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Division of Neuroscience, Oregon National Primate Research Center (X.Q.X., K.L.G., B.E.G., M.S.S.), and Department of Physiology and Pharmacology (M.S.S.), Oregon Health and Science University, Beaverton, Oregon 97006
Address all correspondence and requests for reprints to: Dr. M. Susan Smith, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006. E-mail: smithsu{at}ohsu.edu.
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Abstract |
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Introduction |
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Lactation is a physiological state associated with dramatic metabolic adaptations and changes in energy balance. A major increase in energy demand along with a decrease in adaptive thermogenesis occur during lactation (10, 11). This adaptation has been considered an energy-sparing mechanism to facilitate the availability of energy for milk production. In rodents, the thermogenic function of BAT decreases during lactation, as shown by tissue hypotrophy, a decrease in mitochondrial biogenesis, and an impaired expression of genes encoding UCPs (12, 13). However, little is known about whether the expression of UCPs is changed in other important metabolic tissues such as skeletal muscle or whether other possible factors may be involved in the regulation of UCP expression in these tissues.
A growing body of evidence indicates that leptin, a 16-kDa adipose cell-specific secreted protein, acting through the hypothalamus, plays an important role in decreasing appetite and controlling food intake (14, 15). However, an important component of leptin’s effect is increased energy expenditure, because when differences in food intake are controlled, leptin-treated animals still lose more weight (16). Most notably, leptin has been demonstrated to increase core body temperature (17), stimulate sympathetic nerve activity (18), and increase norepinephrine turnover in BAT (19). It has also been shown that decreased UCP1 expression in BAT of ob/ob mice, a model lacking leptin expression, is at least partially responsible for their increased metabolic efficiency and propensity to become obese. Furthermore, leptin stimulates energy utilization in ob/ob mice by inducing UCP1 activity (20). As UCPs are the main mediators of thermogenesis that play an important role in the modulation of energy balance, we hypothesize that alterations in the expression and function of UCPs might be involved in the major metabolic adaptations occurring during lactation. The present study is designed to examine the changes in expression of UCPs during lactation and compare them with those after 48-h fasting. We chose fasting as a positive control because it is another condition of negative energy balance with decreased thermogenesis, and the regulation of UCPs in this model has been well characterized (5). In addition, the effects of leptin treatment on UCP expression during lactation were examined.
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Materials and Methods |
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. Trunk blood was collected at the time of decapitation. Interscapular brown adipose tissue (BAT) and hindlimb gastrocnemius skeletal muscle were quickly removed and dissected free of connective tissues. The tissues were stored at -80 C. All animal procedures were approved by the Oregon National Primate Research Center institutional animal care and use committee.
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-hydroxy-ethyl)-aniline to form a purple color that is read colorimetrically at 550 nm. The intraassay coefficient of variance of this assay was 5.5%. The amount of FFA in the sample is directly proportional to the intensity of the color produced and is expressed as milliequivalents per liter of standard oleic acid (ranging from 0–2 mEq/liter).
RNA isolation and real-time RT-PCR
BAT and skeletal muscle were homogenized in TRIzol reagent (Invitrogen, Carlsbad, CA), and total cellular RNA was isolated according to the manufacturer’s specifications. The quality and concentration of the RNA were determined by measuring the absorbance at 260 and 280 nm, and RNA completeness was confirmed by RNA gel. Real-time PCR was used to quantify UCP mRNA levels (21). The principle of TaqMan real-time PCR is based on DNA amplification and cleavage of an internal probe that is hybridized to the amplified DNA by the 5'-3' exonuclease activity of the Taq DNA polymerase during PCR cycles. RNA samples were prepared for real-time PCR by random primed RT reaction using random hexamer primers (Promega Corp., Madison, WI) and 1 µg RNA. The RT reaction was then diluted 1:50 for PCR analysis. Reactions were conducted in triplicate for increased accuracy. Ten microliters of reaction mixture contained 5 µl TaqMan Universal PCR Master Mix, 300 nM specific target gene primers, 80 nM 18S RNA gene primers, 250 nM specific probes, and 2 µl cDNA. The amplification was performed as follows: 2 min at 50 C, 10 min at 95 C, then 40 cycles each at 95 C for 15 sec and 60 C for 60 sec in the ABI PRISM 7700 Sequences Detector System (PE Applied Biosystems, Foster City, CA). After PCR was completed, baseline and threshold values were set to optimize the amplification plot, and the data were exported to an Excel spreadsheet. Standard curves were drawn on the basis of the log of the input RNA vs. the critical threshold cycle, which is the cycle in which the fluorescence of the sample was greater than the threshold of baseline fluorescence. These standard curves allowed for the critical threshold values to be converted to relative RNA concentrations for each sample. 18S RNA amplifications were conducted with the Pre-Developed TaqMan Assay Reagent (PE Applied Biosystems), and other primers and probes were designed using Primer Express software from PE Applied Biosystems. The sequences of primers and probes used were as follows: UCP1 forward, TCC CTC AGG ATT GGC CTC TAC; UCP1 reverse, GTC ATC AAG CCA GCC GAG AT; UCP1 probe, 6-carboxyfluorescein (Fam)-AACGCCTGCCTCTTTGGGAAGCAA-6-carboxytetramethylrhodamine (Tamra); UCP2 forward, GTT TCA AGG CCA CCG ATG TG; UCP2 reverse, GGG AAA GTG ATG AGA TCT GCA AT; UCP2 probe, Fam-CCCCACAGCCACCGTGAAGTCCCT-Tamra; UCP3 forward, ACT GGA GGC GAG AGG AAA TAC A; UCP3 reverse, ATG TTG GGC CAA GTC CCT TT; and UCP3 probe, Fam-CCCTGACTCCTTCCTCCCTGGCGA-Tamra.
Mitochondrial protein preparation and Western blot
Procedures for mitochondrial protein preparation were described previously (22). BAT and skeletal muscle were weighed and placed in isolation medium (100 mM KCl, 50 mM Tris-HCl, and 2 mM EDTA, pH 7.4) on ice. All of the following steps were performed at 4 C. Tissues were shredded with a sharp blade, minced with sharp scissors, rinsed with isolation medium four or five times, stirred for 2 min in the homogenizing medium [100 mM KCl, 50 mM Tris-HCl, 2 mM EDTA, 1 mM ATP, 5 mM MgCl2, 0.2% BSA, and 18.7 U protease (protease type VIII, Sigma-Aldrich Corp., St. Louis, MO)/g tissues, pH 7.4], and gently homogenized using a Polytron tissue homogenizer (Brinkmann Instruments, Westbury, NY). The homogenate was stirred for 3 min, then centrifuged at 490 x g for 10 min. The supernatant was filtered through muslin and centrifuged at 10,368 x g for 10 min. Mitochondrial-enriched pellets were resuspended in isolation medium, combined, and centrifuged at 10,368 x g for 10 min and then at 3,841 x g for 10 min, and resuspended in isolation medium. The protein concentration was determined using the Bio-Rad protein assay (Bio-Rad Laboratories, Hercules, CA). Samples containing mitochondrial protein from BAT (20 µg) or skeletal muscle (60 µg) were mixed with 2x sodium dodecyl sulfate loading buffer, incubated at 90 C for 5 min, electrophoresed on 12% PAGE Gold Precast Gels (Cambrex Bio Science, Rockland, ME), and then transferred to polyvinylidene difluoride membranes (Bio-Rad Laboratories). After transfer, membranes were blocked with blocking buffer (Pierce Chemical Co., Rockford, IL) for 1 h at room temperature and incubated with polyclonal anti-UCP1 (1:10,000), anti-UCP2 (1:1,000), and anti-UCP3 (1:5,000); all antibodies were made in goats (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). After washing, the membranes were further incubated with donkey antigoat horseradish peroxidase-conjugated secondary antibody (1:10,000; Jackson ImmunoResearch Laboratories, Inc., West Grove, PA). Immunoreactive products were detected using enhanced chemiluminescence (Pierce Chemical Co.) and exposed to X-OMAT sheet film (Eastman Kodak Co., Rochester, NY). Protein levels were quantified using the video-based image analysis system (Scion Image, Scion Corp., Frederick, MD). The protein levels were determined by multiplying the area of the band by the average OD of the band.
Statistical analysis
Data are expressed as the mean ± SEM. One-way ANOVA, followed by the Newman-Keuls multiple range test or t test, was used to determine significant differences among groups.
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Results |
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reports 24-h food and water intake, body weight (measured on the day rats were killed) and serum leptin and FFA levels in the various groups in this study. Food and water consumption during the 24 h before rats were killed were normalized and expressed as grams per 100 g body weight. Food and water intakes in lactating animals were 3- to 4-fold higher than those in normal cycling rats. Leptin treatment did not significantly change food intake, but decreased water intake by 20%, whereas removal of the pups for 48 h (0 pups) reduced food and water intakes to levels similar to those in diestrous controls. All lactating rats were significantly heavier than diestrous rats. Compared with cycling diestrous rats, both fasted and lactating animals had a significant decrease in serum leptin levels. The decrease induced by lactation was not fully restored by exogenous leptin. However, it should be noted that these animals were killed 24 h after the last leptin injection; thus, most of the exogenous leptin would be cleared by that time. Removal of pups for 48 h resulted in serum leptin levels significantly higher than those observed in diestrous animals, as previously reported (23). Compared with control, diestrous rats, fasting increased serum FFA levels by 1.9-fold. In contrast, lactation significantly reduced FFA levels by 50%, and leptin treatment had no effect to restore FFAs to controls. However, removal of pups did restore FFA levels to control values.
Changes in mRNA levels of UCPs in BAT
Figure 1, A–D, demonstrates the amplification plots of UCP1, UCP2, UCP3, and 18 S RNA, which was selected as a reference standard to normalize the DNA quality and quantity among different samples. At a 10-fold serial dilution, all of the tested genes showed good amplification plots starting from 20 pg and yielded standard curves with correlation coefficients higher than 0.99 (Fig. 1, E–H).
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shows the changes in expression of UCP1 (A), UCP2 (B), and UCP3 (C) mRNAs in the study. As expected, fasting almost fully abolished UCP1 mRNA expression in BAT. Similarly, UCP1 mRNA expression was reduced 70% during lactation. To determine whether leptin is associated with lactation-induced down-regulation of UCP1, the effects of injection of leptin or removal of pups for 2 d were examined. The reduction in UCP1 mRNA during lactation was reversed by either exogenous leptin replacement or removal of the pups. Furthermore, administration of leptin increased UCP1 mRNA expression to a value significantly higher than that observed in control diestrous rats. In contrast to UCP1, UCP2 mRNA levels did not differ among the various groups. Changes in UCP3 mRNA expression in BAT were similar to those in UCP1. Both fasting and lactation significantly diminished the expression of UCP3 mRNA, and the effect of lactation was reversed by leptin administration or removal of the pups.
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shows UCP2 (A) and UCP3 (B) mRNA levels in the gastrocnemius muscle in the various groups. UCP2 mRNA was not changed under any of the tested experimental conditions. UCP3 mRNA expression was increased 3-fold in response to fasting. In contrast, lactating rats demonstrated a dramatically lowered expression of UCP3 mRNA. Again, treatment with leptin or removal of the pups reversed the effect of lactation on UCP3 mRNA expression in skeletal muscle.
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). Densitometric analysis demonstrated about a 50% decrease in UCP1 protein in response to fasting. Similarly, UCP1 protein was decreased 70% during lactation. Interestingly, leptin treatment did not result in a recovery of UCP1 protein, as it did in mRNA levels (Fig. 2). However, removal of pups for 48 h did restore UCP1 protein levels (Fig. 4A, upper row, and Fig. 4B). In agreement with mRNA levels of UCP2 in BAT, mitochondrial UCP2 proteins remained unaltered during fasting or lactation (Fig. 4A, middle row, and Fig. 4C). Similar to changes in UCP1 protein, densitometric analysis showed that fasting and lactation decreased UCP3 protein by 20% and 50%, respectively, compared with that in diestrous rats. Leptin administration did not significantly alter the lactation-induced down-regulation of UCP3 protein, but removal of pups for 48 h completely restored UCP3 protein levels (Fig. 4A, lower row, and Fig. 4D).
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, upper row, and Fig. 5B). In agreement with a previous report (25), fasting induced a significant increase in UCP3 protein level, which correlates with its large increase in mRNA expression. A 50% decrease by densitometric analysis in UCP3 protein level was observed during lactation compared with diestrous controls. However, unlike the observation of UCP3 mRNA expression in the same tissues, leptin administration did not fully reverse the lactation-induced down-regulation of UCP3 protein, whereas removal of pups was fully effective (Fig. 5A, lower row, and Fig. 5C).
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Discussion |
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Lactation is a natural model of chronic negative energy balance and is characterized by the suppression of pulsatile LH secretion, increases in serum oxytocin and PRL levels, and a large increase in food intake, with relatively normal serum insulin and glucose levels and slightly elevated basal corticosterone levels (10, 11, 23, 28). There are several overlapping physiological adaptations between fasting and lactation despite the food deprivation in the former and the hyperphagia in the latter. For instance, fasted and lactating rats have decreased adaptive thermogenesis and low circulating leptin levels (10, 11, 23, 29), as confirmed in the present studies. Due to these similarities, it was expected that UCP expression in BAT would be similarly regulated in these models. Indeed, both BAT UCP1 and UCP3 expression were similarly decreased during fasting and lactation, and lactating animals also had a significant reduction in UCP1 and UCP3 protein levels. Therefore, the reduction in BAT UCP1 and UCP3 expression may be part of the metabolic adaptations and energy sparing that occur during lactation. The mechanism behind the changes in UCP1 and UCP3 could be due to many factors, including the decrease in sympathetic nervous system activity or hormonal changes associated with lactation, i.e. leptin, PRL, and oxytocin (8, 9, 30).
One likely factor is leptin, which has been shown to be an important regulator of UCP expression (20). However, the mechanisms responsible for the remarkable reduction in serum leptin observed during lactation are unclear. After removal of the pups, leptin and insulin reach higher than normal levels, most likely reflecting the high level of adiposity present during lactation (23). These results also suggest that leptin secretion is actively suppressed during lactation. The suckling stimulus alone, in the absence of the metabolic drain associated with milk production, does not result in a suppression of leptin secretion, indicating the importance of the metabolic drain. However, it is unknown what factors may be acting on adipose tissue to suppress leptin production during lactation, but it is unlikely to be oxytocin or PRL, because these hormones are increased by the suckling stimulus in the absence or presence of a metabolic drain (11, 23). There are several reports about the effect of PRL on leptin production. PRL suppressed insulin-induced leptin secretion in cultured adipocytes (31), but stimulated it in vivo in transgenic female mice that either overexpressed PRL (31) or were PRL receptor deficient (32) as well as in rats treated with exogenous PRL (33). The significance of these effects of PRL on leptin secretion remains to be elucidated, but it is clear from our previous results that during lactation, leptin and PRL are modulated independently.
Leptin treatment prevents the decrease in UCP1 and UCP3 expression caused by fasting (5, 25, 26). Consistent with the situation during fasting, low circulating leptin levels during lactation could be the cause of the decrease in UCP1 and UCP3 expression. Indeed, leptin replacement during midlactation significantly increased UCP1 and UCP3 mRNA expression; however, neither UCP1 nor UCP3 protein levels were altered by this treatment, suggesting that leptin may be able to directly stimulate BAT UCP1 and UCP3 mRNA expression, but does not directly alter protein expression. In contrast, removal of the nursing pups for 48 h, a model of natural hyperleptinemia, resulted in a full recovery of UCP1 and UCP3 mRNA and protein levels. It should be noted that in this model, there is also a removal of the energy drain due to milk production, reduced PRL levels (23), and normal FFA levels, all of which may be necessary for the full recovery of UCP protein levels. PRL has also been shown to inhibit UCP1 content in BAT (8, 9). Therefore, it is possible that suckling-induced hyperprolactinemia may play a role in the regulation of UCP1 expression in BAT. Its effect on UCP3 expression has not been reported. In conclusion, low circulating leptin levels during fasting and, at least in part during lactation, may be responsible for the fall in BAT UCP1 and UCP3 expression, allowing for energy conservation.
One major difference between fasted and lactating rats is that circulating FFA levels are elevated during fasting but reduced during lactation due to the increased FFA uptake by mammary tissue (34). This difference may be a reason for the divergent effects of fasting and lactation on UCP3 expression in skeletal muscle despite the low serum leptin levels in these conditions. The remarkable increase in UCP3 expression during fasting agrees with previous reports (25, 35, 36). Skeletal muscle is the primary tissue responsible for the clearance of dietary glucose and lipids from circulation. During fasting, when the overall strategy is to conserve energy and to spare glucose for use by the brain, the fuel requirement of skeletal muscle is diminished, and its predominant fuel is shifted toward lipids. UCP3 is likely to be specifically involved in regulating the use of lipids as fuel substrates in skeletal muscle (37, 38, 39). This hypothesis is supported by our present study and evidence showing an up-regulation of UCP3 in skeletal muscle under conditions where the preference for fuel substrate is shifted toward lipids, such as in fasting and high fat feeding (25, 39). Furthermore, mice lacking UCP3 showed a tendency toward impairment in the starvation-induced shift in fatty acid metabolism (40). It has also been demonstrated that the increased UCP3 expression in skeletal muscle in response to fasting is due to high circulating FFAs, because infusion of FFAs into ad libitum-fed animals caused similar increases in UCP3 expression (41). Leptin has also shown to increase UCP3 expression in ad libitum-fed animals, an effect that is thought to be indirect through modulation of changes in FFAs. Therefore, it is not surprising that in fasted rats, treatment with leptin does not further increase UCP3 expression (25, 41).
In contrast to the fasted rat, UCP3 is significantly decreased in skeletal muscle during lactation. This decrease is compatible with two physiological events: a reduction in nonshivering thermogenesis (42) and a decrease in the utilization of fatty acids by muscle, which favors the delivery of these substrates to the mammary gland for milk production (34, 43). Lactating animals that have had the nursing pups removed for 48 h are hyperleptinemic, have normal FFA levels, and show a full recovery of UCP3 mRNA and protein expression. In contrast, lactating rats treated with leptin have low FFA levels and increased UCP3 mRNA expression, but only partial recovery of UCP3 protein levels. Therefore, the levels of FFAs do not appear to be a critical factor for leptin to stimulate UCP3 mRNA expression, although they may be a key determinant for regulating UCP3 protein levels. The stimulatory effect of leptin on UCP3 mRNA expression in skeletal muscle during lactation is similar to that reported for ad libitum-fed animals (25).
Overall, these data point toward a stimulatory action of leptin on UCP1 and UCP3 expression in BAT and skeletal muscle. However, we do not know from these studies whether these effects are mediated solely via direct actions on BAT and skeletal muscle or through indirect methods, such as modulation of sympathetic tone through actions in the central nervous system (44). The importance of the removal of the central actions of leptin during lactation is supported by evidence from our laboratory that neuropeptide Y and proopiomelanocortin expressions within the hypothalamus are significantly increased and suppressed, respectively, in this model (11). The changes in these hypothalamic neuropeptides would not only support the orexigenic drive necessary to meet the energy demands of milk production, but would also decrease energy expenditure through suppression of sympathetic tone. The changes in UCP expression that we observed here are consistent with the decrease in sympathetic tone that has been reported during lactation (30).
In summary, we observed both similarities and differences between fasting and lactation in the regulation of UCP expression in BAT and skeletal muscle. Both fasting and lactation caused a similar down-regulation of UCP1 and UCP3 in BAT, which would be consistent with energy conservation through a decrease in nonshivering thermogenesis. The differences observed in the regulation of UCP3 in skeletal muscle (increase in fasting, decrease in lactation) may represent different energy-sparing adaptations. Further investigation is needed to elucidate which neurotransmitters and signaling pathways are involved in the regulation of UCP expression during lactation.
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Footnotes |
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Abbreviations: BAT, Brown adipose tissue; Fam, 6-carboxyfluorescein; FFA, free fatty acid; P0, d 0 postpartum; Tamra, 6-carboxytetramethylrhodamine; UCP, uncoupling protein.
Received July 7, 2003.
Accepted for publication October 28, 2003.
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