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Endocrinology Vol. 141, No. 12 4576-4582
Copyright © 2000 by The Endocrine Society

ARTICLES

Role of Leptin in Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Expression1

Tetsuya Kakuma, Zhuo-Wei Wang, Wentong Pan, Roger H. Unger and Yan-Ting Zhou

Gifford Laboratories, Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235; and Veterans Affairs North Texas Healthcare System, Dallas, Texas 75216

Address all correspondence and requests for reprints to: Roger H. Unger, M.D., Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-8854. E-mail: runger{at}mednet.swmed.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Peroxisome proliferator-activated receptor-{gamma} coactivator-1 (PGC-1), a cold-induced protein expressed in brown adipose tissue (BAT), plays a role in adaptive thermogenesis by up-regulating uncoupling proteins (UCP). Here, we explore its relationship to the thermogenic actions of leptin, which also up-regulates UCPs. We find that PGC-1 messenger RNA (mRNA) is markedly reduced in BAT of obese leptin-deficient (ob/ob mice) and leptin-unresponsive (db/db mice and Zucker diabetic fatty fa/fa rats) rodents. Whereas, after cold exposure (6 C for 7 h), PGC-1 mRNA increases 2.6-fold in BAT of lean +/+ rats, it rises only 30% in fa/fa rats. Four days after induction of hyperleptinemia (>30 ng/ml) in Wistar rats, by adenovirus gene transfer, PGC-1 mRNA in BAT was 2.3-fold and UCP-1, 4-fold above controls. In isolated white adipocytes, PGC-1 mRNA increased 4.4-fold within 6 h of incubation with 20 ng/ml of leptin. We conclude that leptin action is required for normal basal and cold-stimulated PGC-1 expression in BAT in rodents and that hyperleptinemia rapidly up-regulates its expression, at least in part, by direct action.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A NOVEL TRANSCRIPTIONAL coactivator of nuclear receptors, termed peroxisome proliferator-activated receptor (PPAR) {gamma} coactivator-1 (PGC-1), has recently been cloned by Puigserver et al. (1). Expressed in brown adipose tissue (BAT), but not in white adipose tissue (WAT), it is induced in BAT and skeletal muscle by exposure to cold. A role for PGC-1 in adaptive thermogenesis was therefore proposed (1, 2). PGC-1 stimulates mitochondrial biogenesis and respiration in muscle by inducing uncoupling protein-2 (UCP-2) and through regulation of nuclear respiratory factors (3). It seems to be a strong candidate to mediate some of the effects that thyroid hormone and ß-adrenergic agonists exert on both cold- and diet-induced thermogenesis in muscle and BAT (1, 4, 5). It is also involved in transcriptional control of the expression genes encoding enzymes of fatty acid (FA) oxidation through activation of PPAR{alpha} (6, 7).

Leptin is also recognized as an important regulator of thermogenesis (8, 9, 10), but a relationship to PGC-1 has not been established. Nevertheless, there are potential links between leptin activity and PGC-1. Hyperleptinemia induced by adenovirus gene transfer is associated with increased expression of UCP-1 and UCP-2 (11, 12) in WAT and certain nonadipose tissues (pancreatic islets); conversely, in congenitally leptin-unresponsive obese (fa/fa) rats, the expression of uncoupling proteins is low in nonadipose tissues (13). This study was designed to determine whether leptin is involved in the regulation of PGC-1 expression.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male Wistar rats were purchased from Charles River Laboratories, Inc. (Wilmington, MA). Male obese homozygous (fa/fa) Zucker diabetic fatty (ZDF)-drt rats and their lean wild-type (+/+) ZDF littermates were bred in our laboratory from ZDF/drt-fa (F10) rats purchased from Dr. R. Peterson (University of Indiana School of Medicine, Indianapolis, IN). Their genotype was confirmed using the method of Phillips et al. (14). Mutant C57BL/6J-ob/ob mice, C57BL/KS-J-db/db mice, and wild-type controls (+/+) were purchased from the Animal Resources of The Jackson Laboratory (Bar Harbor, ME). Seven- to 9-week-old animals were used in all experiments. Animal experimentation was in accordance with institutional guidelines.

Tissue preparation and total RNA extraction
All animals were killed under sodium pentobarbital anesthesia. Epididymal WAT, interscapular BAT, skeletal muscle, and heart were surgically removed and immediately frozen in liquid nitrogen and stored at -70 C until use. Total RNA was extracted by the TRIzol isolation method according to the manufacturer’s protocol (Life Technologies, Inc., Gaithersburg, MD).

Cloning of rat PGC-1 complementary DNA (cDNA) using RT-PCR
Total RNA (2 µg) from heart of lean (+/+) and obese homozygous (fa/fa) ZDF rats was treated with ribonuclease-free deoxyribonuclease (Promega Corp., Madison, WI), and first-strand cDNA was generated in a vol of 20 µl using the oligo (dT) primer in the 1st-strand cDNA synthesis kit (CLONTECH Laboratories, Inc., Palo Alto, CA). Primers used for cloning are shown in Table 1Goa and are specific for mouse PGC-1 (1). PCR was carried out with Taq DNA polymerase (Roche Molecular Biochemicals, Indianapolis, IN) and 20 pmol each of sense and antisense primer. The reaction profile was as follows: denaturation at 94 C for 1 min, annealing a 55 C for 1 min, and extension at 72 C for 1 min, for 30 cycles. The PCR products of 1144 bp (P1-P2), 796 bp (P3-P4), and 789 bp (P5-P6) were subcloned into a pCR 2.1 vector (TA cloning kit; Invitrogen, San Diego, CA), producing pCR-rPGC-1A (P1-P2), pCR-rPGC-1B (P3-P4), and pCR-rPGC-1C (P5-P6) for sequencing. The nucleotide sequences were determined by the dideoxynucleotide chain termination method, using synthetic oligonucleotide primers that were complementary to the vector sequence and ABI373A automated DNA Sequencing System (Perkin-Elmer Corp., Norwalk, CT). All DNA sequences were confirmed by reading both DNA strands.


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  		Table 1. RT-PCR primer sequences

 
Northern blot analysis
Total RNA (20 µg) was electrophoresed on 1.2% formaldehyde-agarose gel and transferred onto a positively charged nylon membrane Hybond-N+ (Amersham Pharmacia Biotech, Arlington Heights, IL), in 50 mM NaOH, by capillary blotting (15). The membrane was then briefly neutralized in diethylpyrocarbonate-treated 2x SSC buffer (20x SSC is 3 M NaCl, 0.3 M sodium citrate, pH 7.0). Prehybridization and hybridization were carried out as previously described (16), except that the buffer [0.2 M Na2HPO4/NaH2PO4 (pH 7.4), 7% SDS, 1 mM EDTA, 1% BSA] was used as a hybridization buffer. cDNA probes for the rat PGC-1 (center) and protein-1 (UCP-1) were prepared by RT-PCR using the primers shown in Table 1Gob. The identity of the appropriately sized products was confirmed by mapping with multiple restriction endonucleases and sequencing. The 623-bp and 812-bp DNA fragments excised after digesting pCR-rPGC-1A and pCR-rPGC-1B with EcoRI restriction enzyme were also used as 5'- and 3'-region probes of PGC-1. Hybridization signals were analyzed by Molecular Imager GS-363 (Bio-Rad Laboratories, Inc., Hercules, CA).

Semiquantitation of PGC-1 messenger RNA (mRNA) using RT-PCR
cDNA synthesis, using total RNA (4 µg) from WATs, was carried out as described above. Rat-specific P3 and P4 primers were used to amplify PGC-1 cDNA. The other primers used are indicated in Table 1Goc. Linearity of the PCR was tested by amplification of 200 ng total RNA per reaction. The linear range extended from 30–39 cycles for PGC-1, from 24–33 cycles for leptin, and from 18–27 cycles for ß-actin. In no case did the amount of RNA used for PCR reaction exceed 200 ng per reaction. The samples were amplified 35 cycles for PGC-1, 30 cycles for leptin, and 25 cycles for ß-actin by using the following parameters: 94 C for 1 min, 55 C for 1 min, and 72 C for 1 min. They were processed thereafter as described elsewhere in detail (11). PCR products detected by Southern blotting were quantified using Molecular Imager System GS-363 and expressed as the ratio of signal intensity for PGC-1 and leptin mRNA relative to ß-actin mRNA.

Cold exposure study
To determine the effects of cold exposure, 8- to 9-week-old obese homozygous (fa/fa) and lean wild-type (+/+) ZDF rats were previously acclimated to a temperature of 23 C in individual metabolic cages for 1 week and then suddenly exposed to 6 C for 7 h, following which they were killed to collect tissues. Thermoneutrality for rats is 25 C (17).

Adenovirus-induced hyperleptinemic rat model
A total of 1012 plaque-forming units of recombinant adenovirus, containing either the rat leptin cDNA (AdCMV-leptin) or (as a control) the bacterial ß-galactosidase gene (AdCMV-ß-gal), was infused into the jugular vein of 7- to 8-week-old Wistar rats, as previously described (18). Food intake and body weight were measured daily. Diet-matched animals were provided with the same amount of food each day as had been ingested by AdCMV-leptin-infused animals on the previous day. Blood samples were collected from the tail vein at about 1400 h.

Plasma leptin was assayed using a leptin assay kit (Linco Research, Inc., St. Charles, MO). The levels ranged from 31 to over 50 ng/ml (off-scale) in AdCMV-leptin-infused rats and 1.7 ng/ml or less in AdCMV-ß-gal-infused control rats.

Primary culture of white adipocytes
Isolation of adipocytes from lean (+/+) Zucker rats was performed as described previously (19, 20). Briefly, minced epididymal fat pads were digested at 37 C for 4 h in a buffer containing type II collagenase (1.5 mg/ml), albumin (3.5%), and glucose (0.55 mM). The digestion mixture was swirled and poured through 100-µm nylon mesh into 50-ml conical polypropylene tubes. Cells were washed two times with Krebs-Ringer bicarbonate buffer (pH 7.4) containing 5% albumin and were cultured for 6 h at 37 C in DMEM supplemented with 10% FCS, antibiotics (penicillin and streptomycin), and with or without recombinant leptin (Linco Research, Inc.).

Statistical analysis
All results are expressed as the mean ± SEM. The statistical significance of the difference in mean values was assessed by Student’s unpaired t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Cloning of rat PGC-1 cDNA using RT-PCR
To study PGC-1 in lean (+/+) and obese (fa/fa) Zucker diabetic fatty (ZDF) rats, it was necessary to obtain the nucleotide sequence of rat PGC-1 cDNA. RT-PCR was performed using total RNA extracted from the heart of such rats. The entire coding region of the cDNA was cloned by the combination of 3 sets of primers specific for mouse PGC-1 cDNA (1). Sequences of both strands were determined for more than 90% of the cDNA fragment. No differences in the deduced amino acid sequence of PGC-1 were noted in obese ZDF (fa/fa) and wild-type lean ZDF (+/+) rats. Rat PGC-1 is composed of 796 amino acid residues with a predicted molecular mass of 90,565 Da and is 98% identical to its mouse counterpart. An LXXLL motif (aa 142–146) and three consensus sites for phosphorylation by protein kinase A (aa 237–240, 372–375, and 654–657) are well conserved between rat and mouse (1); however, the alanine of codon 169 in the mouse is deleted in the rat. The PPAR{gamma}-binding site (aa 292–338) is identical, but two substitutions were noted in the nuclear respiratory factor-1 interaction domain (aa 181–403) (1, 3). The sequence data have been submitted to the GenBank, with the accession number AB025784.

Isoforms of rat PGC-1 mRNA
Northern blotting of BAT of Wistar rats revealed three bands corresponding to 6, 3.5, and 1.5 kb (Fig. 1aGo), in contrast to mouse PGC-1, which had three major hybridization signals of 6.5, 5, and 3.5 kb, as reported by Lowell’s group (21). Because the 6-kb band contained both the LXXLL motif (aa 142–146) and the PPAR{gamma} docking domain (aa 292–338) (1, 3), it was selected for quantification in the study. This band was expressed in skeletal and cardiac muscle at 57% and 118% of the level in BAT. In WAT, however, PGC-1 mRNA was barely detectable by Northern analysis, confirming the earlier report (1) (Fig. 1bGo).



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  		Figure 1. a, The isoforms of PGC-1 mRNA, detected with three different cDNA probes. Probe 1 (center) was 839 bp and included the LXXLL motif and PPAR{gamma}-binding domain. Probe 2 (5' side) was 623 bp and included only the LXXLL motif. Probe 3 (3' side) was 812 bp and included only one protein kinase A (PKA) phosphorylation site (1 ). Intron-exon boundaries were based on the human PGC-1 gene sequence of Esterbauer et al. (27 ). b, Comparison of PGC-1 expression, quantified by Northern blotting, in BAT, heart, and skeletal muscle and WAT. The PGC-1 mRNA in the latter tissues is expressed as percent of the level in BAT. n = 5; *, P < 0.005; ¶, P < 0.05, compared with BAT; e, exon; NRF, nuclear respiratory factors; aa, amino acid.

 
Diminished expression of PGC-1 mRNA in BAT and WAT of ZDF (fa/fa) rats and ob/ob and db/db mice
Thermogenesis is impaired in leptin-deficient and leptin-unresponsive rodents (22), and UCP-1 is reduced in their BAT (23). To determine whether underexpression of PGC-1 might account for this, Northern blot analysis of PGC-1 was carried out in BAT from leptin-unresponsive (fa/fa) rats and wild-type ZDF (+/+) controls (Fig. 2aGo). PGC-1 mRNA in BAT of ZDF (fa/fa) rats was only 33 ± 2% of that of the wild-type controls (P < 0.01). PGC-1 mRNA in BAT of ob/ob mice, measured by Northern blot analysis, was 74 ± 6% of +/+ controls; and in db/db mice, 62 ± 8% of controls (P < 0.05) (Fig. 2aGo).



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  		Figure 2. Comparison of PGC-1 mRNA in BAT and WAT of normal rodents and rodents that lack leptin action. a, Northern blot analysis of PGC-1, in lean +/+, and obese fa/fa ZDF rats; lean +/+ and obese ob/ob C57BL6/J mice; and lean +/+ and obese db/db C57BL/KSJ mice. b, RT-PCR of PGC-1 mRNA in the same six groups of rodents.

 
In WAT of normal (+/+) controls, PGC-1 mRNA was barely detectable by Northern analysis, consistent with the earlier report (1). It was readily detected by RT-PCR. In ZDF (fa/fa) rats, PGC-1 mRNA was only 31 ± 2% of controls (P < 0.01). In ob/ob mice, it was 18 ± 1% (P < 0.01); and in db/db mice, 44 ± 8% of controls (P < 0.05) (Fig. 2bGo). However, the biological significance of such differences at the low expression level is unclear.

Effect of leptin-unresponsiveness on the PGC-1 response to cold exposure
In normal animals, PGC-1 expression in BAT is enhanced by cold exposure (1). To determine whether leptin action is necessary for this thermogenic response, PGC-1 mRNA in BAT was compared in lean (+/+) and obese (fa/fa) ZDF rats exposed to 6 C for 7 h. The level of PGC-1 mRNA in lean ZDF (+/+) rats was increased 2.6-fold after cold exposure, confirming a previous report in mice (1); but in ZDF (fa/fa) rats, it rose only 30%, to a level below the basal unstimulated level in the +/+ controls (Fig. 3Go).



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  		Figure 3. Effects of 7 h of cold exposure (6 C) on expression of PGC-1 mRNA in BAT of lean +/+ ZDF rats and obese fa/fa ZDF, quantified by Northern blotting.

 
Augmented expression of PGC-1 mRNA in hyperleptinemic rats
Hyperleptinemia, induced by adenovirus gene transfer, depletes the triacylglycerol of WAT, presumably through enhanced intracellular oxidation of fatty acids and dissipation of the energy as heat (11). This is suggested by the striking increase in expression of the enzymes of FA oxidation and of the thermogenic proteins UCP-1 and UCP-2 in WAT. To determine whether an increase in PGC-1 might play a role in the response to hyperleptinemia, Wistar rats were infused iv with recombinant adenovirus containing the leptin cDNA (AdCMV-leptin). The plasma leptin concentration exceeded 30 ng/ml in all of these rats, compared with less than 2 ng/ml in diet-matched control rats infused with adenovirus containing the ß-galactosidase cDNA (AdCMV-ß-gal). The hyperleptinemic rats exhibited a reduction of more than 85% in food intake and a weight loss of 46 ± 4 g during the 6 days of observation. As shown in Fig. 4Go, PGC-1 mRNA expression rose significantly by the second day in BAT of the hyperleptinemic rats and was 2.9 times higher on day 6 (P < 0.05). UCP-1 expression increased 3.8 fold by day 4 (P < 0.05). On day 4, PGC-1 was 68% above controls (P < 0.005) in skeletal muscle (Fig. 5aGo). In WAT, PGC-1 mRNA increased 5.2 fold, by Northern analysis (P < 0.005) (Fig. 5bGo).



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  		Figure 4. Effect of adenovirus-induced hyperleptinemia. PGC-1 mRNA in BAT of normal Wistar rats was measured by Northern blotting at 2, 4, and 6 days after adenovirus-induced hyperleptinemia (AdCMV-leptin). AdCMV-ß-gal infusion was used in control rats, and they were diet-matched to the leptin-treated group. UCP-1 mRNA was also measured on day 4. mRNA levels were expressed as change from the pretreatment (0 day) values. *, P < 0.05, compared with 0-day value; ¶, P < 0.005; #, P < 0.05, compared with AdCMV-ß-gal in each group.

 


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  		Figure 5. Effects of leptin on PGC-1 expression. a, PGC-1 mRNA, quantified by Northern blotting in skeletal muscle of Wistar rats 4 days after infusion of AdCMV-leptin or AdCMV-ß-gal; b, PGC-1, quantified by Northern blotting in WAT of the same rats; c, PGC-1 mRNA semiquantitation by RT-PCR in isolated white adipocytes cultured for 6 h with or without 20 ng/ml recombinant leptin.

 
Evidence of direct leptin-mediated up-regulation of PGC-1
Leptin exerts its biologic effects both via the hypothalamus and through direct contact with certain of its target tissues, including white adipocytes (20, 24). To determine whether the PGC-1 up-regulation induced by hyperleptinemia was a direct effect of leptin on WAT or mediated via hypothalamic actions of leptin, 20 ng/ml of recombinant leptin was added to primary cultures of white adipocytes harvested from the epididymal fat pads of normal rats. A 4.4-fold increase in PGC-1 mRNA (P < 0.05) was observed 6 h later (Fig. 5cGo), and leptin mRNA declined to 39 ± 8% of the control value (P < 0.005), providing evidence of its direct action. These findings suggest that leptin can act directly on white adipocytes in the absence of any hypothalamic influence to elicit the change in PGC-1 expression.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The discovery of leptin in 1994 (25) and of a tissue-specific transcriptional coactivator, PPAR{gamma} coactivator-1 (PGC-1), in 1998 (1) has expanded our understanding of thermoregulation, in which both play an important role. The present study provides evidence of a relationship between PGC-1 expression and the action of leptin. PGC-1 mRNA was subnormal in both BAT and WAT of thermogenically impaired leptin-deficient ob/ob mice and leptin-unresponsive db/db mice and (fa/fa) ZDF rats. Exposure of the (fa/fa) ZDF rats to 6 C for 7 h resulted in a much smaller increase in the PGC-1 mRNA of their BAT than in lean wild-type control ZDF rats, in which PGC-1 rose 2.6-fold. In fact, after cold exposure, PGC-1 expression in fa/fa was still below the unstimulated level of +/+ rats at room temperature. This indicated that normal basal expression and cold-induced up-regulation of PGC-1 in BAT require the integrity of the leptin gene and its response system. However, because cold exposure has been reported not to increase leptin mRNA or plasma leptin levels (26), the role of leptin in the response to cold seems to be permissive rather than regulatory.

In normal rats, hyperleptinemia resulting from adenovirus-induced ectopic overexpression of the leptin gene (18) caused a 5-fold increase of PGC-1 expression in WAT, a tissue in which it is normally expressed at very low levels (1), and a 2.9-fold increase in BAT. The time course of the latter response indicates that it was underway by the second posttreatment day (Fig. 4Go). UCP-1 rose dramatically in BAT, whereas, as reported previously (11), both UCP-1 and UCP-2 increased in WAT. The in vivo effect of hyperleptinemia on PGC-1 expression may have been mediated, at least in part, via direct leptin action on the adipocytes, given that a similar increase in PGC-1 expression was observed in vitro in WAT cultured with recombinant leptin. This supports earlier evidence that leptin action can act directly on adipocytes both in vivo (24) and in vitro (20).

In summary, leptin action in BAT is required for normal basal and stimulated expression of PGC-1 mRNA. It is underexpressed in the BAT of rodents with obesity because of congenital leptin deficiency and leptin-unresponsiveness and overexpressed in chronic hyperleptinemia, suggesting that PGC-1 may be involved in the normal thermogenic action of leptin.


   Acknowledgments
 
The authors thank Cai Li, Ph.D., for his helpful suggestions; Shu Yuan Chen, M.D., Ph.D., for surgical assistance; Susan Kennedy for outstanding secretarial work; and Kay McCorkle for excellent technical assistance.


   Footnotes
 
1 The nucleotide sequence(s) reported in this paper has been submitted to the GenBank nucleotide sequence databases, with the accession number(s) AB025784. We acknowledge the grant support of the Department of Veterans Affairs Institutional Support, the National Institutes of Health (DK-02700–37), The National Institutes of Health/Juvenile Diabetes Foundation Diabetes Interdisciplinary Research Program, and Novo-Nordisk A/S. Back

Received May 9, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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