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Dietary fat interacts with QTLs controlling induction of Pgc-1 and Ucp1 during conversion of white to brown fat

Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION DISCLOSURES References

 
To identify novel regulatory factors controlling induction of the brown adipocyte-specific mitochondrial uncoupling protein (Ucp1) mRNA in the retroperitoneal white fat depot, we previously mapped quantitative trait loci (QTLs) that control this trait to chromosomes 2, 3, 8, and 19. Since the peroxisome proliferator activator receptor- coactivator-1 (PGC-1) regulates Ucp1 and other genes of energy metabolism, we have evaluated whether the QTLs controlling Ucp1 mRNA levels also modulate Pgc-1 mRNA levels by analysis of backcross progeny from the A/J and C57BL/6J strains of mice. The results indicate that a locus on chromosome 3 orchestrates expression of Pgc-1 and Ucp1 in retroperitoneal fat of mice fed a low-fat diet; however, the effect of this locus on Pgc-1 is lost, and a significant correlation between Ucp1 and Pgc-1 is severely reduced in mice fed a high-fat diet. An additional QTL located on chromosome 5 has also been identified for the selective regulation of Ucp1 mRNA levels. Similar to the effects of a high-fat diet on the chromosome 3 QTL, linkage of the chromosome 5 QTL is also lost in mice on a high-fat diet. Thus dietary fat has a profound influence on PGC-1-regulated pathways controlling energy metabolism in white fat. The allelic variation observed in the regulation of Ucp1 and Pgc-1 expression in brown adipocytes of white fat but not interscapular brown fat suggests that fundamentally different regulatory mechanisms exist to control the thermogenic capacities of these tissues.

adipocyte; differentiation; genetics; energy metabolism; fat pad

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION DISCLOSURES References

 
THE IDENTIFICATION of brown adipocytes in the parametrial fat depots of female mice, a traditional white fat depot, was first described by Ashwell and colleagues (45). Subsequently, there have been many reports of an increase in the number of brown adipocytes in white fat of several mammalian species exposed to the cold or treated with ß3-adrenergic agonists (5, 7, 9, 12, 15, 25). The ability to induce brown adipocytes in white fat depots by adrenergic stimulation appears to be a fairly common property among mammalian organisms that may also include fat tissues from adult humans (4, 11). The origin of the precursor cells that give rise to the brown adipocytes is still not resolved, but evidence showing the gradual acquisition of the brown adipocyte morphology by white adipocytes (12), the absence of significant de novo cell proliferation (16), and the very rapid induction of Ucp1 mRNA to maximal levels following adrenergic stimulation (12) all suggest that white adipocytes are converted to brown adipocytes. Whether this represents a form of transdifferentiation of a subpopulation of white adipocytes that have the capacity to respond to adrenergic signals to initiate the brown fat differentiation program without chromatin remodeling is unknown. A physiological role for an increase in the numbers of brown adipocytes in white fat depots was first suggested by Champigny et al. (5), who noted that dogs treated with a ß3-adrenergic agonists had induced levels of Ucp1 mRNA in peritoneal fat depots and reduced girths; this correlation between increased brown adipocytes in white fat and reduced adiposity was subsequently corroborated in the rat (15) and in the mouse (7, 12). A significant reduction in triglyceride stores has also been demonstrated in a number of transgenic experiments that promote expression of Ucp1 in white fat (3, 10, 18, 36, 37).

The molecular mechanism by which brown adipocytes can be induced in white fat depots is poorly understood. Studies with transgenic mice indicate that transcription pathways associated the adrenergic signaling through the protein kinase A (PKA) pathway can initiate the brown adipocyte differentiation pathway (3, 36). However, mice with an inactivated gene for the translational inhibitor 4E-BP1 have an increase in brown adipocytes through an unresolved mechanism that causes twofold higher levels of PGC-1 protein in white adipose tissues (37). Alternatively, by analysis of the transcriptional machinery controlling Ucp1 expression, several transcription factors, including the thyroid hormone receptor, peroxisome proliferator activator receptors and (PPAR and PPAR), and the PPAR coactivator, PGC-1, have been identified, which together can induce aspects of brown adipocyte differentiation following the introduction of expression vectors into preadipocyte cell cultures not previously shown to express Ucp1 (31). Taking advantage of a phenotypic difference in induction of brown adipocytes and Ucp1 mRNA levels between inbred strains of mice, we have mapped quantitative trait loci (QTLs) controlling Ucp1 expression to four different mouse chromosomes (19). Three of these QTLs are located in chromosomal regions that carry no candidate genes previously implicated in Ucp1 expression. Although the fourth QTL on chromosome 8 is located very near Ucp1, it is not known whether the variant gene in the QTL is Ucp1. To obtain more insight into the signaling and transcription pathways regulating induction of brown adipocytes in white fat, we have begun to ask how the QTLs controlling Ucp1 expression affect some of the upstream regulatory factors implicated in Ucp1 expression. The importance of PGC-1 as a modulator of Ucp1, as well as a tissue-specific transducer of nutritional status and energy balance, has been demonstrated in numerous studies (14, 23, 26, 29, 31, 41, 42, 44). Experiments showing that ectopic expression of Pgc-1 in a white adipocyte cell line induces mitochondrial uncoupling protein 1 (Ucp1) mRNA and cold exposure stimulates Pgc-1 expression in interscapular brown adipose tissue (BAT) have led to the conclusion that PGC-1 is necessary for inducing the thermogenic capacity of adipose tissues, including the developmental bifurcation that leads to white or brown adipocytes (27, 31). If this reasoning is correct, then mouse strains that vary in their capacity for converting white fat to brown fat should also vary in Pgc-1 expression. In support of a role for Pgc-1 in the induction of brown adipocytes in white adipose tissues, we show that the induction of Pgc-1 mRNA levels in retroperitoneal fat by cold exposure is genetically determined and that a subset of QTLs controlling Ucp1 expression also control Pgc-1 expression. Of particular interest is a QTL on chromosome 3, which not only accounts for most of the genetic variance of Pgc-1 expression, but also, the regulatory effect of the chromosome 3 gene on expression of both Ucp1 and Pgc-1 is highly dependent on the fat content of the diet.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION DISCLOSURES References

 
Animals.
A/J and C57BL/6J (B6) breeding pairs were obtained from the Jackson Laboratory (Bar Harbor, ME). All experimental mice, including parental mice and (C57BL/6JxA/J)F1 and (C57BL/6JxA/J)F1xA/J backcross progeny were 2-mo-old male mice bred at the Pennington Biomedical Research Center (Baton Rouge, LA). The low-fat chow diet, fed ad libitum, consisted of 5.4 wt% fat, 32.1% starch, 4.7% sugars, and 20% protein (Picolab 5053 rodent diet 20). In experiments with the high-fat diets, male mice were weaned onto a diet consisting of 36 wt% fat, 23% protein, and 18% sucrose (Research Diets D12331). Two to three mice per pen were exposed to cold for the specified time interval while maintained on the same diet. Following cold exposure, mice were rapidly killed by cervical dislocation, and tissues were removed for RNA isolation.

Total RNA extraction and expression analysis.
Retroperitoneal and interscapular BATs were homogenized in Tri-Reagent (MRC, Cincinnati, OH), and total RNA was isolated using protocols provided by MRC (6). Three nanograms of total RNA was used per 50 µl RT-PCR reaction to quantitatively determine Ucp1, Pgc-1, Nrf1, or cyclophilin B mRNA using the ABI Prism 7900 (Applied Biosystems) sequence detection system with specific primers and Taqman probes designed by Primer Express (Applied Biosystems) (19). mRNA values were adjusted for total RNA used per PCR reaction with cyclophilin B. P values for determination of statistical differences in mRNA levels during the time course of cold exposure of A/J and B6 mice were determined by ANOVA single-factor analysis in Excel. Correlation coefficients r, R², and correlation P values for mRNA expression levels were determined using Statview v5.0 (SAS).

Genotype analysis.
Individual tail DNAs were genotyped with microsatellite (MIT) markers by PCR (19). We analyzed 400 (C57BL/6JxA/J)F1xA/J backcross males in each cohort, one maintained on a chow diet and the other on a high-fat diet. Genome-wide scans were performed independently on these two groups of backcross progeny using the 20 highest and 20 lowest Pgc-1 and Ucp1 mRNA values in each group, with MIT markers spaced at 20-cM intervals on each chromosome. In each group, all 400 backcross males were genotyped with a higher density of markers in chromosomal regions showing significant linkage to Ucp1 and Pgc-1 expression. Linkage P values were determined for each MIT marker by ANOVA single-factor analyses in Excel. LOD scores were generated for each composite group of 400 BC mice using MapManager QTb8 (28).

DNA sequencing.
DNA sequencing was performed on an Applied Biosystems 3100 using the BigDye Terminator Cycle Sequencing Kit by PE Biosystems (Foster City, CA).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION DISCLOSURES References

 
Genetic variation in Pgc-1 induction in adipose tissue.
Male A/J and C57BL/6J (B6) mice at 2 mo of age were exposed to cold (5°C) for up to 7 days. Within 6 h of cold exposure Pgc-1 mRNA levels in the retroperitoneal fat depot (RP) of A/J mice increased fivefold, whereas a smaller, delayed increase in expression occurred in B6, resulting in a difference of two- to threefold between strains (Fig. 1A). As shown in several earlier studies, A/J has high levels of Ucp1 expression in RP fat after 7 days of cold exposure, whereas expression remains very low in the B6 strain (Fig. 1C). It is striking that although both Ucp1 and Pgc-1 were strongly induced by cold in interscapular brown fat, there was no difference in gene expression between the two strains (Figs. 1, B and D). The stimulation of Pgc-1 mRNA to peak levels is observed within 6 h in both retroperitoneal fat and interscapular brown fat of A/J mice, even though retroperitoneal fat consists almost exclusively of cells with the white adipocyte morphology and BAT mostly brown adipocytes. These data suggest that a form of transdifferentiation is occurring in retroperitoneal fat characterized first by early increases in Pgc-1 and Ucp1, the thermogenic effector of brown adipocytes, followed by a complex morphological conversion of white to brown adipocytes as shown in previous studies (12, 16). In addition to Ucp1 expression, mitochondrial biogenesis is another essential requirement of the acquisition of the brown adipocyte phenotype, since brown adipocytes have among the highest densities of mitochondria known in eukaryotic cells. The ectopic expression of Pgc-1 can stimulate mitochondrial biogenesis in preadipocytes and muscle cell lines by increasing the expression and transcriptional activity of nuclear respiratory factor 1 (NRF1) (42). NRF1 is a transcriptional activator of nuclear genes encoding mitochondrial proteins and mitochondrial transcription factor A (mtTFA), an activator of transcription and replication of the mitochondrial genome (33, 39). Accordingly, we analyzed levels of Nrf1 mRNA in retroperitoneal fat and brown fat of cold-exposed animals and surprisingly did not find a cold-stimulated increase in Nrf1 mRNA in either fat depot (Fig. 1, E and F, P > 0.05 in RP), despite the observed increases in Pgc-1. In addition, no statistically significant difference in Nrf1 levels between strains was observed in retroperitoneal fat (P > 0.05).

View larger version (24K): [in this window] [in a new window]   Fig. 1. Cold-induced mRNA levels (in arbitrary units) for Pgc-1 (A and B), Ucp1 (C and D), and Nrf1 (E and F) in retroperitoneal fat (RP, left) and interscapular brown adipose tissue (BAT, right). A/J and C57BL/6J males maintained on a chow diet from weaning to 2 mo of age were exposed to 5°C for 3 h, 6 h, or the number of days specified. Each time point represents the mean of 4–12 mice ± SE.

Pgc-1 expression and induction of Ucp1.

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View larger version (20K): [in this window] [in a new window]   Fig. 2. Correlation between Pgc-1 and Ucp1 mRNA levels in mice fed a 4.5 wt% fat diet. A: 400 (B6xA/J)F1xA/J backcross males were exposed to 5°C for 7 days. B: 2-mo-old males from AxB and BxA recombinant inbred strains (19) were exposed to the cold 7 days and analyzed for mRNA levels. The number of animals for each recombinant inbred strain averaged about 5.

The relationship between QTLs controlling Ucp1 and Pgc-1 expression.

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View this table: [in this window] [in a new window]   Table 1. Chromosomal linkage to cold-induced expression of Pgc-1 and Ucp1

View larger version (13K): [in this window] [in a new window]   Fig. 3. Interval map of the chromosome 3 quantitative trait locus (QTL). Four hundred (B6xA/J)F1xA/J backcross mice were exposed to cold for 7 days while on a chow diet, phenotyped for Ucp1 and Pgc-1 mRNA levels in retroperitoneal fat, and genotyped on chromosome 3 using MIT markers. LOD values were generated using MapManager QTb. The bolded region surrounding D3Mit101 represents the 1-LOD confidence interval (21).

Pgc-1

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The effects of an altered environment, i.e., diet, on the expression of Ucp1 and Pgc-1.
The emergence of a highly significant QTL on chromosome 5 for Ucp1 with 400 backcross progeny generated at the Pennington Biomedical Research Center between during 1999 and 2000 that was not detected in a similar backcross of over 1,000 progeny bred at the Jackson laboratory between 1996 and 1998 suggests that the chromosome 5 QTL associated with the regulation of Ucp1 was highly influenced by an environmental factor. Since induction of brown adipocytes in retroperitoneal fat is occurring within a tissue that functions to manage fat stores, we sought to introduce a plausible and relevant environmental perturbation. Accordingly, a high-fat diet was fed to the parental strains and to a second cohort of 400 backcross mice from weaning to 2 mo of age and during a 7-day period when they were exposed to the cold. Total RNA was isolated from the RP and genomic DNA from the tail for a QTL analysis of Ucp1 and Pgc-1 mRNA levels. A modest increase in the levels of Ucp1 and Pgc-1 mRNA in the A/J and B6 parental strains and in backcross progeny fed a high-fat diet did not suggest that the high-fat diet was having a major effect on the QTLs controlling either Ucp1 or Pgc-1 (Table 2). However, the strong correlation between Ucp1 and Pgc-1 mRNA levels in mice fed a low-fat diet was lost when they were fed a high-fat diet (Fig. 4, r = 0.41). These data suggest that the pattern of QTLs associated with expression of Pgc-1 and Ucp1 would be altered in mice fed a high-fat diet.

View this table: [in this window] [in a new window]   Table 2. Effects of a high-fat diet on Pgc-1 and Ucp1 mRNA levels

View larger version (21K): [in this window] [in a new window]   Fig. 4. Correlation between Pgc-1 and Ucp1 mRNA levels in mice fed a 36 wt% fat diet. Pgc-1 and Ucp1 mRNA levels were determined in 400 backcross animals maintained on a high-fat diet (HFD) from weaning and exposed to the cold for 7 days.

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View this table: [in this window] [in a new window]   Table 3. Linkage to cold-induced expression of Pgc-1 and Ucp1 in backcross mice fed a high-fat diet

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION DISCLOSURES References

Pgc-1

Pgc-1

Pgc-1

Similar to Ucp1 expression, induction of Pgc-1 expression in RP white fat is a mutifactorial trait dependent on both genotype and environment. The latter includes both the ambient temperature and fat content of the diet. It is particularly curious that these variables are restricted to phenotypes of retroperitoneal fat. We have detected no significant variation between A/J and B6 mice for either Ucp1 or Pgc-1 in interscapular brown fat. One interpretation is that the difference is simply a consequence of the absence of any brown adipocytes in the retroperitoneal fat of B6 mice, whereas with equal numbers of brown adipocytes in interscapular fat in the two strains, there are no differences in Ucp1 or Pgc-1 expression. It would follow then that even in retroperitoneal fat all phenotypes associated with Ucp1 or Pgc-1 expression would simply reflect the number of brown adipocytes. However, we know that this simple interpretation is not valid from our initial studies of recombinant inbred lines of mice where we observed that although the AxB8 and AxB15 strains had similar levels of Ucp1 mRNA, they differed greatly in the number of brown adipocytes that could be detected in the tissue following cold induction and in the levels of Pgc-1 mRNA (12). We now show in this paper that the variation of Ucp1 and Pgc-1 is determined by some QTLs in common and others that independently act on either gene, signifying a complex interplay of allelic variation and environment to generate a phenotype. The molecular mechanisms for these effects of a high-fat diet are not known, but they reflect profound changes in the involvement of genes on several different chromosomes. As shown in the Venn diagram in Fig. 5, some highly significant QTLs that appeared to have a major role in the regulation of Ucp1 and Pgc-1 were lost completely, others had lower significance, and still others showed increased significance. One of the most prominent changes occurred in the QTL located on chromosome 3, since a highly significant linkage found in mice fed a low-fat diet was lost when the mice were fed a high-fat diet. Whatever the identity of the gene on chromosome 3, it appears to mediate strain-specific differences in the regulation of Ucp1 in the presence of a low-fat diet but not a high-fat diet. The 1-LOD confidence interval of this QTL is 7 Mb extending from D3Mit76 to D3Mit75, and it includes 150 putative transcribed genes. None of the transcripts identified by the Celera and National Center for Biotechnology Information (NCBI) databases in this region have previously been implicated in expression of Pgc-1, Ucp1, or adipogenesis, and experiments are underway to determine their expression patterns in RP fat. We need to understand why the loss of an allelic effect by chromosome 3 when mice are fed the high-fat diet has no apparent negative effect on Pgc-1 or Ucp1 expression. The effects of a high-fat diet on chromosome 3 will be more comprehensively evaluated when congenic strains for chromosome 3 become available (work in progress in our laboratory). Finally, the sensitivity of the gene(s) at the chromosome 3 QTL, as well as its effects on the expression of both Ucp1 and Pgc-1, suggests that it could be a hot spot for regulation of obesity-related genes similar to the recently proposed hotspot on chromosome 2 (34).

View larger version (22K): [in this window] [in a new window]   Fig. 5. Venn diagram illustrating the chromosomal linkages to Pgc-1 and Ucp1 mRNA levels in backcross progeny depending on whether they were fed a low- or high-fat diet.

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If Pgc-1 expression is elevated in mice fed a high-fat diet, then why is the association between Pgc-1 and Ucp1 reduced? One obvious mechanism to consider is that in mice fed a high-fat diet, PGC-1 is no longer necessary for Ucp1 expression. Simple inspection of the data in Fig. 4 shows that there are many mice with elevated levels of Pgc-1 mRNA but low levels of Ucp1 mRNA. Given the complexity of transcription factors associated with Ucp1 expression, some with apparently redundant functions, it is plausible that a requirement for PGC-1 in Ucp1 expression is reduced under some physiological conditions that activate other regulatory pathways. For example, dietary fat differentially increases circulating leptin levels in the A/J and B6 strains, and leptin regulates thermogenesis and fatty acid metabolism in adipose tissues (8, 22, 40). Fatty acids, endogenous ligands for PPARs, can increase PPAR binding to PGC-1 and activate transcription of Ucp1 as well as mitochondrial fatty acid oxidation enzymes (1, 38, 43). Another explanation to consider is that the Pgc-1 mRNA levels do not accurately reflect either the actual levels of PGC-1 protein in the cell nucleus or its functional state. With respect to the latter, it has been shown that cytokine-stimulated phosphorylation of PGC-1 by p38 MAP kinase enhances its transcriptional activity and that the activity of PGC-1 is also regulated by a repressor (17). Although p38 MAP kinase has been implicated in Ucp1 expression in cell cultures (2, 35), we know nothing about its potential role in the induction of Ucp1 in retroperitoneal fat.

A high-fat diet is also known to suppress adrenergic signaling through reduced ß3-adrenergic receptor gene expression (7) and, correspondingly, could affect signaling mechanisms through PKA, CREB, and MAP kinase pathways to reduce the contribution of PGC-1 to Ucp1 transcription (2, 20, 32, 35, 46). Conversely, the higher carbohydrate content of the low-fat diet may promote the participation of Pgc-1 in Ucp1 regulation. A pivotal role for PGC-1 in carbohydrate and lipid metabolism is evident from recent studies showing that coactivation of PPAR, PPAR, and glucocorticoid receptors by PGC-1 modulates expression of enzymes of lipid and glucose homeostasis (14, 26, 30, 31, 38, 44).

Although PGC-1 is associated with Ucp1 regulation in both the interscapular brown adipocyte and the diffuse brown adipocytes in white fat, genetic variation in cold-induced expression between strains is observed only in white fat. Fundamentally different mechanisms for regulating Ucp1 expression must exist for the brown adipocytes in the traditional white fat vs. brown fat tissues. We speculate that the function of discrete brown fat depots formed at birth and persisting through adulthood is primarily to protect the animal from the cold, whereas the diffuse brown adipocytes induced in white fat depots are associated with the regulation of body weight, thus the sensitivity of retroperitoneal fat to dietary fat. Consistent with this hypothesis are the findings that many of the transgenic models associated with UCP1 overexpression and reduced obesity are characterized by induction of brown adipocytes in white fat depots (3, 10, 18, 36, 37). In the human population, variation in nonexercise thermogenesis is responsible for 10-fold differences in fat storage (24). Identification of the genes underlying QTLs regulating thermogenesis in white adipose tissues will be important for the development of new drugs for treatment and prevention of obesity.

	DISCLOSURES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION DISCLOSURES References

 
This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-58152.

	ACKNOWLEDGMENTS

 
We thank Rebecca McCabe, James Mancuso, and Michael Morris for excellent technical assistance.

	FOOTNOTES

 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: L. P. Kozak, The Pennington Biomedical Research Center, Louisiana State Univ., 6400 Perkins Road, Baton Rouge, LA 70808 (E-mail: kozaklp{at}pbrc.edu).

10.1152/physiolgenomics.00057.2003.

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