Fat accumulation in Caenorhabditis elegans is mediated by SREBP homolog SBP-1
© Springer-Verlag 2009
Received: 27 July 2009
Accepted: 22 October 2009
Published: 20 November 2009
Research into the metabolism of fats may reveal potential targets for developing pharmaceutical approaches to obesity and related disorders. Such research may be limited, however, by the cost and time involved in using mammalian subjects or developing suitable cell lines. To determine whether invertebrates could be used to carry out such research more efficiently, we investigated the ability of Caenorhabditis elegans (C. elegans) to accumulate body fat following the consumption of excess calories and the mechanisms it uses to metabolize fat. C. elegans worms were grown on media containing various sugars and monitored for changes in body fat and expression of sbp-1, a homolog of the mammalian transcription factor SREBP-1c, which facilitates fat storage in mammals. The fat content increased markedly in worms exposed to glucose. In situ analysis of gene expression in transgenic worms carrying the GFP-labeled promoter region of sbp-1 revealed that sbp-1 mRNA was strongly expressed in the intestine. An sbp-1 knockdown caused a reduction in body size, fat storage, and egg-laying activity. RT-PCR analysis revealed a considerable decrease in the expression of fatty acid synthetic genes (including elo-2, fat-2, and fat-5) and a considerable increase of starvation-inducible gene acs-2. Normal egg-laying activity and acs-2 expression were restored on exposure to a polyunsaturated fatty acid. These findings suggest that SBP-1 and SREBP regulate the amount and composition of fat and response to starvation in a similar manner. Thus, C. elegans may be an appropriate subject for studying the metabolism of fats.
The rapidly increasing prevalence of obesity in developed nations has been accompanied by an increased interest in the study of fat metabolism with the goal of identifying targets for the development of products that may prevent or cure obesity and conditions for which obesity is a risk factor (including type 2 diabetes mellitus and the dyslipidemias). Research activities may be limited, however, by the cost and the time involved in using mammalian subjects or developing suitable cell lines. The use of invertebrates may overcome both of these barriers to research. The nematode Caenorhabditis elegans, for example, may provide a more efficient means of screening research materials and medications and studying the metabolism of fat because of its short lifespan and the ease with which fat can be visualized in its body. The feasibility of using C. elegans in fat metabolism studies will depend, of course, on whether it accumulates fat when it consumes more energy than it needs and whether it uses metabolic pathways similar to those used in mammals to synthesize and store fat.
The process of converting excess energy into fat begins in mammals when insulin induces the translocation of the glucose transporter GLUT into the cell, thereby increasing intracellular glucose levels [1–5]. This is followed by an increase in sterol regulatory element-binding protein (SREBP)-1c basic helix-loop-helix-zipper (bHLH-zip) transcription factor [6–15]. SREBP-1c is transported to the nucleus, where it undergoes dimerization and then binds to the e-box and consensus sterol response element (SRE) (15, 16) regions of genes that contribute to fat synthesis including acyl-cocarboxylase (acc-1), fatty acid synthase (fas), several desaturases, long fatty acid elongase, and glycerol-3-phosphate-acyltransferase [16–23]. SREBP-1c also regulates the production of insulin receptor substrate (irs)-2 (a component of the insulin signal pathway) and, thus, promotes insulin resistance . Because rat homolog of SREBP-1c is involved in adipocyte differentiation, it was called adipocyte determination and differentiation dependent (ADD1) . These actions make SREBP-1c a potential target for the development of therapeutics for obesity and associated diseases.
SREBP-1c has been found in a variety of animals, including yeast, but it is not always involved with fat accumulation, functioning instead as a sensor of intracellular cholesterol and oxygen levels ( [26, 27, 28]). C. elegans has a homolog of SREBP: Y47D38.7/sbp-1/lpd-1. C. elegans nematodes lacking this gene demonstrate delayed growth, lower fat levels, and altered rates of expression of fat synthesis genes, specifically Acc-1, fas-1, fatty acid elongases (elo-5 and elo-6), and stearoyl-CoA desaturases (fat-6 and fat-7) [29–32]. Furthermore, it was recently reported that a co-activator, ARC105/MDT-15, is necessary for SREBP and SBP-1 activity in mammals and C. elegans, respectively . These observations suggest that SBP-1 has the same function in C. elegans as SREBP-1c does in mammals.
Caenorhabditis elegans produces three Δ9 desaturases (fat-5, fat-6, and fat-7), as well as Δ3, Δ5, Δ6, and Δ12 desaturases; thus, it can produce multiple kinds of fatty acids [34–38]. By contrast, mammals lack Δ3 and Δ12 desaturases, which prevents them from producing polyunsaturated fatty acids (PUFAs) endogenously and makes it necessary for them to obtain PUFAs from food. These essential PUFAs include docosahexanoic acid (DHA), eicosapentanoic acid (EPA), linoleic acid, and α-linolenic acid, all of which are necessary for normal nerve activity. Transcription of the genes that produce Δ5, Δ6, and Δ9 desaturases in mammals is controlled by SREBP-1c [18, 19]. This suggests that the expression of desaturases in C. elegans is regulated by SBP-1. The expression of fat-6 and fat-7 is indeed regulated by SBP-1 . However, the expression of these two genes (along with fat-5) is also controlled by two other transcription factors: nhr-49 or nhr-80 [39–41]. sbp-1 and nhr-49, in turn, are both regulated by the same co-activator (mdt-15) [33, 42].
The purpose of this study was to determine whether excess energy is stored as fat in C. elegans as it is in mammals and whether the expression of the srebp homolog sbp-1 also changes during the fat-accumulation process. We used RNA interference (RNAi) of sbp-1 to determine how SBP-1 affects relevant physiological phenomena and gene expression in C. elegans.
Worms and culture
Wild-type Caenorhabditis elegans Bristol N2 (Caenorhabditis Genetics Center, Minnesota, USA) were cultured at 20°C on NGM (Nematode Growth Medium) agar plated with E. coli OP50 as previously described . Each worm was transferred on the new plate in each 7 days.
Synchronization of the growth stage
To synchronize the growth stage of nematode, adult worms were treated with 10% NaClO solution [10 N NaOH/NaClO (10:1)] at room temperature, until the skin of the individual of 80% was destroyed. The eggs were collected and cultured overnight in S-basal (0.1 mol/l NaCl, 50 mmol/l potassium phosphate buffer) at 20°C until hatching.
Nile red assays
The synchronized L1 worms were cultured on media including 500-nM Nile red. Three or four days later, worms were collected, treated with 0.2% PFA solution, and observed under a fluorescence microscope (DMRXA, Leica) using N3 filter. Image analysis was performed using ImageJ, a public domain Java-based image-processing program inspired by NIH Image.
Effect of fatty acid
The sbp-1 RNAi worms were cultured on NGM plate containing 1 mM fatty acid (stearic acid, oleic acid, or linoleic acid, WAKO) and 0.1% tergitol type NP-40 (SIGMA). After 3 or 4 days culture, the worms were subjected to Nile red analysis, the egg laying, RT-PCR, and GFP assays.
Construction of feeding RNAi plasmid
PCR was performed to amplify the sbp-1 cDNA regions using PCR-2720 (Applied Biosystems, Foster City, CA, USA). Primer was designed to have restriction site at 5′-end and to make PCR products with ~500 ntds in length. The amplified PCR products were digested by each restriction enzyme and subcloned into plasmid L4440 (provided from Fire laboratory) designed for feeding-RNAi (RNAi plasmid). The nucleotide sequences of plasmid DNA were analyzed by using Big Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems) and ABI PRISM 377 DNA Sequencer (Perkin Elmer Biosystems). The primers were designed from DNA sequences according to the Wormbase database (http://www.wormbase.org). PCR (95°C for 5 min; 25–30 cycles of 95°C for 1 min, 52°C for 30 s, 72°C for 1.5 min; 72°C for 7 min) was performed using the following primers; sbp-1F, CATGAATTCATTCGAGGGAGACGTCCC, sbp-1R, CATGAATTCCTGATGTGGAGTCATCG C.
Escherichia coli strain HT115 was transfected with RNAi plasmid and treated with 35 mM IPTG (Isopropyl-β-d-thiogalactopyranoside, Wako, Chuo, Osaka, Japan) to induce the RNA expression. These transformants were plated on NGM agar containing 1 mM IPTG and incubated at 37°C for 1 h (RNAi plate). L4440, an empty vector, was used as a negative control of RNAi. Because the E. coli HT115 transformant and the RNAi plate lose RNAi efficiency along with time, they were prepared newly in every experiment. After treatment of adult worms with 10% NaClO solution [10 N NaOH/NaClO (10:1)], eggs were collected and cultured overnight in S-basal (0.1 mol/l NaCl, 50 mmol/l potassium phosphate buffer) at 20°C until hatching. Hatched L1 larvae or adult worms were then cultured on NGM RNAi plates at 20°C to induce RNAi.
The movement analysis
The number of movements per 1 min of the pumping and the thrashing was counted under the microscope.
Egg-laying analysis: adult nematodes
L1 larva or adult nematode was cultured on RNAi plate at 20°C for 3 days (L1 larva) or 1 day (adult). The number of eggs laid by each worm for 24 h was counted.
RNA preparation and PCR
Primers for RT-PCR
Transgenic worm carrying promoter-GFP plasmids
Primers for RT-PCR
Effect of sugars on fat accumulation
Effect of glucose on gene expression
Effect of sbp-1 knockdown on phenotype
Effect of sbp-1 knockdown on gene expression
Effect of fatty acids on phenotype in C. elegans with sbp-1 knockdown
Influence of sugar on fat accumulation in C. elegans
Fat accumulation increased when glucose or fructose was used as an energy source (Fig. 1); galactose and xylose (a sugar that resolves only minimally) had little effect. These observations suggest that fat levels increase with the intake of excess calories from sugar in C. elegans as they do in mammals. In mammals, acylglycerol triglyceride levels increase through up-regulation of the bHLH transcription factor SREBP-1c under the influence of nutritional status, glucose and insulin [6, 8–15, 44]. Previous reports suggest that the function of the SREBP homolog SBP-1 in nematodes is similar to that of SREBP in mammals. We investigated this possibility further by monitoring sbp-1 expression in L1 worms grown in the presence of 10 mM glucose. RT-PCR analysis revealed that sbp-1 expression did not change throughout the maturation process. However, larvae that matured in the absence of glucose developed into adult worms that expressed sbp-1 when exposed to 10, 100, or 500 mM of glucose during adulthood (Fig. 1). This suggests that the mechanism responsible for regulation of sbp-1 expression in response to the intake of excess calories from glucose is preserved in C. elegans as is that for SREBP-1c in mammals.
SBP-1 regulates the phenotype of C. elegans
In situ analysis of gene expression in transgenic worms carrying a GFP-labeled sbp-1 promoter region revealed that sbp-1 expression occurs primarily in the intestine, regardless of the developmental stage of the worm (Fig. 2b). This supports an earlier hypothesis that the intestine is the organ of fat accumulation in nematodes . So far, our understanding of the role of SBP-1 in nematodes is limited. In this study, an sbp-1 knockdown through feeding RNAi resulted in a reduction in the fat content of the worm, as well as in body size and egg-laying activity (Fig. 3)—all of which are the characteristics of starvation and the presence of an eat-2 mutant . Under starvation conditions, fatty acid combustion occurs following a decrease in fat-7 expression and an increase in acs-2 expression [40, 41]. In the same way, β-oxidization was induced and weight was not changed by feeding the high fat food in mouse that lacked Δ9 stearoyl-CoA desaturase (SCD-1) (Dobrzyn et al. 2005). It has been reported that the fat-7 expression decreases in sbp-1 knockdown worms and that egg-laying activity is reduced in sbp-1 knockdown worms [33, 38]. Our observations correspond with these findings. Moreover, in sbp-1 knockdown animals, fat-7 expression decreased and acs-2 expression increased (Fig. 4a). It is not clear, however, why the number of eggs laid decreased.
SBP-1 regulates the expression of genes responsible for fatty acid synthesis
SBP-1 appears to be involved in the expression of genes that participate in fatty acid synthesis, as indicated by decreased expression of acc-1, fas-1, fat-6, and fat-7 in sbp-1 knockdown worms [29, 33]. The nematode has Δ12 and Δ3 desaturases (these are absent in most mammals), which convert saturated fatty acids into mono- or polyunsaturated fatty acids. So far, the role of Δ12 or Δ3 desaturases in C. elegans is not completely understood. To explore their relationship with SBP-1, we used RT-PCR to determine whether sbp-1 knockdown in these animals affects desaturase activity: we found that elo-2, fat-2, fat-5, fat-6, and fat-7 expression increased remarkably in these worms, indicating that the gene products are regulated by SBP-1. By contrast, fat-1, fat-3, and fat-4 expression did not change (Fig. 4a), indicating that their products are either regulated by other factor or controlled by multiple mechanisms. The relationship between the Δ12 desaturases (which are involved in the production of linoleic acid [C18:2]) and SBP-1 remains inconclusive, given that one Δ12-desaturase-producing gene (fat-2) responded to the sbp-1 knockdown and another (fat-1) did not. Because the Δ12 desaturases are not found in humans or mice, we cannot look to mammals for potential similarities in control and function. So far, little is known about factors contributing to the expression of fat-1 in C. elegans. Our in situ GFP analysis of transgenic worms revealed that this gene is expressed only in the neural area (Fig. 4b). The GFP level in the neural area was not affected when feeding sbp-1 RNAi was introduced to these worms, which suggests that fat-1 is not regulated by SBP-1.
More information is available about the Δ9-desaturases—fat-5, fat-6, and fat-7—and the elo-2 that responded to SBP-1 in our study. An elo-2 knockdown causes delayed growth and other effects in nematodes ; this is consistent with the effects of palmitic acid elongase, which is controlled by SREBP-1c in mammals. Recent reports that a knockdown of the gene for another fatty acid elongase—elovl6—causes insulin resistance in mice  suggest a clinical role for elo-2 that may be worthy of further investigation. Knockdowns of fat-5, fat-6, and fat-7 or a mutation in fat-6 and fat-7 cause severely delayed growth and a decreased accumulation of fat in C. elegans . Additional information is available concerning the regulation of these genes: fat-7 expression is induced through activation of the nuclear receptor nhr-80 in animals carrying a fat-6 mutant ; and fat-5, fat-7, and acs-2 expression is activated by nhr-49 through its interactions with mdt-15 and SBP-1 [33, 42]. The failure of fat-3 (a Δ5 desaturase) and fat-4 (a Δ6 desaturase) to respond to an sbp-1 knockdown suggests that they are controlled by another entity or that they respond to multiple controls. The latter is suggested in mammals by the change in mRNA levels for genes coding the Δ5 and Δ6 desaturases that occurs in response to changes in both SREBP-1c and PPAR-γ activity. In this case, the loss of function by one transcription factor can be compensated for by the other .
In situ analysis of gene expression in transgenic worms carrying a GFP-labeled promoter region of fat-4 revealed that fat-4 is expressed predominantly in the intestine (Fig. 4b). The introduction of sbp-1 RNAi feeding into these worms caused GFP fluorescence in the intestine to decrease and allowed fat-4 expression to be detected in the neural area. Because the RNAi feeding method is not available for neurons, changes in fat-4 expression cannot be detected by RT-PCR (Fig. 4a). It has been hypothesized that PUFAs such as DHA and EPA have important roles in central nerve function [48, 49]. Recently, it was suggested that the schizophrenia-related gene FABP7 participates in the uptake of PUFAs into the neuron  and that the neuronal damage responsible for Parkinson’s disease in murine studies is mitigated with the uptake of PUFAs . Because the expression of fat-1, fat-4 (Fig. 4b), and fat-3 [36, 52] was detected in the neural area, it has been suggested that these animals produce PUFAs endogenously for their own use.
The effect of fatty acid on the phenotype of sbp-1 RNAi worm
In vitro exposure of L1 worms with sbp-1 knockdown to oleic or linoleic acid restored body size but did not restore the accumulation of fat (Fig. 5a). However, when RNAi worms of fat-6, fat-7, and fat-2 (which participate in endogenous PUFA biosynthesis) were exposed to oleic or linoleic acid, fat accumulation was restored (data not shown). This suggests that SBP-1 possibly affects the expression of genes concerned with fat accumulation as well as genes concerned with the biosynthesis of fatty acids. In fact, SREBP controls the expression of genes involved in triglyceride composition in mammals. The sbp-1 knockdown phenotypes (“Clear” and “inside hatching”) observed in this study are similar to those seen in worms bred under starvation conditions. Consistent with this, we observed an increase in the expression of the starvation-inducible gene acs-2 in sbp-1 RNAi worms (Fig. 4b). It is known that acs-2 expression is upregulated in fat-6 and fat-7 mutants and in fat-6 and fat-7 knockdown animals. Thus far, there have been no reports that a lack of oleic acid induces acs-2 expression or β-oxidation of fatty acids. In our study, exposure of sbp-1 knockdown worms to oleic acid actually suppressed acs-2 expression (Fig. 6a). The same effect was achieved with linoleic acid, however, which complicates the interpretation of our results. Body size and the number of eggs laid by sbp-1 knockdown worms were restored to normal through exposure to oleic or linoleic acid (Fig. 5), and it has been suggested that these fatty acids have similar effects. However, additional studies involving other unsaturated fatty acids and an analysis of the fatty acid content of the worm are required to confirm this hypothesis.
In this study, we found that the uptake of excess calories from sugar results in the accumulation of fat in C. elegans, as it does in mammals. The mechanism for fat accumulation is almost the same in C. elegans as it is in mammals, which suggests that this nematode could be a time-saving and cost-effective alternative for studying fat metabolism.
This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan. We wish to thank Dr. Motomichi Doi (Advanced Industrial Science and Technology, Neuroscience Research Institute) for technical help for microinjection.
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