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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5356-5360
Copyright © 2005 by The Endocrine Society

Upstream Transcription Factor-1 Gene Polymorphism Is Associated with Increased Adipocyte Lipolysis

Johan Hoffstedt, Mikael Rydén, Hans Wahrenberg, Vanessa van Harmelen and Peter Arner

Department of Medicine, Karolinska Institute, SE-141 86 Stockholm, Sweden

Address all correspondence and requests for reprints to: Dr. Johan Hoffstedt, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. E-mail: johan.hoffstedt{at}medhs.ki.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: Variations in lipid metabolism between individuals could be due to genetic factors. A transmission of a haplotype of the upstream transcription factor-1 (USF-1) gene containing the minor alleles at the usf1s1 and usfs2 loci is described. We investigated whether these polymorphisms are associated with adipocyte lipolysis.

Methods and Results: A total of 196 healthy obese women were investigated for in vitro lipolysis regulation in sc fat cells, which was set in relation to the usf1s1 C->T and usf1s2 G->A polymorphisms in the usf1 gene. The two polymorphisms were in complete linkage disequilibrium. The usf1s1/2 T/A allele was associated with increases in the maximum lipolytic action of noradrenaline (P = 0.005), dobutamine (P = 0.008), terbutaline (P = 0.008), CGP12177 (P = 0.015), and forskolin (P = 0.006). In contrast, no significant genotype effect on lipolytic sensitivity (i.e. half-maximum effective concentration) for any of the drugs was demonstrated. Analysis of adipose tissue mRNA expression in 78 women from genes regulating lipolysis at the postadrenoceptor level showed an increased level of protein kinase A subunit R1{alpha} in the T/A genotype (P = 0.02).

Conclusions: Polymorphism in the usf1 gene is associated with increased lipolytic effect of catecholamines in fat cells, which is localized at the postadrenoceptor level, possibly, at least, involving protein kinase A.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A FUNDAMENTAL ASPECT of adipocyte function is to store energy in the form of triglycerides during surplus nourishment and to release this energy as free fatty acids and glycerol during starvation. The latter process, termed lipolysis, has in previous studies been found to be associated with a large interindividual variation, above all with respect to catecholamine-induced effects in fat cells (1). In the search for underlying mechanisms, genetic variance may be important. Accordingly, genetic variance affecting adipose tissue lipolysis has been found in several genes regulating the catecholamine-signaling pathway, as reviewed previously (2). For instance, polymorphisms in the ß2- and ß3-adrenoceptor (AR) genes associate with altered receptor sensitivity to agonist stimulation, and a dinucleotide repeat in the hormone-sensitive lipase (HSL) gene markedly reduces the ability of catecholamines to stimulate lipolysis.

In a recent study, Pajukanta et al. (3) showed an association between familial combined hyperlipidemia (FCHL) and upstream transcription factor 1 (USF-1) in family studies. Transmission of a rare haplotype at the usf1s1 and usf1s2 loci was reduced, suggesting a protective role of USF-1 in FCHL. USF-1 has been shown to regulate several genes involved in lipid metabolism, including apolipoprotein CIII (apo CIII) (4), apo A5 (5), acetyl-coenzyme A carboxylase-{alpha} (6), and fatty acid synthase (7). The usf1 gene may be of particular importance for catecholamine-induced lipolysis in fat cells, because it is involved in the transcriptional regulation of HSL (8).

We tested the hypothesis that usf1 gene polymorphism is involved in lipolysis regulation by comparing lipolytic activities in vitro of sc fat cells with usf1s1 and usfs2 genotypes of USF-1. For this purpose, we used a large and unique material of 196 obese, otherwise healthy, female subjects. This is the first genetic examination of this cohort.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 196 obese women who were otherwise healthy and free of medication were included. They were consequently recruited to study the influence of genetic variance on adipocyte lipolysis regulation. Body mass index ranged from 30–52 kg/m2, and age ranged from 19–65 yr. All were living in the Stockholm area and were at least second generation Scandinavian. None was completely sedentary or involved in athletic performances. All ate a standard Swedish diet. None had undergone a slimming effort or experienced a change (>1 kg) in body weight during the last 6 months before the study according to self report. They came to the laboratory at approximately 0730 h after an overnight fast. A venous blood sample was obtained for DNA and analysis of plasma levels of fatty acids, glycerol, glucose, insulin, triglycerides, cholesterol, high-density lipoprotein cholesterol, apo A-1, and apo B by the hospital’s accredited chemistry laboratory. Thereafter, an adipose sample (1–2 g) was obtained by needle biopsy from the abdominal sc area under local anesthesia as previously described (9). The study was explained in detail to each subject, and his or her informed consent was obtained. The study was approved by the hospital’s committee on ethics.

Fat cell studies

In 78 women, there was enough adipose tissue for mRNA experiments (see below). This tissue was frozen in liquid nitrogen and kept frozen at –70 C. The remaining adipose tissue was collagenase treated, and isolated fat cells were collected and subjected to lipolysis experiments exactly as previously described (10). In brief, fat cells were incubated in buffer (pH 7.4) containing albumin and glucose at 37 C in the absence (basal) or presence of increasing concentrations of noradrenaline (natural hormone, nonselective {alpha}2- and ß-AR agonist), dobutamine (a selective ß1-AR agonist), terbutaline (a selective ß2-AR agonist), CGP12177 (a selective ß3-AR agonist), and forskolin (an adenylyl cyclase activator, increases cAMP). After 2-h incubation, the medium was removed for determination of glycerol, which is an indicator of lipolysis. Glycerol release was related to the number of fat cells incubated. The maximum lipolytic effects of the various drugs were determined as the rate of glycerol release at maximum effective concentration of drug minus basal glycerol release. Lipolytic sensitivity for noradrenaline, dobutamine, terbutaline, and CGP12177 was assessed by estimating the EC50 from the concentration-response curves. The EC50 was logarithmically transformed and expressed as the pD2 value. The accuracy of the lipolysis method has been validated in detail previously (1). ARs in fat cells act according to the so-called spare receptor hypothesis. Thus, a maximum effect is obtained when only a fraction of receptors is occupied. Therefore, changes in pD2 reflect variations in AR agonist action at or near the target receptors, whereas changes in maximum action mirror events at more distal (postreceptor) levels.

Genotyping

DNA was extracted from frozen (–20 C) venous blood. Genotyping of the two single nucleotide polymorphisms (SNPs) usf1s1 (C/T) and usf1s2 (G/A) were performed using dynamic allele-specific hybridization (DASH) (11). Information on the two SNPs may be found at the dbSNP website (www.ncbi.nlm.nih.gov/SNP) under their respective identification numbers, rs3737787 (usf1s1) and rs2073658 (usf1s2). All PCRs were run in 20-µl volumes including 1.5 mM MgCl2 and 5 ng genomic DNA as previously described (11). The annealing temperature for all reactions was 60 C. For the usf1s1 polymorphism, the sequences for the primers used were 5'-CGGCCTGCAGTGGTATGAAACA-3' (sense) and 5'-GGGTGGGCAAGGCTGTCAGTGC-3' (antisense), and that for the probe was 5'-CAGTGCACGTCCACATT-3'. The primers and probe used for the usf1s2 polymorphism were 5'-GAGACACCACACCTAGCTACCAT-3' (sense), 5'-ACAAGATTTAGCAGGTATTAGGAC-3' (antisense), and 5'-TAGGACCATTTATGGTA-3' (probe). A biotin moiety was added at the 5' end of the forward primer sequences. The position of the polymorphic site is underlined in the probe sequence. The genotyping of the usf1s1 polymorphism failed in 12 subjects.

mRNA analysis

Adipose tissue that was available for mRNA analyses (n = 78) was used as follows. Total RNA was extracted from 300 mg adipose tissue using the RNeasy minikit (QIAGEN, Hilden, Germany), and the RNA concentration and purity were assessed spectrophotometrically. One microgram of total RNA from each sample was reverse transcribed to cDNA using the Omniscript RT kit (QIAGEN) and random hexamer primers (Invitrogen Life Technologies, Tastrup, Denmark). The Agilent 2100 bioanalyzer (Agilent Technologies, Kista, Sweden) was used to confirm the integrity of the RNA. In a final volume of 25 µl, 5 ng cDNA was mixed with 2x SYBR Green PCR MasterMix (Bio-Rad Laboratories, Hercules, CA) and primers (Invitrogen Life Technologies). The primer pairs were selected to yield a single amplicon based on dissociation curves and analysis by agarose gel electrophoresis. The primers used were 5'-CTCAGTGTGCTCTCCAAGTG-3' (sense) and 5'-CACCCAGGCGGAAGTCTC-3' (antisense) for HSL, 5'-GCAGGCACTCGTACAGACTC-3' (sense) and 5'-CCGCATCTTCCTCCGTGTAG-3' (antisense) for protein kinase A type 1{alpha} regulatory subunit (PRKAR1A), 5'-TGTGATGGTGTTGGAAGATGTG-3' (sense) and 5'-GAGAGGTAGCAGTGATTGTAGC-3' (antisense) for protein kinase A type IIß regulatory subunit (PRKAR2B), 5'-GCGGATCGGAAGGTTCAG-3' (sense) and 5'-GCCCTGCTGGTCAATGAG-3' (antisense) for protein kinase catalytic subunit {alpha} (PRKACA), 5'-GTGTCAGACGGCGAGAATG-3' (sense) and 5'-TGGAGGGAGGGAGGGATG-3' (antisense) for adipose triglyceride lipase (ATGL) and 5'-TGACTCAACACGGGAAACC-3' (sense) and 5'-TCGCTCCACCAACTAAGAAC-3' (antisense) for 18S. Quantitative real-time PCR was performed in an iCycler IQ (Bio-Rad Laboratories). The mRNA levels were determined by a comparative threshold cycle (Ct) method (see user bulletin 2, ABI PRISM 7700, Applied Biosystems, Foster City, CA). The subject with the highest Ct value was used as a reference; all other Ct values for the target gene and reference gene, respectively, were subtracted from this Ct value. The Ct values were then normalized to rRNA for 18S.

Statistical methods

Values are the mean ± SD. Student’s unpaired t test or analysis of covariance, using age as covariate, was used for statistical evaluation. A value of P ≤ 0.05 was considered statistically significant.

Power calculation

We made a calculation to estimate the smallest mean difference in the lipolysis rate (maximal noradrenaline minus basal glycerol release/107 cells) between genotypes that can be detected in the present study material of 196 subjects to have a power of 80% to yield a statistically significant result. The calculation was performed assuming allele frequencies of 0.7 (A) and 0.3 (B) for two alleles of a specific SNP, which would correspond to homozygous genotype AA (n = 96) and the homo/heterozygous genotype BB/AB (n = 100). The criterion for significance was set at 0.05. The test was two-tailed, which means that an effect in either direction will be interpreted. On the average, a study of this design would enable us to report a mean lipolysis rate difference of 20% corresponding to means of 10.0 (AA genotype) vs. 12.0 µmol glycerol/107 cells (BB/AB genotype) and a common within-group SD of 5.0 based on SD estimates of 50% of the corresponding mean value. The calculation was made using SPSS Sample Power program (www.spss.com/se).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The allele frequency for the usf1s1 polymorphism was C 0.69 and T 0.31, and that for the usf1s2 polymorphism was G 0.69 and A 0.31. The two genotypes were in Hardy-Weinberg equilibrium and were found to be in complete linkage disequilibrium (r2 = 1.0) (12). Consequently, in the following analyses, only data for one of the polymorphisms, usf1s2, are presented.

In Table 1Go, the effects of the usf1s2 polymorphism on clinical parameters are shown. Subjects either homozygous or heterozygous for the A allele were compared with subjects homozygous for the G allele. No effect of the usf1s2 A allele on any of the examined clinical parameters was found.


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  		TABLE 1. Clinical data for the usf1s2 polymorphism

 
With respect to lipolysis measurements, no effect of the usf1s2 A-allele on basal (nonstimulated) lipolysis, 11.6 ± 6.9 (A allele) vs. 12.1 ± 7.2 (G allele) µmol glycerol/107 cells (P = 0.59) was found. However, an effect was demonstrated on the maximum lipolytic action of all the investigated drugs (Table 2AGo). The relationship was particularly evident for noradrenaline. As shown in Fig. 1Go, cells from the A allele subjects had a 23% higher maximum lipolytic effect of noradrenaline than those with the G allele had. The A allele effect was also significant for ß1- (dobutamine), ß2- (terbutaline), and ß3- (CGP12177) AR-mediated lipolytic response. Furthermore, the maximum lipolytic rate for the postreceptor active drug forskolin was also higher in subjects carrying the usf1s2 A allele. In contrast, no effect of the usf1s2 A allele on lipolytic adrenergic sensitivity (i.e. pD2) for noradrenaline, dobutamine, terbutaline, or CGP12177 was demonstrated (Table 2BGo).


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  		TABLE 2. Lipolysis data for the usf1s2 polymorphism

 


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  		FIG. 1. Relationship between usf1s2 genotypes and noradrenaline-induced lipolysis. Concentration-response curves from three representative subjects carrying the AA, AG, and GG genotypes are shown.

 
To correlate these findings with possible alterations in gene expression, we assessed the mRNA expression of a set of genes regulating lipolysis at the postreceptor level. In 78 (NAA = 8, NAG = 33, and NGG = 37) women, adipose tissue was still available for mRNA analysis. As shown in Fig. 2Go, a significant effect of the usf1s2 SNP on mRNA levels of PRKAR1 was found (P = 0.021, by analysis of covariance adjusted for age, because a significant interaction among usf1s2 genotypes, PRKAR1A, and age was found in this subcohort). The adipose tissue PRKAR1A mRNA level from AA subjects was 17% higher than from AG/GG carriers. In contrast, there was no difference in mRNA levels of HSL (P = 0.93), ATGL (P = 0.55), PRKAR2B (P = 0.28), or PRKACA (P = 0.22) between usf1s2 genotypes (mRNA values not shown).



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  		FIG. 2. Relationship between usf1s2 genotypes and adipose tissue PRKAR1 mRNA levels. Values are the mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Polymorphisms in genes regulating lipolysis may be important factors in the chain of events leading to altered adipose tissue and lipid metabolism. Genetic variance could at least in part explain the large interindividual variation in the action of catecholamines on lipolysis in apparently healthy subjects (1). A striking finding of the present study is the close relationship between the usf1s1/s2 polymorphisms and catecholamine-stimulated lipolysis in human fat cells. Carriers of the usf1s1/2 T/A allele have an approximately 25% higher rate of catecholamine-stimulated lipolysis in vitro than homozygous carriers of the G allele. The allele effect was also independent of age and body mass index. To the best of our knowledge the present study sample is the by far the largest one available for genetic studies of lipolysis. According to the power calculation, we can detect rather small variations in lipolysis for relatively common polymorphisms such as the ones in USF1 in a sample of about 200 subjects as our study group. In addition, we do not need to make statistical adjustments for multiple comparisons with other genes, because USF1 is the first gene examined in this cohort. At present, we do not know how strong the relationship between the usf1s1/2 polymorphisms and in vivo lipolysis is. We are not aware of any large study sample that can be used for genetic analysis of lipolysis in vivo. However, a recent direct comparison of catecholamine-induced lipolysis in vitro (isolated fat cells) and in vivo (microdialysis) revealed a relatively close correlation between these two lipolysis measures in sc adipose tissue (13), which is the adipose depot examined in the present study.

The mechanism for increased lipolysis in T/A carriers is not known. However, the finding of increased maximum ß1,2,3-AR-induced as well as increased maximum forskolin-stimulated lipolysis (reflecting activation of adenylyl cyclase, increasing cAMP) of T/A allele carriers suggests an effect of the usf1s2 gene variation on postreceptor-related events and not on agonist sensitivity (reflects receptor-related events). We therefore measured the mRNA levels of several genes implicated in regulating postreceptor-mediated adipocyte lipolysis. A small (17%), but significant, effect of the usf1s2 genotype on mRNA levels of protein kinase A regulatory subunit type 1{alpha} (PRKAR1A) was found, which indicates a transcriptional role for USF-1 in PRKAR1A gene expression. Interestingly, data from gene knockout studies in mice (14) as well as data from human subjects (15) have demonstrated that even small increases in PRKAR1A expression result in a more pronounced activation of protein kinase and, thus, of lipolysis. The molecular mechanisms underlying this effect are probably due to the higher affinity of PRKAR1A for cAMP compared with PRKAR2B. The stoichiometry between PRKAR1A and PRKAR2B is therefore of importance in fine-tuning lipolysis, suggesting that the slightly elevated PRKAR1A expression demonstrated in this study could account for the differences in lipolytic activity.

Although USF-1 has been shown to induce transcription of the human HSL promoter in 3T3-F442A cells (8), we failed to demonstrate an effect of the usf1s2 gene variation on human adipose tissue mRNA levels of the two lipases studied, i.e. HSL and the recently discovered (16) ATGL. However, previous studies in humans have shown that catecholamine-induced lipolysis is directly proportional to the protein content and enzyme activity of HSL in sc fat cells (17). Thus, it may be hypothesized that USF-1 has an indirect effect on adipocyte lipase activity by inducing a step more proximal in the lipolytic cascade, i.e. the cAMP-dependent, protein kinase A-mediated phosphorylation of HSL/ATGL. Indirect support for such an effect of the USF-1 polymorphism lies in published results for FCHL. This condition is linked to the investigated USF-1 polymorphism (3), and catecholamine-induced adipocyte lipolysis is decreased in FCHL due to impaired HSL function (10).

It is of interest to compare the lipolytic effect of USF1 polymorphism with that of genetic variance in HSL (18). Intronic variation in HSL was associated with a 50% decrease in maximum lipolytic activation, a greater effect than that presently observed for USF1, which is more than a 20% increase. This might be due to the fact that events at the final rate-limiting step of the lipolytic cascade, HSL, have more pronounced effects on lipolysis than events at earlier steps, such as protein kinase A.

Our data showed that the usf1s1/s2 SNPs do not associate with variations in the clinical phenotypes, such as body mass index, the plasma lipid profile, or circulating levels of free fatty acids or glycerol. This is in contrast with two previous studies showing association of USF1 SNPs with triglyceride levels in families with FCHL (3) and with plasma lipid levels and peak glucose during an oral glucose tolerance test in male offspring of patients with premature myocardial infarction (16). The reason for this is probably that the present study included healthy subjects only. Although obese, they all had plasma levels of both lipids and glucose within the normal range and showed no sign of cardiovascular or metabolic disease. It is quite possible that the adipocyte lipolysis-related effects of genetic variance in USF1 lead to clinical consequences when a pathophysiological state is present, such as diabetes or FCHL.

The usf1s1 and usf1s2 SNPs both are localized within the intron of the usf1 gene, which indicates that they may not be functional themselves. Furthermore, these two SNPs were found to be in tight linkage disequilibrium with the two SNPs recently studied by Putt et al. (19), 475C>T and 1748C>T, indicating that all these polymorphisms may be markers of a hitherto unrecognized functional domain. However, by in silico analysis, Pajukanta et al. (3) identified a putative internal promoter in intron 7 of the usf1 gene, in the vicinity of the usf1s2 SNP, suggesting that genetic variation at the usf1s2 locus is of functional significance. The usf1s2 locus may thus influence this promoter to initiate translation from the internal AUGs in exon 8 of the usf1 gene, thereby repressing the normal function of the protein or vice versa, as previously discussed (20).

The success rate for genotyping for usf1s1 was 94%, which is not uncommon for crude design using the DASH technique (11). However, the success rate for usf1s2 was 100%. Because the two SNPs were in complete linkage disequilibrium, we saw no reason to attempt successful genotyping of the 12 failures using costly and elaborate improvements of DASH (11).

In summary, a relatively common polymorphism in the usf1 gene is associated with an increased ability of catecholamines to stimulate lipolysis in fat cells, which is most likely explained by an increased postreceptor function, possibly at the level of protein kinase A, involving regulatory subunit type 1{alpha}.


   Acknowledgments
 
We are grateful for the excellent technical assistance of Britt-Marie Leijonhufvud, Katarina Sjöberg, Kerstin Wåhlén, Elisabeth Dungner, and Eva Sjölin.


   Footnotes
 
This work was supported by grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Swedish Diabetes Association, the Novo Nordic Foundation, the Bergvall Foundation, the Thuring Foundation, the Wiberg Foundation, and the Swedish Medical Society.

First Published Online June 28, 2005

Abbreviations: apo, Apolipoprotein; AR, adrenoceptor; ATGL, adipose triglyceride lipase; Ct, threshold cycle; DASH, dynamic allele-specific hybridization; FCHL, familial combined hyperlipidemia; HSL, hormone-sensitive lipase; PRKAR1A, protein kinase A type 1{alpha} regulatory subunit; SNP, single nucleotide polymorphism; USF-1, upstream transcription factor-1.

Received February 24, 2005.

Accepted June 20, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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L. Peltonen, M. Perola, J. Naukkarinen, and A. Palotie
Lessons from studying monogenic disease for common disease.
Hum. Mol. Genet., April 15, 2006; 15(suppl_1): R67 - R74.
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