1c RNA compared with the cornstarch meal in all fiber types despite similar plasma glucose and insulin concentrations. There was no increase in SREBP-1a RNA above food deprivation levels and no effect of diet on SREBP-1a RNA at any of the time points measured for all muscles examined (data not shown). Feeding food-deprived rats a cornstarch diet resulted in a doubling of the 125-kDa SREBP-1 protein in soleus muscle and a 50% increase in gastrocnemius and white quadriceps muscles (Fig. 2).
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Because feeding increased the RNA for SREBP-1c, we next determined whether food deprivation decreased SREBP-1c RNA. Food deprivation decreased (P < 0.05) SREBP-1c RNA and portal vein plasma insulin and glucose concentrations at all time points after food was withdrawn (Fig. 3, Table 4). The greatest decrease in SREBP-1c RNA occurred 24 h after food was withdrawn.
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Feeding a cornstarch diet increased the RNAs for acetyl-CoA-carboxylase-1 and hexokinase-II, both of which have purported binding sites for SREBP in their gene promoters and are regulated by insulin (22). In contrast, the RNAs for pyruvate dehydrogenase kinase-4, uncoupling protein-3 and malonyl-CoA- decarboxylase were decreased (P < 0.05). The RNA for acetyl-CoA-carboxylase-2 was not significantly changed with refeeding (Table 5).
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DISCUSSION |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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In the present study, SREBP-1c RNA was increased by feeding, a condition characterized by hyperinsulinemia and hyperglycemia. Recent studies in humans demonstrate that in response to a euglycemic-hyperinulinemic clamp, SREBP-1c RNA was increased in skeletal muscle, indicating a role for insulin in the regulation of SREBP-1c in skeletal muscle (22,23). However, it has also been shown that the signals that regulate SREBP-1c RNA are tissue specific. For example, in liver, insulin (6,8) is the primary regulatory signal, whereas in kidney, glucose, not insulin (24), is the primary signal to increase SREBP-1c RNA. Whether the expression of SREBP-1c in skeletal muscle is regulated primarily by insulin, glucose or the combination of hyperinsulinemia and hyperglycemia is a question that has yet to be answered.
Skeletal muscle is not a homogenous tissue and is comprised of specific fiber types that differ in enzymatic composition, metabolic capacities and insulin sensitivity (25,26). In the present study we examined the regulation of SREBP-1c RNA expression in three skeletal muscles that differed in fiber type. In general, the qualitative response of SREBP-1c RNA in response to feeding was similar among the muscles studied. These data suggest that postprandial regulation of SREBP-1c RNA may not be dependent on fiber type in skeletal muscle.
When food-deprived rats were refed a high fat diet, the increase in SREBP-1c RNA was blunted compared with the cornstarch diet. Differences in the portal vein concentrations of glucose and insulin at the terminal time points were not observed. Although it cannot be ruled out that the high fat meal elicited lower glucose and insulin levels over the entire course of the feeding period, the current data suggest that SREBP-1c expression in skeletal muscle may be modulated by lipid delivery/flux into muscle. Polyunsaturated fatty acids have been shown to decrease SREBP-1c by accelerating SREBP-1c transcript decay and decreasing the nuclear content of SREBP-1 in liver (19), indicating that in some tissues, SREBP-1c is regulated directly by the nutrient composition of the diet. Further studies are required to determine whether fatty acids can regulate SREBP-1c in skeletal muscle.
In the present study, refeeding a starch meal also increased SREBP-1 protein levels in all muscles studied. In addition, we observed increased expression of hexokinase II and acetyl CoA carboxylase-1 and a decreased expression of uncoupling protein-3, malonyl-CoA decarboxylase and pyruvate dehydrogenase kinase-4 RNA. These changes in gene expression are in agreement with several previous studies, although the factors regulating these changes have not been fully characterized (27–31). Given the well-defined role of SREBP-1 in other tissues, it is tempting to speculate that SREBP-1 protein may be involved in the regulation of one or more of the genes. It is interesting to note that several of the genes that changed in response to food deprivation and refeeding in the present study or insulin infusion in skeletal muscle (22) have been reported to contain putative binding sites for SREBP-1 on their promoters (22). Additionally, it was demonstrated recently that adenovirus-mediated overexpression of SREBP-1c was able to block peroxisome proliferator-activated receptor agonist induction of uncoupling protein-3 RNA in cultured muscle cells (21), suggesting that SREBP-1c may also be capable of suppressing gene transcription as has been demonstrated for phosphoenolpyruvate carboxykinase in the liver (32). Thus, SREBP-1c may be involved in both positive and negative regulation of gene transcription in response to nutritional status in skeletal muscle.
In summary, we have demonstrated that SREBP-1c RNA and protein levels are regulated by nutritional status in skeletal muscle of rats such that feeding increased and food deprivation decreased SREBP-1c. SREBP-1c RNA content also appears to be influenced by diet composition because a high fat meal attenuated the meal-induced increase in SREBP-1c RNA. In conclusion, SREBP-1c RNA and SREBP-1 protein levels respond to nutritional and nutrient status in skeletal muscle, suggesting that SREBP-1c may function to regulate transcription in response to nutritional status in skeletal muscle.
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FOOTNOTES |
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3 Abbreviations used: HF, high fat meal; SREBP, sterol response element binding protein; ST, high cornstarch meal.
Manuscript received 6 December 2002. Initial review completed 9 January 2003. Revision accepted 24 February 2003.
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LITERATURE CITED |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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